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Hedayati-Asl AmirMahak Cancer Childrenrsquos Hospital
Stem Cell Transplantation Department
Stem Cell Transplantation for Pediatric Lymphoma
Lymphoma
bull Lymphoma is the third most common cancer in children lt15 years of age
bull The prognosis for children with newly diagnosed
chemosensitive non-Hodgkinrsquos lymphoma (NHL) and Hodgkinrsquos disease (HD) has improved significantly
The Revised EuropeanndashAmerican Classification of LymphoidNeoplasms
Major histologic subtypes of HDNodular lymphocyte predominantClassical HD whose subtypes include bull Lymphocyte rich bull Nodular sclerosingbull Mixed cellularity bull Lymphocyte depleted bull ALCL Hodgkinrsquos-like HD in children Mixed cellularity Nodular lymphocyte predominant Nodular sclerosing
Childhood NHLbull Classified as
Intermediate (30) diseaseHigh grade (70) disease
bull Classified into four major subtypesBurkittrsquos lymphoma (BL)Lymphoblastic lymphoma (LL) Diffuse large B-cell lymphoma (DLBL)Anaplastic large cell lymphoma (ALCL)
Lymphoma
bull As standardized treatment protocols show high efficacy an increasing effort has been undertaken to reduce long-term side effects associated with treatment
bull Use of gonadotoxic substances such as procarbazine has been reduced
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Lymphoma
bull Lymphoma is the third most common cancer in children lt15 years of age
bull The prognosis for children with newly diagnosed
chemosensitive non-Hodgkinrsquos lymphoma (NHL) and Hodgkinrsquos disease (HD) has improved significantly
The Revised EuropeanndashAmerican Classification of LymphoidNeoplasms
Major histologic subtypes of HDNodular lymphocyte predominantClassical HD whose subtypes include bull Lymphocyte rich bull Nodular sclerosingbull Mixed cellularity bull Lymphocyte depleted bull ALCL Hodgkinrsquos-like HD in children Mixed cellularity Nodular lymphocyte predominant Nodular sclerosing
Childhood NHLbull Classified as
Intermediate (30) diseaseHigh grade (70) disease
bull Classified into four major subtypesBurkittrsquos lymphoma (BL)Lymphoblastic lymphoma (LL) Diffuse large B-cell lymphoma (DLBL)Anaplastic large cell lymphoma (ALCL)
Lymphoma
bull As standardized treatment protocols show high efficacy an increasing effort has been undertaken to reduce long-term side effects associated with treatment
bull Use of gonadotoxic substances such as procarbazine has been reduced
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
The Revised EuropeanndashAmerican Classification of LymphoidNeoplasms
Major histologic subtypes of HDNodular lymphocyte predominantClassical HD whose subtypes include bull Lymphocyte rich bull Nodular sclerosingbull Mixed cellularity bull Lymphocyte depleted bull ALCL Hodgkinrsquos-like HD in children Mixed cellularity Nodular lymphocyte predominant Nodular sclerosing
Childhood NHLbull Classified as
Intermediate (30) diseaseHigh grade (70) disease
bull Classified into four major subtypesBurkittrsquos lymphoma (BL)Lymphoblastic lymphoma (LL) Diffuse large B-cell lymphoma (DLBL)Anaplastic large cell lymphoma (ALCL)
Lymphoma
bull As standardized treatment protocols show high efficacy an increasing effort has been undertaken to reduce long-term side effects associated with treatment
bull Use of gonadotoxic substances such as procarbazine has been reduced
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Childhood NHLbull Classified as
Intermediate (30) diseaseHigh grade (70) disease
bull Classified into four major subtypesBurkittrsquos lymphoma (BL)Lymphoblastic lymphoma (LL) Diffuse large B-cell lymphoma (DLBL)Anaplastic large cell lymphoma (ALCL)
Lymphoma
bull As standardized treatment protocols show high efficacy an increasing effort has been undertaken to reduce long-term side effects associated with treatment
bull Use of gonadotoxic substances such as procarbazine has been reduced
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Lymphoma
bull As standardized treatment protocols show high efficacy an increasing effort has been undertaken to reduce long-term side effects associated with treatment
bull Use of gonadotoxic substances such as procarbazine has been reduced
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull Hodgkin lymphoma is a highly curable (70 -90 ) disease with modern chemotherapy plusmn radiation
Kuruvilla J ASH education book 2009
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Relapsed and Refractory
bull However in children with relapsed and refractory NHL the prognosis is not as promising and the best treatment approach for this poor risk group continues to be a challenge
bull Between 25 and 30 of patients with advanced stage HD still relapse and in subsets of this group the outcome is dismal
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Stem Cell Transplantation
bull Aggressive chemotherapy followed by autologous bone marrow transplantation has been used with some improvement in survival
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Best Approachbull Some centers have investigated allogeneic stem
cell transplantation in pediatric patients with recurrentrelapsed lymphoma
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Clinical Presentation (NHL)
bull Approximately 70 of children with NHL present with advanced disease andor have metastatic involvement including BM central nervous system andor bone
bull Children with limited stage NHL have an excellent prognosis with an estimated 5-year event-free survival (EFS) of 90ndash95 The prognosis for advanced stage disease has also improved and varies based on subtype (60ndash90 5-year EFS)
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Clinical Presentation (HD)bull Patients with HD commonly present with cervical or
supraclavicular lymphadenopathy and most will present with some degree of mediastinal involvement
bull Treatment is largely determined by ndash Disease stagendash Patientrsquos age at diagnosisndash The presence or absence of lsquoBrsquo symptomsndash The presence of hilar lymphadenopathy andor bulky nodal disease ndash The rapidity of response to therapy
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Clinical Presentation (HD)
bull With current therapy bull (DFS) in both children and adults with newly
diagnosed localized and advanced stage HD ranges between 85ndash100 and 70ndash90 respectively
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Patient 1
bull 13 years old girl presented with left supraclavicular lymph node enlargement for 1months with B symptoms
bull Lymph node biopsy confirmed the diagnosis of classical Hodgkin lymphoma nodular sclerosing
bull CT scan showed presence of bilateral supraclavicular and mediastinal lymphadenopathy
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Reed-Sternberg Cells
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
CD15CD 30 Immunostain
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
BMA no marrow infiltration Normal CBC Albumin level ESR Diagnosis Classical Hodgkin lymphoma nodular
sclerosing stage IIB She received 6 cycles of ABVD and achieved CR However 2 years later she presented with left cervical
lymphadenopathy Repeat biopsy confirmed the diagnosis of relapse
Hodgkin lymphoma nodular sclerosing CT scan cervical mediastinal and left hilar
lymphadenopathy
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull She received gemcitabine vinorelbine chemotherapy and then underwent autologous stem cell transplant with CEAM and eventually achieved complete remission and remained in CR
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Patient 2bull 18 years old boy presented with 2 months history of weight loss and 2
weeks history of night sweats and progressively worsening shortness of breath
bull Noted to have bilateral cervical and axillary lymphadenopathy
bull Left axillary lymph node biopsy confirmed the diagnosis of Classical Hodgkin Lymphoma Nodular Sclerosing type
bull CT scan showed presence of bilateral cervical axillary mediastinal lymph nodes enlargement with mediastinal mass 15 x 10 cm pleural effusion with paraaortic inguinal lymphadenopathy and hepatosplenomegaly
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull Hb 97 gL WBC 12000bull Albumin 28 gdLbull BMA no evidence of marrow infiltrationbull Diagnosis Classical Hodgkin lymphoma nodular
sclerosing Stage IVB bulky disease bull Treated with 8 cycles of escalated ABVD and RTbull However repeat CT scan showed mediastinal mass 8cm
x 9cmbull Treated with ESHAP then refer for ASCT
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
SCT for childhood HDbull Indications for stem cell transplant in Hodgkin Lymphoma
bull Autologous stem cell transplant in Hodgkinl ymphoma
bull Myeloablative allogeneic stem cell transplant
bull Reduced-Intensity conditioning SCT
bull Role of novel agents ndash Brentuximab in HSCT
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
High-risk patients with HD
bull Refractory to initial therapybull Primary induction failure bull Relapse after primary initial chemotherapy
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Stem cell transplantation in childhood Hodgkinrsquos disease
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Prognostic Factors
bull Disease status bull Chemoresponsiveness to salvage chemotherapybull Tumor bulk bull Remission durationbull Extranodal relapsebull Performance statusbull Relapse in previous radiation field
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Major Prognostic Factor
bull The length of first remission is a major prognostic factor in attaining a durable second remission with chemotherapy alone in relapsed HD
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Pediatric Literature
bull Extranodal disease at the time of relapse bull Large mediastinal mass going into AutoSCT bull Resistant disease predict for poor OS EFS and
PFS
bull Additional poor prognostic ndash Lactate dehydrogenase (LDH) ratio of more than onendash Interval from diagnosis to AutoSCT of lt15 monthsndash Female sex
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Children and Adolescents
at risk for long-term complications including
Myelodysplastic syndrome (MDS) AML Breast cancer
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Prognosis of HL has Significantly Improved over Years
Treatment failure occurs in 10 of patients with limited-stage disease Armitage JO N Engl J Med 2010363(7)
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
HODGKINrsquoS DISEASELYMPHOMASALVAGE REGIMENS
Regimen Patients CRPR to ASCTDHAP 102 87 60(dexamethasone ara-C cisplatin)
Mini-BEAM 89 77 82(BCNU etoposide ara-C melphalan 2 series)
Dexa-BEAM 225 75 75(above plus dexamethasone 3 series)
GDP 34 62 88(gemcitabine dexamethasone oxaloplatin)
ICE 65 84 86(ifosfamide carboplatin etoposide)
GND 38 64 --(gemcitabine vinorelbine liposomal doxorubicin)
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
SALVAGE REGIMENS
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
ASCT as standard therapy for HL Relapsingafter 1st Line Chemotherrapy
BNLI Trial ( BEAM + ABMT vsmini BEAM )
Linch et al Lancet 1993
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Linch et alLancet 19933411051( UK Group )
Schmitz et al Lancet 20023592065( EBMT German Group )
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
HD R1 Trial ( GHSGEBMT )( Dexa-BEAM+ASCT vs Dexa-BEAM )
Schimtz et al Lancet 2002
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
BNLI ( UK group ) GHSGEBMT group
Event Free Survival Freedom from treatment failure
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Adverse Prognostic Factors after ASCT
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Pre-Auto Transplant PETGa Scans PredictPoor Outcome in Pts with RelRefractory
Hodgkin Lymphoma
Jabbour et al Cancer 20071092481
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
PET-CT is desirable at diagnosis and essential at restaging
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
High Dose Chemotherapy Regimes in ASCT
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Preparative Regimen
bull CBV (cyclophosphamide BCNU [carmustine] etoposide [VP-16]) bull BEAM (BCNU etoposide cytarabine [Ara-C] and melphalan)
bull Fractionated total body radiation has often been given in conjunction with etoposide and cyclophosphamide
bull Some centers use CCNU (lomustine) as an alternative to BCNU because of a lower incidence of respiratory complications (CEAM)
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Choice of Donor Cell
bull Peripheral blood stem cells (PBSCs) are the donor cells of choice
bull More rapid hematologic recovery and
shortened hospital stay
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Identification of high risk patients in first remission
bull Although controversial and investigational there is a limited literature on the use of autologous hematopoietic cell transplantation in high risk patients with advanced disease in first remission
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Autologous SCT in Chemoresistant HodgkinLymphoma
N 641048707 Median age 22 year old1048707 Stage IIIIV 771048707 Prior Radiotherapy 501048707 Median fu 42 years1048707 Chemoresistant lt 50reduction in tumor bulkafter salvage chemo
Estimated 5 years PFS 17 OS 31
Gopal et al Cancer 2008 1131344
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Adjunctive Radiotherapy
bull Adjuvant involved-field irradiation is widely used either before or after autologous hematopoietic cell transplantation
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Radiotherapy alone or with chemotherapy in stage I-II
Hodgkin lymphoma
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
TREATMENT OF RELAPSE FOLLOWING TRANSPLANTATION
bull Only highly selected patients can tolerate a second autologous transplant
bull Single agent chemotherapy is often used in this setting
bull Local regional irradiation or allogeneic HCT may also be of benefit
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Tandem ASCT
N = 2451048707 Stratified by risk factors - CR lt 12 months- Stage IIIIV at relapse- Relapse in previous XRT area1048707 Poor risk rarrge 2 risk factors rarr Double SCT1048707 Intermediate risk rarr1 risk factors rarr single SCT
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
New Therapeutic Options for Relapsed PatientsAntiCD30 MoAb
ndash SGN-35(Brentuximab Vedotin) is a CD30-targetedantibody conjugated to an auristatin E derivative(MMAE)ndash MMAE is a potent anti-tubulin agent selectivelydelivered to CD-30 positive cells via antibody-drugconjugate technology
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Brentuximab vedotin ( SGN-35)
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Pivotal Phase II single arm multicenter study ofBrentuximab vedotin ( SGN-35) in patients withrelapsed or refractory Hodgkin Lymphoma after
ASCTn=1021048707 18mgkg q3 week up to 16 cycles1048707 Primary end point ORR1048707 Median age 31 (75 between 18-39 )1048707 Median duration of follow up 9 months1048707 Objective response rate 751048707 CR 341048707 Side effects peripheral sensory neuropathyneutropenia diarrhoea nausea fatigueChen et al JCO 2011 ASCO meeting abstract 8031
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Myeloablative Allogeneic Stem Cell Transplant
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Allogeneic graft vs host lymphoma effect
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Allo SCT
bull Several studies have suggested that there may be a significant GvLy effect after high-dose therapy and AlloSCT
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull 3 year OS and DFS were 21 and 15 with 3 year probability of relapse 65 (Gajewski JL et al JCO 199614 572-578 )
bull Peniket AJ et al reported 4 year OS PFS TRM were 24 16 52 ( Peniket AJ et al BMT 200331667-678 )
High treatment related mortality ( up to 50 )and poor long term results
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Reduced Intensity ConditioningAllogeneic Stem Cell Transplant
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
RIC vs Myeloablative
NRM at 3 mth 28(MA)vs 15 (RIC)1 year 46 vs 23
Sureda et al JCO 200826455
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Allo-SCT in children and adolescents withrecurrent HL
The type of conditioning had no impact on NRM RIC regimens were associated with an increased risk of progression with a lower PFS
Claviez et al Blood 2009
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Impact of cGVHD after alloSCT in relapserate and PFS
Sureda et al JCO 200826455
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull Prospective multicenter phase II study Primary refractory disease after two lines of chemotherapy relapses after first-line therapy with a short complete remission (lt12 months) multiply relapsed patients and patients who relapsed after an ASCT
Sureda et al Haematologica 201297(2)
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
RIC-Allo in RR HL
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
HSCT in HL
bull Autologous SCT Relapsed or Primary refractory disease
bull Allogeneic SCT Chemosensitive relapse following HDCTASCT if time to relapse gt1 year
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Allo-SCT vs ASCT Advantages and Disadvantages
bull Advantagesndash Infusion of a tumor-free cell productndash Graft-versus-HL effectbull Disadvantagesndash Higher non-relapse mortalityndash Availability of a histocompatibledonor
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
EBMT Standard Indications for ASCT andAllo-SCT in Lymphoid Malignancies
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
BMT for Non-Hodgkinrsquos Lymphoma Indications
bull Refractory diseasebull Relapsebull High risk in CR1bull Lymphoblasticbull Burkittrsquosbull Gamma delta-t-cell lymphoma
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Stem cell transplantation for childhood NHL
bull Aggressive chemotherapy followed by autologous BMT has been used with some improvement in survival
bull There is little consistency in therapeutic approaches and there is no formal recommendation on the best approach for this poor prognostic subgroup
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
When to do stem cell transplantation
bull Poor prognostic features have been defined as
bull (1) a delayed or partial response to first-line therapybull (2) central nervous system or BM involvement at presentation bull (3) time to relapse from initial diagnosis
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Stem cell transplantation in childhood NHL
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
SCT amp NHL
bull Most pediatric SCT programs will reserve SCT in children with NHL to be used after the first relapse progression or induction failure
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Chemoresponsebull Chemoresponse is another important prognostic
indicator and chemosensitive disease is considered by many in the field as an essential criterion for undergoing high-dose therapy and AutoSCT
bull Histology may also play a role in response in children and adolescents with relapsedrefractory NHL
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
SCT in Lymphoblastic Lymphoma
bull Relapsed BL and diffuse large B-cell lymphoma had a better survival following high-dose therapy and AutoSCT compared to patients with relapsed LL
bull Pediatric patients with relapsed LL had a survival of 39 following high dose therapy and AutoSCT
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
B-cell lymphomabull Dismal prognosis for those patients with B-cell NHL who relapsed after high-dose chemotherapy and AutoSCT (LMB-84)
bullThe major factor determining survival in this study was the remission status of patients before AutoSCT
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
ALCLbull The prognosis for children who develop progressive or recurrent
disease is poor with lt50 DFS
bull These results raise the question whether AutoSCT in CR1 should be considered for pediatric patients who present with high-risk ALCL
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Relapsed ALCLbull The BFM group recently reported on the feasibility and
efficacy of intensive reinduction therapy followed by AutoSCT or AlloSCT in children and adolescents with relapsed ALCL after BFM frontline therapy
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
(GvLy)
bull These results favor a potential allogeneic graft vs lymphoma (GvLy) response
bull Further classification and larger trials are needed for this heterogenous ALCL subtype to determine an appropriate risk-stratified treatment approach for pediatric ALCL
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Allo vs Autobull There was a similar DFS between AlloSCT vs AutoSCT in patients with LL
bullThere was a significantly decreased risk of relapse following AlloSCT
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Non-MA AlloSCT
bull Non-MA non-toxic regimens to reduce regimen-related morbidity and mortality with MA AlloSCT
bull But still achieve a GvLy disease effect is currently under investigation
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Future Investigations following SCT
bull Focus on reducing minimal residual diseasebull Targeted adoptive cellular immunotherapy to reduce disease
relapse Use of targeted therapy such as
Monoclonal antibodies including rituximaab (anti-CD20)Epratuzamab (anti-CD22)SGN-30 (anti-CD30)Immunotoxin therapy (denileukin diftitox)Anti-CD22-calichimiacin
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Targeted Cellular Therapiesbull EBV-specific cytotoxic T-cell lymphocytes for HD
bull Anti-CD19 or anti-CD20 cytotoxic T-cell lymphocytes or natural killer cells for B-cell NHL
bull And the end
Reducing the burden of lymphoma prior and post-SCT
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
ASCT for HD
bull We report our experience with high-dose chemotherapy and autologous SCT and outcome in children with Hodgkinrsquos disease
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
bull Twenty-one patients aged 8 to 25 years (median 14 years MF = 156)
bull Status at transplant was bull (CR2) n = 11bull (CRgt2) n = 7 bull partial remission (PR) n = 3
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Conditioning Regimen-CBVbull Cyclophosphamide Carmustine and Etoposide
(CBV) 7 ptsCyclophosphamid 1500 mgm2 times 4BCNU 300 mgm2 times 1Etoposide 250 mgm2 times 4
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Conditioning Regimen-CEAM
bull CCNU Etoposide Cytarabine and Melphalan (CEAM) 14 pts
CCNU 200 mgm2 on day -3Etoposide 1000 mgm2 on day -3 and -2 Cytarabine 1000 mgm2 on days -3 -2Melphalan 140 mgm2 on day -1
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Result
bull The median mononuclear cell dose was 54 times 108 kg
bull The median time to absolute neutrophil count gt 05 times 109L was 11 days
bull The median time to platelet count gt 20 times 109 was 14 days
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Result
bull Grade 2 and grade 3 mucositis was seen in 60 our patients
bull Transplant-related mortality at 100 days not occurred
bull Only one patient relapsed 18 months after transplant
bull Twenty one children remain alive
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
Conclusion
bull ASCT is feasible in HD bull Low early toxicity bull Result in durable remissions bull Should be considered for children with advanced
HD bull Long-term survivors must continue to be closely
followed
