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Allogeneic Hematopoietic Stem Allogeneic Hematopoietic Stem Cell Transplant for the Cell Transplant for the Medical Oncologist Medical Oncologist John Kuruvilla MD FRCPC John Kuruvilla MD FRCPC

Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

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Page 1: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Allogeneic Hematopoietic Stem Cell Allogeneic Hematopoietic Stem Cell Transplant for the Medical Transplant for the Medical

OncologistOncologist

John Kuruvilla MD FRCPCJohn Kuruvilla MD FRCPC

Page 2: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

ObjectivesObjectivesObjectivesObjectives

• Understand basic principles of Allogeneic Transplant:

– Types of Preparative Regimens

– Stem Cell Source

– Donor Types

Page 3: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

Hematopoietic Stem Cell Hematopoietic Stem Cell TransplantationTransplantation

• Premise – a platform to deliver:Premise – a platform to deliver:

– Dose intensive therapy (chemotherapy and/or Dose intensive therapy (chemotherapy and/or radiation) for myeloablation and immune ablationradiation) for myeloablation and immune ablation

– Hematopoietic Stem Cells (replacing damaged or Hematopoietic Stem Cells (replacing damaged or abnormal bone marrow)abnormal bone marrow)

– Immunotherapy (graft-versus tumour effect)Immunotherapy (graft-versus tumour effect)

Page 4: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Stem CellsStem CellsStem CellsStem Cells

• By nature have capacity of:By nature have capacity of:

– Self renewalSelf renewal

– Ability to differentiate into all mature peripheral blood Ability to differentiate into all mature peripheral blood cellscells

• Practical surrogate marker is CD34Practical surrogate marker is CD34

– Cell surface marker found on immature WBCCell surface marker found on immature WBC

– Counts have been associated with hematopoietic Counts have been associated with hematopoietic recoveryrecovery

Page 5: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Components of an Allogeneic SCT Components of an Allogeneic SCT procedureprocedure

Components of an Allogeneic SCT Components of an Allogeneic SCT procedureprocedure

• Pre SCT TherapyPre SCT Therapy

• Conditioning Regimen – the chemotherapy / radiation Conditioning Regimen – the chemotherapy / radiation regimen that may have anti-cancer properties and that regimen that may have anti-cancer properties and that provides bone marrow / immune modulation for the graftprovides bone marrow / immune modulation for the graft

• Donor stem cell source – the person providing stem cells Donor stem cell source – the person providing stem cells (sibling, MUD, Mismatch MUD, Haploidentical)(sibling, MUD, Mismatch MUD, Haploidentical)

• Type of stem cells – bone marrow, peripheral blood, umbilical Type of stem cells – bone marrow, peripheral blood, umbilical cord bloodcord blood

• GVHD Prophylaxis – agents that may “temper” the donor GVHD Prophylaxis – agents that may “temper” the donor immune system in the recipientimmune system in the recipient

• Post SCT therapyPost SCT therapy

Page 6: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Transplant Conditioning RegimensTransplant Conditioning RegimensTransplant Conditioning RegimensTransplant Conditioning Regimens

• Myeloablative regimens have been typical Myeloablative regimens have been typical approachapproach

– Limited use of transplant due to high toxicity (upper Limited use of transplant due to high toxicity (upper age limit of 60 and medically fit)age limit of 60 and medically fit)

– Based on drugs that can be dose escalated (typically Based on drugs that can be dose escalated (typically alkylators) and radiationalkylators) and radiation

– Standard regimens: CY-TBI and BU-CYStandard regimens: CY-TBI and BU-CY

Page 7: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Bu-Cy vs Cy-TBI in myeloid diseases Bu-Cy vs Cy-TBI in myeloid diseases – Bu-Cy favoured?– Bu-Cy favoured?

Bu-Cy vs Cy-TBI in myeloid diseases Bu-Cy vs Cy-TBI in myeloid diseases – Bu-Cy favoured?– Bu-Cy favoured?

• Survival appears similar in 4 RCTsSurvival appears similar in 4 RCTs

• Easier to give Bu-Cy over Cy-TBI (lack of TBI allows for Easier to give Bu-Cy over Cy-TBI (lack of TBI allows for easier treatment planningeasier treatment planning

• Meta-analyses performed:Meta-analyses performed:

– Acute leukemia: CY-TBI had lower relapse and TRM with Acute leukemia: CY-TBI had lower relapse and TRM with improved DFSimproved DFS

– CML: CY-TBI had higher relapse, lower TRM and similar DFSCML: CY-TBI had higher relapse, lower TRM and similar DFS

– CY-TBI had higher rates of cataracts [odds ratio (OR) 12.69, p CY-TBI had higher rates of cataracts [odds ratio (OR) 12.69, p = 0.01], interstitial pneumonitis and later growth or = 0.01], interstitial pneumonitis and later growth or development problems [OR 5.04, p = 0.008].development problems [OR 5.04, p = 0.008].

– BU-Cy associated with higher rates of VOD [OR 0.43, p < BU-Cy associated with higher rates of VOD [OR 0.43, p < 0.00001], hemorrhagic cystitis, and TRM. 0.00001], hemorrhagic cystitis, and TRM.

Shi-Xia Leuk Lymphoma 2010

Page 8: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Trade-offs in Traditional BMT Trade-offs in Traditional BMT Regimens – is less better?Regimens – is less better?

Trade-offs in Traditional BMT Trade-offs in Traditional BMT Regimens – is less better?Regimens – is less better?

• BMT is a modality that allows the delivery of BMT is a modality that allows the delivery of radiation in disseminated disease (ie. leukemia)radiation in disseminated disease (ie. leukemia)

• Toxicities with both are substantial and limit the Toxicities with both are substantial and limit the delivery of therapydelivery of therapy

• Newer chemotherapy and immunosuppressive Newer chemotherapy and immunosuppressive agents lead to the development of new regimensagents lead to the development of new regimens

– Less myeloablationLess myeloablation

– More “immunosuppressive” transplant which More “immunosuppressive” transplant which facilitates engraftment of stem cellsfacilitates engraftment of stem cells

– Less direct anti tumour effectLess direct anti tumour effect

Page 9: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Champlin Criteria of a RIC RegimenChamplin Criteria of a RIC RegimenChamplin Criteria of a RIC RegimenChamplin Criteria of a RIC Regimen

• Defines as reduced intensity:Defines as reduced intensity:

– any regimen that does not require stem cell support any regimen that does not require stem cell support for hematopoietic recovery andfor hematopoietic recovery and

– results in low non-hematologic toxicity andresults in low non-hematologic toxicity and

– mixed donor recipient chimerism in a substantial mixed donor recipient chimerism in a substantial proportion of patients in the early post transplant proportion of patients in the early post transplant period (around day +30) period (around day +30)

Champlin in Giralt+Slavin (text)

Page 10: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

The ultimate non-myeloablative The ultimate non-myeloablative regimen – the original Seattle protocolregimen – the original Seattle protocol

The ultimate non-myeloablative The ultimate non-myeloablative regimen – the original Seattle protocolregimen – the original Seattle protocol

• 2 Gy TBI2 Gy TBI

• CsA + MMFCsA + MMF

• Tested in AML and CMLTested in AML and CML

– Problems with graft failureProblems with graft failure

– Add additional agents (fludarabine) to improve Add additional agents (fludarabine) to improve outcomeoutcome

Storb Mol Ther (Review) 2006

Page 11: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Transplant Regimens – Non-Transplant Regimens – Non-myeloablative or Reduced Intensitymyeloablative or Reduced Intensity

Transplant Regimens – Non-Transplant Regimens – Non-myeloablative or Reduced Intensitymyeloablative or Reduced Intensity

• Non-myeloablative transplant – autologous marrow Non-myeloablative transplant – autologous marrow and immune recover possibleand immune recover possible

– Fludarabine 30 mg/m2 X 3+ 2 Gy TBIFludarabine 30 mg/m2 X 3+ 2 Gy TBI

• Reduced Intensity Conditioning (RIC)Reduced Intensity Conditioning (RIC)

– Concept: less drug = less toxicityConcept: less drug = less toxicity

– Regimens vary agents and doses of drugsRegimens vary agents and doses of drugs

• Fludarabine + Busulfan 3.2 mg/kg X 2 + 2 Gy TBI Fludarabine + Busulfan 3.2 mg/kg X 2 + 2 Gy TBI

• Fludarabine + Busulfan 3.2 mg/kg X 4 + 4 Gy TBI Fludarabine + Busulfan 3.2 mg/kg X 4 + 4 Gy TBI

Page 12: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

RIC vs Myeloablative ToxicityRIC vs Myeloablative ToxicityRIC vs Myeloablative ToxicityRIC vs Myeloablative Toxicity

• Initial studies lead to a variety of possible regimensInitial studies lead to a variety of possible regimens

– Fludarabine-TBIFludarabine-TBI

– Fludarabine-CyclophosphamideFludarabine-Cyclophosphamide

– Fludarabine-MelphalanFludarabine-Melphalan

– Fludarabine-BusulfanFludarabine-Busulfan

• All share the RIC concept – transplant more as All share the RIC concept – transplant more as immunotherapyimmunotherapy

Page 13: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Immunosuppressive and Immunosuppressive and Myelosuppressive Properties of Myelosuppressive Properties of Common Preparative RegimensCommon Preparative Regimens

Immunosuppressive and Immunosuppressive and Myelosuppressive Properties of Myelosuppressive Properties of Common Preparative RegimensCommon Preparative Regimens

Storb et al. ASH Education book 2011

Page 14: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

NMDP Operational Criteria for a RIC NMDP Operational Criteria for a RIC RegimenRegimen

NMDP Operational Criteria for a RIC NMDP Operational Criteria for a RIC RegimenRegimen

• TBI – up to 500 cGy single fraction or 800 cGy TBI – up to 500 cGy single fraction or 800 cGy fractionatedfractionated

• Total busulfan up to 9 mg/kgTotal busulfan up to 9 mg/kg

• Total melphalan up to 140 mg/mTotal melphalan up to 140 mg/m22

• BEAM regimen (debatable by some)BEAM regimen (debatable by some)

Giralt BBMT 2009

Page 15: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Matched Pair Comparison of Flu-Bu-Matched Pair Comparison of Flu-Bu-ATG and Bu-Cy (Calgary and CIBMTR)ATG and Bu-Cy (Calgary and CIBMTR)Matched Pair Comparison of Flu-Bu-Matched Pair Comparison of Flu-Bu-

ATG and Bu-Cy (Calgary and CIBMTR)ATG and Bu-Cy (Calgary and CIBMTR)

• 120 cases, 215 controls120 cases, 215 controls

• TRM ; Flu-Bu 12%, BuCY 34%, p<0.001TRM ; Flu-Bu 12%, BuCY 34%, p<0.001

• 2-4 A-GVHD: Flu-Bu:15% BuCY:34%, p<0.0012-4 A-GVHD: Flu-Bu:15% BuCY:34%, p<0.001

• Relapse: Flu-Bu:42%, BuCY: 20%, p<0.001Relapse: Flu-Bu:42%, BuCY: 20%, p<0.001

• C-GVHD and DFS similarC-GVHD and DFS similar

Page 16: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

FluBu-ATG and BuCY matched pair FluBu-ATG and BuCY matched pair comparisoncomparison

FluBu-ATG and BuCY matched pair FluBu-ATG and BuCY matched pair comparisoncomparison

• Interesting and suggests trade-offsInteresting and suggests trade-offs

– Toxicity vs. efficacyToxicity vs. efficacy

• Should this be tested in a phase III trial?Should this be tested in a phase III trial?

• Can the platform be improved?Can the platform be improved?

Page 17: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Summary – Conditioning RegimensSummary – Conditioning RegimensSummary – Conditioning RegimensSummary – Conditioning Regimens

• Wide variety of intensity in regimensWide variety of intensity in regimens

• Safety and comorbidity typically drives decisionSafety and comorbidity typically drives decision

– Age and organ function can limit choice (age 50, 55 Age and organ function can limit choice (age 50, 55 or 60 is often an arbitrary cutoff to limit myeloablative or 60 is often an arbitrary cutoff to limit myeloablative procedures)procedures)

• RIC or non-myeloablative procedures allows RIC or non-myeloablative procedures allows greater availability of transplant proceduresgreater availability of transplant procedures

Page 18: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Sources of Hematopoietic Stem CellsSources of Hematopoietic Stem CellsSources of Hematopoietic Stem CellsSources of Hematopoietic Stem Cells

• Bone MarrowBone Marrow

• Peripheral BloodPeripheral Blood

• Cord BloodCord Blood

• Stimulated (G-CSF) or notStimulated (G-CSF) or not

Page 19: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Collection of Stem CellsCollection of Stem CellsCollection of Stem CellsCollection of Stem Cells

• Bone Marrow – involves marrow harvestBone Marrow – involves marrow harvest

– Anaesthesia, OR, procedure timeAnaesthesia, OR, procedure time

• Peripheral Blood – requires g-csf to increase Peripheral Blood – requires g-csf to increase peripheral concentration of CD34+ cells and peripheral concentration of CD34+ cells and subsequent apheresissubsequent apheresis

• Umbilical Cord Blood – collected from umbilicus at Umbilical Cord Blood – collected from umbilicus at time of birth and storedtime of birth and stored

• Trade-off – procedures vary substantially for patient Trade-off – procedures vary substantially for patient but RCTs are availablebut RCTs are available

Page 20: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Donor Stem Cell Source – AllogeneicDonor Stem Cell Source – AllogeneicDonor Stem Cell Source – AllogeneicDonor Stem Cell Source – Allogeneic

• RCTs confirmed benefit of PB (g-csf mobilized) RCTs confirmed benefit of PB (g-csf mobilized) over BM (steady state) with improved survivalover BM (steady state) with improved survival

– Higher rate of chronic GVHD in patients receiving Higher rate of chronic GVHD in patients receiving PB graftsPB grafts

• Pilot data of g-csf mobilized BM demonstrates Pilot data of g-csf mobilized BM demonstrates shorter time to engraftment and less C-GVHDshorter time to engraftment and less C-GVHD

– RCTs evaluating g-csf mobilized PB vs. BM are RCTs evaluating g-csf mobilized PB vs. BM are ongoingongoing

• Bone marrow still preferred in situation where Bone marrow still preferred in situation where GVHD is NOT needed (aplastic anemia)GVHD is NOT needed (aplastic anemia)

Page 21: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Impact of Donor Stem Cell Source on Impact of Donor Stem Cell Source on Allo-SCT: Improved SurvivalAllo-SCT: Improved Survival

Impact of Donor Stem Cell Source on Impact of Donor Stem Cell Source on Allo-SCT: Improved SurvivalAllo-SCT: Improved Survival

Bensinger NEJM 2001

Page 22: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Meta-analysis of G-PB vs. BMMeta-analysis of G-PB vs. BMMeta-analysis of G-PB vs. BMMeta-analysis of G-PB vs. BM

• Compared to PBSCT, BM had:Compared to PBSCT, BM had:

– Lower rates of neutrophil and PLT engraftmentLower rates of neutrophil and PLT engraftment

– Decrease in the development of grades II-IV A-GVHD (HR, Decrease in the development of grades II-IV A-GVHD (HR, 0.75; 95% CI, 0.63-0.90; p = 0.002) 0.75; 95% CI, 0.63-0.90; p = 0.002)

– Decrease in the rates of overall C-GVHD (HR, 0.70; 95% CI, Decrease in the rates of overall C-GVHD (HR, 0.70; 95% CI, 0.59-0.83; p < 0.0001)0.59-0.83; p < 0.0001)

– Higher incidence of relapse (HR, 1.91; 95% CI, 1.34-2.74; p = Higher incidence of relapse (HR, 1.91; 95% CI, 1.34-2.74; p = 0.0004)0.0004)

– Comparable TRM (1.08; 95% CI, 0.56-2.10; p = 0.81)Comparable TRM (1.08; 95% CI, 0.56-2.10; p = 0.81)

– Comparable LFS (HR, 1.04; 95% CI, 0.83-1.30; p = 0.73)Comparable LFS (HR, 1.04; 95% CI, 0.83-1.30; p = 0.73)

– Comparable OS (HR, 1.06; 95% CI, 0.81-1.39; p = 0.65)Comparable OS (HR, 1.06; 95% CI, 0.81-1.39; p = 0.65)

Chang Ann Hematol 2011

Page 23: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Next Generation of TrialsNext Generation of TrialsNext Generation of TrialsNext Generation of Trials

• Can benefits of bone marrow (lower GVHD) be Can benefits of bone marrow (lower GVHD) be combined with benefits of PBSCs (improved combined with benefits of PBSCs (improved engraftment and relapse rates)?engraftment and relapse rates)?

• Pilot data of g-csf mobilized BM showed promising Pilot data of g-csf mobilized BM showed promising results and lead to the RCTS:results and lead to the RCTS:

– CBMTG 0601 (related donors) and othersCBMTG 0601 (related donors) and others

– NMDP trial in MUDNMDP trial in MUD

Page 24: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Allogeneic Stem Cell CollectionAllogeneic Stem Cell CollectionAllogeneic Stem Cell CollectionAllogeneic Stem Cell Collection

• G-CSF mobilized PBSC became standard of careG-CSF mobilized PBSC became standard of care

• Mobilization failure unlikely as donors are healthy Mobilization failure unlikely as donors are healthy and typically have normal marrow functionand typically have normal marrow function

– Mobilize with G-CSF aloneMobilize with G-CSF alone

• Concerns:Concerns:

– Effect of G-CSF (case reports of leukemia)Effect of G-CSF (case reports of leukemia)

– Familial hematologic disorders (ie. finding Familial hematologic disorders (ie. finding malignant/pre-malignant disorders during donor malignant/pre-malignant disorders during donor workup)workup)

Page 25: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Summary – Stem Cell SourceSummary – Stem Cell SourceSummary – Stem Cell SourceSummary – Stem Cell Source

• Outside of a clinical trial, g-csf mobilized PBSC are Outside of a clinical trial, g-csf mobilized PBSC are typically preferredtypically preferred

– More rapid engraftment and lower relapseMore rapid engraftment and lower relapse

• Donor preference an issue (type of procedure)Donor preference an issue (type of procedure)

• BM can be considered in transplants where BM can be considered in transplants where GVHD/GVT effect is less important (ie. Aplastic GVHD/GVT effect is less important (ie. Aplastic anemia or benign disorders)anemia or benign disorders)

Page 26: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Types of DonorTypes of DonorTypes of DonorTypes of Donor

• AutologousAutologous

• Syngeneic (identical twin)Syngeneic (identical twin)

• AllogeneicAllogeneic

– Sibling (matched / mismatch)Sibling (matched / mismatch)

• Alternative donorAlternative donor

– Unrelated Donor (matched / mismatch)Unrelated Donor (matched / mismatch)

– HaploidenticalHaploidentical

– Umbilical Cord BloodUmbilical Cord Blood

Page 27: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Donor Selection and MatchingDonor Selection and MatchingDonor Selection and MatchingDonor Selection and Matching

• Most successful results initially with identical twins Most successful results initially with identical twins (fully matched)(fully matched)

• Siblings more likely to be matched than MUD Siblings more likely to be matched than MUD depending on degree of testingdepending on degree of testing

• Transplant strategy would require more intensive Transplant strategy would require more intensive immunosuppression as quality of match decreasesimmunosuppression as quality of match decreases

• Large prospective series limited – no RCT of sibling Large prospective series limited – no RCT of sibling vs. other stem cell sourcevs. other stem cell source

Page 28: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Matching – MHC and HLAMatching – MHC and HLAMatching – MHC and HLAMatching – MHC and HLA

• Major Histocompatibility Complex (part of immune system)Major Histocompatibility Complex (part of immune system)

– Class 1 – found on all nucleated cells and involved in antigen Class 1 – found on all nucleated cells and involved in antigen presentationpresentation

– Class 2 – found on immune cells (APCs)Class 2 – found on immune cells (APCs)

• In humans, the MHC subset that presents APCs on immune In humans, the MHC subset that presents APCs on immune cells are called HLA genes (Human Leukocyte Antigens)cells are called HLA genes (Human Leukocyte Antigens)

– Class 1 genes: HLA-A, HLA-B, HLA-CClass 1 genes: HLA-A, HLA-B, HLA-C

– Class 2 genes: HLA-DPA, HLA-DP, HLA-DQ, HLA-DRA, HLA-Class 2 genes: HLA-DPA, HLA-DP, HLA-DQ, HLA-DRA, HLA-DRB1DRB1

• HLA genes are highly polymorphicHLA genes are highly polymorphic

Page 29: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Matching and DonorsMatching and DonorsMatching and DonorsMatching and Donors

• Beyond the scope of the current discussionBeyond the scope of the current discussion

• Brief summary of NMDP RecommendationsBrief summary of NMDP Recommendations

– All should have high resolution testing (4 digit) for All should have high resolution testing (4 digit) for HLA-A, HLA-B, HLA-C and HLA-DRB1 (8/8 testing)HLA-A, HLA-B, HLA-C and HLA-DRB1 (8/8 testing)

– Mismatches at HLA-DP and HLA-DQ did not affect Mismatches at HLA-DP and HLA-DQ did not affect survivalsurvival

– DRB3, DRB4 and DRB5 have unknown significanceDRB3, DRB4 and DRB5 have unknown significance

http://marrow.org/Physicians/Transplant_Advances/HLA_Typing_Advances.aspx#table-1

Page 30: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Alternative Donor OptionsAlternative Donor OptionsAlternative Donor OptionsAlternative Donor Options

• Mismatched transplants are also an optionMismatched transplants are also an option

– 9 / 10 or 8 / 109 / 10 or 8 / 10

• Haploidentical transplantation allows almost everyone to Haploidentical transplantation allows almost everyone to have a donor but represents a huge immunologic barrier have a donor but represents a huge immunologic barrier (high risk)(high risk)

– Haploidentical donor can be a parent so most people Haploidentical donor can be a parent so most people potentially have a donorpotentially have a donor

• Degree of mismatch increases risk of TRMDegree of mismatch increases risk of TRM

Page 31: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Donor Stem Cell SourceDonor Stem Cell SourceDonor Stem Cell SourceDonor Stem Cell Source

• Syngeneic stem cells are lowest risk from TRM Syngeneic stem cells are lowest risk from TRM standpointstandpoint

– Concern of lack of immunologic effect (ie. No GVT)Concern of lack of immunologic effect (ie. No GVT)

• Sibling transplants have traditionally had best Sibling transplants have traditionally had best outcomes (from NRM and GVHD standpoint)outcomes (from NRM and GVHD standpoint)

– Outcomes for MUD transplants have improved Outcomes for MUD transplants have improved (better regimens and supportive care)(better regimens and supportive care)

• Cord blood is appealing as less matching may be Cord blood is appealing as less matching may be necessary but stem cell dose (given size of necessary but stem cell dose (given size of recipient) is often an issue (solution of 2 cords)recipient) is often an issue (solution of 2 cords)

Page 32: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Alternative Donor Transplantation – Alternative Donor Transplantation – Cord vs. HaploidenticalCord vs. Haploidentical

Alternative Donor Transplantation – Alternative Donor Transplantation – Cord vs. HaploidenticalCord vs. Haploidentical

• BMT CTN Phase II trial of RIC allo using double UCB (n=50) BMT CTN Phase II trial of RIC allo using double UCB (n=50) or Haplo-marrow (n=50)or Haplo-marrow (n=50)

– Flu-Cy-200 cGy TBIFlu-Cy-200 cGy TBI

– GVHD prophylaxis with CsA+MMF or FK506+MMFGVHD prophylaxis with CsA+MMF or FK506+MMF

– Haplo received CY on Day+3 and +4Haplo received CY on Day+3 and +4

– 1 year OS: 54 (dUCB) vs 62 (haplo)1 year OS: 54 (dUCB) vs 62 (haplo)

– 1 year PFS: 46 (dUCB) vs 48 (haplo)1 year PFS: 46 (dUCB) vs 48 (haplo)

– 1 year NRM: 24 (dUCB) vs 7 (haplo)1 year NRM: 24 (dUCB) vs 7 (haplo)

– 1 year relapse: 31 (dUCB) vs 45 (haplo)1 year relapse: 31 (dUCB) vs 45 (haplo)

• Based on these results, a phase III trial is planned Based on these results, a phase III trial is planned

Brunstein et al. Blood 2011

Page 33: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

BMT CTN – dUCB vs. HaploBMT CTN – dUCB vs. HaploBMT CTN – dUCB vs. HaploBMT CTN – dUCB vs. Haplo

Primary Endpoint was OS at 6 months – if > 60%, arm was deemed positive

Brunstein et al. Blood 2011

Page 34: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Summary – Donor SourceSummary – Donor SourceSummary – Donor SourceSummary – Donor Source

• Clear HierarchyClear Hierarchy

– SyngeneicSyngeneic

– Matched SiblingMatched Sibling

– Matched Unrelated Matched Unrelated

– Mismatch / UCB / Haplo ? MUDMismatch / UCB / Haplo ? MUD

• Outcomes of MUD, haplo and UCB have improved Outcomes of MUD, haplo and UCB have improved with newer approacheswith newer approaches

• RCTs required to determine optimal donor for RCTs required to determine optimal donor for patients without sibling matchpatients without sibling match

Page 35: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Allogeneic Transplant – GVHD Allogeneic Transplant – GVHD ProphylaxisProphylaxis

Allogeneic Transplant – GVHD Allogeneic Transplant – GVHD ProphylaxisProphylaxis

• Classical conditioning is calcineurin-inhibitor based Classical conditioning is calcineurin-inhibitor based (cyclosporine A or tacrolimus) in combination with (cyclosporine A or tacrolimus) in combination with short course methotrexateshort course methotrexate

• Potent T cell depletion can be achieved ex vivo or Potent T cell depletion can be achieved ex vivo or in vivo with alemtuzumab (anti CD-52), anti-in vivo with alemtuzumab (anti CD-52), anti-thymocyte globulin (ATG)thymocyte globulin (ATG)

• Recently agents such as sirolimus (mTOR inhibitor) Recently agents such as sirolimus (mTOR inhibitor) and MMF are increasingly utilizedand MMF are increasingly utilized

Page 36: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Pre-transplant AssessmentPre-transplant AssessmentPre-transplant AssessmentPre-transplant Assessment

• Disease assessment for responseDisease assessment for response

• Comorbidity is an important predictor of outcome Comorbidity is an important predictor of outcome when older patients are transplantedwhen older patients are transplanted

– Indices can be utilized and have been validatedIndices can be utilized and have been validated

– Pulmonary function, cardiac functionPulmonary function, cardiac function

– Programs have typical criteria for organ functionPrograms have typical criteria for organ function

– Dental assessment (source of bacteremia during Dental assessment (source of bacteremia during neutropenic period)neutropenic period)

Page 37: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

PAM scorePAM scorePAM scorePAM score

• 50 point score based on 8 factors:50 point score based on 8 factors:

– AgeAge

– Donor typeDonor type

– Disease typeDisease type

– Conditioning regimenConditioning regimen

– FEV1FEV1

– DLCODLCO

– CreatinineCreatinine

– ALTALT

Parimon et al Ann Intern Med 2006

Page 38: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

PAM Predictive of 2 year Overall PAM Predictive of 2 year Overall SurvivalSurvival

PAM Predictive of 2 year Overall PAM Predictive of 2 year Overall SurvivalSurvival

Parimon et al Ann Intern Med 2006

Page 39: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Key Question with Comorbidity Key Question with Comorbidity IndicesIndices

Key Question with Comorbidity Key Question with Comorbidity IndicesIndices

• We can identify patients with high risk of treatment We can identify patients with high risk of treatment failure (death due to relapse or non-relapse failure (death due to relapse or non-relapse mortality)mortality)

• Can we alter this endpoint?Can we alter this endpoint?

– Alter transplant strategy (ie use RIC or NMA)Alter transplant strategy (ie use RIC or NMA)

– Avoid transplant strategyAvoid transplant strategy

– Optimize patient and proceedOptimize patient and proceed

• Little data about prospectively risk-stratified Little data about prospectively risk-stratified approachesapproaches

Page 40: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

The Transplant ProcedureThe Transplant ProcedureThe Transplant ProcedureThe Transplant Procedure

• Increasingly common with growing indicationsIncreasingly common with growing indications

• As safety increases, older dogma relaxesAs safety increases, older dogma relaxes

– Isolation not required (outpatient transplants)Isolation not required (outpatient transplants)

– Dietary restrictions applyDietary restrictions apply

– With RIC transplants – patients are quite well and With RIC transplants – patients are quite well and may not even require transfusionmay not even require transfusion

Page 41: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

The Transplantation PeriodThe Transplantation PeriodThe Transplantation PeriodThe Transplantation Period

• Autologous TransplantAutologous Transplant

– TRM 1-3% typically (as high as 5-10% if TRM 1-3% typically (as high as 5-10% if transplanting heavily pre-treated, older, co-morbid)transplanting heavily pre-treated, older, co-morbid)

– Typical hospital stay is approximately 3 weeks, Typical hospital stay is approximately 3 weeks, neutropenic period < 14 daysneutropenic period < 14 days

• Allogeneic TransplantAllogeneic Transplant

– Early TRM is 5-10% (to day +100) and may reach Early TRM is 5-10% (to day +100) and may reach 20%20%

– Typical hospital stay 4 weeks, neutropenic period Typical hospital stay 4 weeks, neutropenic period may be 3 weeksmay be 3 weeks

Page 42: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Early Transplant ComplicationsEarly Transplant ComplicationsEarly Transplant ComplicationsEarly Transplant Complications

• Typical issues involve mucositis, neutropenic fever, Typical issues involve mucositis, neutropenic fever, mild renal or liver dysfunction, infectionmild renal or liver dysfunction, infection

• Less common but worrisome toxicities include other Less common but worrisome toxicities include other organ toxicity due to therapy, VOD of the liver, organ toxicity due to therapy, VOD of the liver, pulmonary hemorrhage, opportunistic infection pulmonary hemorrhage, opportunistic infection (viruses such as CMV), acute or hyper-acute (viruses such as CMV), acute or hyper-acute GVHD, engraftment syndromeGVHD, engraftment syndrome

Page 43: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Late Transplant Complications – AlloLate Transplant Complications – AlloLate Transplant Complications – AlloLate Transplant Complications – Allo

• Chronic GVHD and chronic immunosuppressionChronic GVHD and chronic immunosuppression

• Infection (Viral, fungal, bacterial)Infection (Viral, fungal, bacterial)

• Secondary MalignanciesSecondary Malignancies

• Endocrine dysfunction (hypogonadism, Endocrine dysfunction (hypogonadism, hypothyroidism, osteoporosis etc)hypothyroidism, osteoporosis etc)

• Cognitive dysfunctionCognitive dysfunction

Page 44: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Demonstrating Graft-versus Tumour Demonstrating Graft-versus Tumour Effect – impact of GVHD in ALLEffect – impact of GVHD in ALL

Demonstrating Graft-versus Tumour Demonstrating Graft-versus Tumour Effect – impact of GVHD in ALLEffect – impact of GVHD in ALL

Weiden et al NEJM 1979

Page 45: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Graft versus tumour EffectGraft versus tumour EffectGraft versus tumour EffectGraft versus tumour Effect

• Reducing immunosuppression or giving more donor cells Reducing immunosuppression or giving more donor cells (DLI) has been shown to kill tumour cells and has lead to (DLI) has been shown to kill tumour cells and has lead to sustained remission (ie. cure) in some casessustained remission (ie. cure) in some cases

• Most potent in indolent diseases (CML, CLL or indolent NHL, Most potent in indolent diseases (CML, CLL or indolent NHL, AML)AML)

• Less effective in more aggressive diseases (despite being Less effective in more aggressive diseases (despite being proven in ALL – ie. High grade lymphoma etc.)proven in ALL – ie. High grade lymphoma etc.)

• The Holy Grail = GVT without GVHDThe Holy Grail = GVT without GVHD

Page 46: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

GVT (or GVL) and DLIGVT (or GVL) and DLIGVT (or GVL) and DLIGVT (or GVL) and DLI

• Impact of graft-versus-tumour effect varies based on type of Impact of graft-versus-tumour effect varies based on type of diseasedisease

– Typically this is not a rapid effect and will not deal with highly Typically this is not a rapid effect and will not deal with highly aggressive diseaseaggressive disease

– Demonstrated in acute and chronic leukemia, indolent and Demonstrated in acute and chronic leukemia, indolent and aggressive NHL, HL, MMaggressive NHL, HL, MM

• Donor lymphocyte infusion (DLI) can be collected and used Donor lymphocyte infusion (DLI) can be collected and used to improve chimerism or for anti-tumour effectto improve chimerism or for anti-tumour effect

– Most effective in CMLMost effective in CML

– Least consistent in highly aggressive lymphoma or ALLLeast consistent in highly aggressive lymphoma or ALL

Page 47: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

The Lesson – RCT data in AML CR1The Lesson – RCT data in AML CR1The Lesson – RCT data in AML CR1The Lesson – RCT data in AML CR1

Cassileth NEJM 1998

Page 48: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Interpreting BMT StudiesInterpreting BMT StudiesInterpreting BMT StudiesInterpreting BMT Studies

• Patient selectionPatient selection

– Clearly an issue in institutional resultsClearly an issue in institutional results

• Referral (time) and travel biasesReferral (time) and travel biases

• The patient denominator issueThe patient denominator issue

– If only selecting responders – their outcome is If only selecting responders – their outcome is usually better than non-responders but a transplant usually better than non-responders but a transplant strategy must take into account all patients you wish strategy must take into account all patients you wish to transplantto transplant

• Philosophy for threshold of outcomePhilosophy for threshold of outcome

Page 49: Allogeneic Hematopoietic Stem Cell Transplant for the Medical Oncologist John Kuruvilla MD FRCPC

Summary – Allogeneic TransplantSummary – Allogeneic TransplantSummary – Allogeneic TransplantSummary – Allogeneic Transplant

• A very large and potentially complicated areaA very large and potentially complicated area

• Multiple components in the procedureMultiple components in the procedure

• Both an elegant and brutal procedureBoth an elegant and brutal procedure

• Some knowledge necessary for all who manage Some knowledge necessary for all who manage hematologic malignancieshematologic malignancies