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Linfoma linfoblastico
Vincenzo Cassibba
Divisione di Ematologia e TMO
Ospedale S. Maurizio, Bolzano
BACKGROUND
Lymphoblastic lymphoma (LBL) is a neoplasm of lymphoblasts committedto the B-cell (B-LBL) or T-cell lineage (T-LBL).
They are postulated to arise from precursor B in bone marrow (BM) orthymic T cells at varying stages of differentiation.
Within each lineage group, there is a significant biological and clinicaloverlap between neoplasms diagnosed as LBL and acute lymphoblasticleukemia (ALL). Accordingly, LBL and ALL should be considered the samedisease with different clinical presentations.
By convention, the word “lymphoma” is used if there is a bulky lesion inthe mediastinum or elsewhere, with no or minimal evidence of peripheralblood (PB) and bone marrow (BM) involvement. In general, a threshold of<25% BM blasts is used for defining lymphoma.
Epidemiology and ClinicalCharacteristics of LBL
• Frequency: T-LBL 1.7%, B-LBL <1%within all NHL
• Incidence: in U.S.A. 0.2/100,000 in males,0.1/100,000 in females
• Median age: 22-37 years
• Sex: male (61-75%) >female
• Blasts in BM: <25%
• Mediastinum involvement: 61-85%
• Stage III-IV: 58-95%
• B symptoms: 16-48%
• Elevated LDH: 48-84%
• CNS involvement: 0-10%D Hoelzer and N Gökbuget, Best Practice &Research in Clinical Haematology, 2003
Clinical Characteristics Accordingto Immunophenotype
B-LBL Frequency: 10% of LBL Median age: <18 years Sex: male predominance Sites of involvement: skin, soft
tissue, bone, lymph nodes Outcome: approximately 80%
of children appear to be cured,while this figure is less than50% for adults
T-LBL Frequency: 85-90% of LBL Median age: 20-30 years Sex: male predominance Sites of involvement: mediastinal mass,
pleural/cardiac effusion, lymph nodes, BM,less commonly skin, tonsil, liver, spleen,Weldeyer’s ring, CNS, gonades.
Others: stage III-IV, B symptoms, ⇧LDH Outcome: inferior to B-LBL if treated with
less intensive protocols
WHO 2008
Immunophenotype Analysis ofLBL
B-LBL:TdT+/cCD22+/CD19+/cCD79a+
Pro-B): CD19+, cCD79a+, cCD22+ Common: CD10+ Late pre-B: CD20+, c-µ heavy chain+
CD99+, CD34+ (40%), CD13 (14%),and/or CD33 (16%)
T-LBL: TdT+/cCD3+ Pro-T: cCD3+, CD7+, CD2-, CD1a-, CD34+/-, CD4- and CD8- Pre-T: cCD3+, CD7+, CD2+, CD1a-, CD34+/-, CD4- and CD8- Cortical T: cCD3+, CD7+, CD2+, CD1a+,
CD34-, CD4+ and CD8+ Medullary T: cCD3+, CD7+, CD2+, CD1a-,
sCD3+, CD4+ or CD8+, CD34-,
CD99+, CD34+, CD13+ and CD34+ (19-32%)
immunophenotype does not affect DFS
Genes that Distinguish T-ALL fromT-LBL
E A Raetz et al, Pediatr Blood Cancer, 2006
Prognostic Factors
Higher age (>30-40 years) Stage III-IV BM/CNS involvement Mediastinal involvement Elevated LDH B symptoms Time to CR IPI (age, extranodal sites, LDH, stage, PS)
Risk factors according to Coleman et al, JCO, 1986: stage IV, BM or CNSinvolvement or initial LDH>300 IUL (normal<200).5 years RFR in low risk patients; RFR 94% vs 19% in high-risk patients.
A CONVINCING PROGNOSTIC MODEL HAS NOT YET BEEN DEFINED FOR ADULTLL
Remissioninduction/consolidation + mediastinal irradiation
TREATMENT RESULTS IN ADULT LBL
34-44%57-83%Highgrade NHL*(LSA2-L2)
23-56%79-100%Modified NHL(Stanford/NCOG)
45-67%55-100%ALL protocols
23-53%53-71%Conventional NHL(CHOP)
DFSCRRegimens
*Only one study wich included SCT reached a DFS of 75% (Santini et al, BM Trasp 1989)
Treatment Overview of GMALLStudies 04/89 and 05/93
AC indicates cytarabine; ASP, asparaginase; CYCLO, cyclophosphamide;HD, high dose; MITOX, mitoxantrone; MTX, methotrexate; VM 26, teniposide
D Hoelzer et al, Blood, 2002
Consolidation I
Overall Results in 45 adult T-LBL (1989-1998)
D Hoelzer et al, Blood, 2002
Residual mediastinal tumor was most frequently the reason for late achievement of CR.
Median follow-up: 41 mo. (range 5-89 mo.)
**
**
***
***
Estimate for OS and DFS at 7 Yearsin Adult T-LBL
D Hoelzer et al, Blood, 2002
Median treatment duration: 8 months (range, 38 days-18 months)
Initial Involvement, Relapse Localization,Time to Relapse, and Survival in 15/42
(36%) Relapse Patients
D Hoelzer et al, Blood, 2002
Median time to relapse:147 d. (range, 23-426 d.)
CNS relapse= 2%
GMALL T-LBL Study 1/2004
V I IIInduction
CNS RT24 GY
Med RT36 Gy
Cons 1°
SC-Apher.
CRuCR
CLAEGSCT (Auto, allo)PR
Fail
HD-MTXASP
6MP
IIIRenduction
HD-MTXASP
6MP
VM26ARAC
CYCLOARAC
HD-MTXASP
6MPEnd of Therapy
4 11 16 22 3630 41 46 531
MRD MRD MRD MRD (MRD) MRD MRDMRD
I. T.Weeks
CT CTCT/PET
+RT 46 Gy PET+
D A Thomas et al, Blood, 2004No PCRT; IFRT (30-39 Gy) for all pts with med. dis (70%).
Outcome with the Hyper-CVAD Regimen in33 patients with LBL (1992-2001)
D A Thomas et al, Blood, 2004
CR= 91%3-yr OS=70%3-yr PFS=66%Median follow-up:
48 mo. (range 8-110mo.)
Pattern of Relapse in 10/33 (30%)Patients with LBL
Treated with the Hyper-CVAD Regimen
D A Thomas et al, Blood,2004
Clinical Outcome of 27 Children and Adolescentswith B-LBL Treated with ALL Protocols (BFM 86
and 90)
O Neth et al, Med Pediatr Oncol, 2000
ALL-type Therapy for 105 Childrenwith T-LBL (BFM 90)
A Reiter et al, Blood,2000
MTX 5g/sqm
18 12 Gy
LRT omitted
(LRT 30 Gy+AlloSCT)
Clinical Outcome
A Reiter et al, Blood, 20001/105 sAML (0.95%)
Treatment of childhood T-LBL according to thestrategy for ALL, without radiotherapy: Long term
results of the EORTC CLG 58881 trial
Patients: 121 Treatment: BFM without PCRT and LRT EFS at 6 years: 77.5% OS at 6 years: 86%
A Uytterbroeck et al, Eur J Cancer, 2008
HDT with Auto/Allo-SCT ?
Study Design of a RandomizedTrial of EBMT and UKLG
J W Sweetenham et al, JCO, 2001
Results
J W Sweetenham et al, JCO, 2001
3yr=24%
3 yr=55%N=119
Response to inductiontherapy:
- ORR= 82%
- CR= 56%
- TRM= 0.8%
Randomized pts= 69%
3-yr= 45 vs 56%
Conclusion: the use of HDT and ASCT in adult patients with LBL in 1st remissionafter intensive remission induction therapy did not improve OS compared withconventional-dose therapy in this randomized trial.
P=.065
Probability of DFS and OS by Type ofTransplant (IBMTR/ABMTR) (1989-1998)
J E Levine et al Blood,2003
N=76
N=128
DFS OS
Cumulative incidence of treatment relatedmortality or relapse by type of transplant
E Levine et al Blood, 2003
TRM RELAPSE
M Aljurf and ZA Zaidi, Biol Blood Marrow Transplant, 2005
M Aljurf and Z A Zaidi, Biol Blood Marrow Transplant 2005
• Assessing CT-PET and MRDto boost risk-oriented therapy
Maximum Standardized Uptake Value(SUV) in Four Types of Lymphoma
N Tsukamoto et al, Cancer2007
N Tsukamoto et al, Cancer 2007
Diagnostic PET in T-Lymphoblastic Lymphoma
Sites of involvement:Sites of involvement:MEDIASTINUMMEDIASTINUMR HILUMR HILUMR AXILLAR AXILLALIVER (sIV-sV) LIVER (sIV-sV) D8-D10D8-D10
Postinduction PET in T-Lymphoblastic Lymphoma
MRD: defines sensitivity to early treatmentMRD: defines sensitivity to early treatment 1. surrogate marker of long-term response 1. surrogate marker of long-term response 2. decisional aid for risk-adapted therapy2. decisional aid for risk-adapted therapy
Overt ALLOvert ALL
MRDMRD(RQ-PCR)(RQ-PCR)
1010-3-3
1010-5-5
1010-1-1
CRCR
risk of relapse
risk of relapse
11
22
TIMETIME
INDIND CONSOLIDATION CONSOLIDATION MAINTENANCEMAINTENANCE
33 cure possiblecure possible
11 MRD persistenceMRD persistence22 MRD relapseMRD relapse33 MRD clearingMRD clearing
BM BM (in T-LBL reveals occult disease)(in T-LBL reveals occult disease)
Molecular markerMolecular marker(Ig/TCR(Ig/TCRrearrangement)rearrangement)
ImmunophenotypeImmunophenotype(TdT/cyCD3, (TdT/cyCD3, ……))
Prospective NILG Study (2000)Prospective NILG Study (2000)MRD based treatment decisionsMRD based treatment decisions
MaintenanceMaintenance(1-Y)(1-Y)
11 2828 70701010
1151151616
1541542222
prepreC1C1 C2C2 C3C3 C5C5 C6C6 C8C8HD4HD4 HD7HD7
DayDayWeekWeek
Diagnosis Diagnosis CRCR TP1TP1 TP2TP2 TP3TP3
HH
MRDMRDnegneg
MRDMRDu/ku/k SR SR
MRDMRDpospos
MRDMRDu/k u/k HRHRH/CH/C
11H/CH/C
22H/CH/C
33H/CH/C
44
RR RR RR RR
MaintenanceMaintenance(2-Y)(2-Y)
allogeneicallogeneicSCTSCT
oror (no donor) (no donor)
MRDMRD
MRDMRD
PDN-CYPDN-CY
IDR, VCR, ASP, PDN (ind); IDR, VCR, CY, DXM (cons)IDR, VCR, ASP, PDN (ind); IDR, VCR, CY, DXM (cons)
HD MTX-AraC HD MTX-AraC
Cranial RTRCranial RTR
Treatment elementsTreatment elements
maintenancemaintenance 6MP-MTX for 2 yy6MP-MTX for 2 yyV-P alternating monthly with CY-AraC V-P alternating monthly with CY-AraC (1st y)(1st y)
HD 6MP-VP-melHD 6MP-VP-mel
HD MTX-Ara-CHD MTX-Ara-CHH Blood stem cell harvest / reinfusionBlood stem cell harvest / reinfusionRR
VHRVHR Ph/t(4;11)+Ph/t(4;11)+allogeneic SCTallogeneic SCT
Clinical Characteristics of 30 LBL PatientsTreated with NILG ALL 09/00 Protocol
17 (57) Ann Arbor stage III-IV
17/13 (57/43) Sex: M/F
22/30 (73%) Mediastinal involvement
Characteristics value No of pts (%) number 30 (100)
median age yrs (range) 27 (16-57)
Elevated LDH 18 (60)
Immunophenotype: T-lineage B-lineage
24 (80) 6 (20)
% of blasts in BM: <5 5-20
18 (60) 12 (40)
Clinical Outcome of 30 LBL PatientsTreated with NILG ALL 09/00 Protocol
2 (7)Death in CR (sAML, sDLBCL)
Outcome Value No of pts (%) CR 28 (93)
PR/NR 2 (7)
Relapse:(4 BM; 1 abd.;1mediast.*)
5/30 (17)
1st CCR** 21 (75)
*Mediastinal irradiation (Gy 24-32): 7/22 (32%)
**Median follow-up, years (range): 3.9 (0.8-9.2)
Overall Survival of 30 LBL Patients(NILG Protocol 09/00)
0.0
00.2
50.5
00.7
51.0
0
Cum
ula
tive s
urv
ival
0 2 4 6 8 10
years
.
72% at 5 yrs (n=30)
Disease-Free Survival of 30 LBLPatients (NILG Protocol 09/00)
0.00
0.25
0.50
0.75
1.00
Cum
ulat
ive s
urviv
al
0 2 4 6 8 10years
.
77% at 5 yrs (n=28)
Cumulative Incidence of Relapse(NILG Protocol 09/00)
0.0
00.2
50.5
00.7
51.0
0
Cum
ula
tive s
urv
ival
0 2 4 6 8 10
years
.
18% at 5 yrs (n=28)
Study DesignELIGIBILITY/REGISTRATION
(Clinical Trial: age 18-65 years)AND INDUCTION/CONSOLIDATION
C1
C2
CT-PET (MEDIASTINAL IRRADIATION 36 Gy if residual mass >2 cm) MRD-1 (eligible to ALLO-SCT if >10-4)
C4
C6
C8
chest X-Ray/CTMRD-2
CT-PET MRD-3
C3:C3: MTX 5 g/mMTX 5 g/m 2 2 + Ara+ Ara --CC
CT-PET NEGand MRD NEG
CT-PET POSand/or MRD POS
MAINTENANCEMAINTENANCE ALLOGENEIC SCTALLOGENEIC SCT
orAUTOLOGOUS SCTAUTOLOGOUS SCT +
= IT MTX/AraC/PDN
C5:C5: MTX 5 g/mMTX 5 g/m 2 2 + + AspAsp
C7:C7: MTX 5 g/mMTX 5 g/m 2 2 + Ara+ Ara--CC
w10TP-1
w22TP-3
w16TP-2
ONLY IRRADIATED PATIENTS:ALL PATIENTS:
ALL PATIENTS:
ALL PATIENTS:
MAINTENANCEMAINTENANCE
prew1/d1
w5/d29
w8/d50
w11/d71
w14/d92
w17/d113
w20/d134
w23/d155
RISK-ORIENTED THERAPY
*
*Stem cell harvest
Conclusions
• Intensive ALL-type programs are associated withimproved outcome.
• IT chemotherapy is required to reduce CNS relapse rate.The role of PCRT as an addition to IT prophylaxis isunclear.
• Local recurrence most frequently involves themediastinum. Consolidative mediastinal RT and/or moreintensive ALL-type intensification may decreasemediastinal relapse.• A convincing prognostic model has not yet beendefined. Better assessment of individual risk may bebased on evaluation of early MRD and CT-PET response.
• Patients with adverse prognostic features should beconsidered for SCT.
Rare Oral Cavity Presentation of aB-LBL
A: CD20 diffusely and strongly positive in all neoplastic cellsB: TdT strong nuclear reactivity in neoplastic cellsC: BCL2D: CD99 diffuse cytoplasmic reactivity
DP Cox et al,OOOOE, 2007
Risk Stratification According to IPIin Adult T-LBL
J W Sweetenham et al, JCO, 2001
ALLOGENEIC SCTALLOGENEIC SCT
orAUTOLOGOUS SCTAUTOLOGOUS SCT + MAINTENANCEMAINTENANCE
MAINTENANCEMAINTENANCE
CT-PET NEG MRD NEG
CT-PET POS MRD POS
CY
CY
V/P
V/P
CY
CY
V/P
V/P
CY
CY
V/P
V/P
mo.1
mo.4
mo.8
mo.12
mo.16
mo.20
mo.24
CT-PETMRD
CT-PETMRD
CT-PETMRD
MRD
MRD
MRD
RISK-ORIENTED THERAPY
FOLLOW-UPPROTOCOL
= IT MTX/AraC/PDN
Key:CY
=CY dd 1-4, 6MP/MTX dd 8-28
V/P =VCR d1, PDN dd 1-5, 6MP/MTX dd 8-28
1 YEAR1 YEAR
Evaluation of MRD and PostremissionTherapy
1 rel, alive in 2° CR4 alive in CR
3 alive in CR; 3 deathsin relapse; 1 death inCR (1 DLBCL)
1 alive in CR
1 alive in CR
5 maintenance
7 hypercycle
1 allog. Transpl.
1 RT
14/25 (56)Unknown
3 alive in CR2 deaths in relapse
1 maintenance3 allog. transpl.1 hypercycle
5/25 (20)Positive
5 alive in CR1 death in CR (AML)
6 maintenance6/25 (24)Negative
Outcome Phase B therapyNo of patients (%) MRD
A retrospective analysis of 92 patientswith adult LBL (LNH 87/93)
S Le Gouill et al, Leukemia 2003
5 yr= 32%
5-yr=22%
TRM=4%
Comparative Studies
R Bouabdallah et al, Ann Oncol, 1998
M Hunault et al, Haematologica, 2007
CR= 71%
7-yr OS= 64%
7-yr RFS= 65%
None of theNone of thepatientspatientsreceivedreceived
Mediastinal/Mediastinal/Local RTLocal RT
Genetics of B-LBL
B lymphoblastic leukaemia/lymphoma, not otherwise specified:Nearly all cases have clonal DJ rearrangements of the IGH@gene. Inaddition T-cell receptor gene rearrangement may be seen in up to70% of cases. The majority of patients have cytogeneticabnormalities: del (6q), del (9p), del (12p), t (17;19).
B lymphoblastic leukaemia/lymphoma with recurrent geneticabnormalities:
t(9;22)(q34;q11.2); BCR-ABL1 t(v;11q23); MLL rearranged t(12;21)p13;q22); TEL-AML 1 (ETV6/RUNX1) Hyperdiploidy Hypodiploidy t(5;14)(q31;q32); IL3-IGH t(1;19)(q23;p13.3); E2A-PBX1 (TCF3-PBX1)
WHO 2008
M Aljurf and Z A Zaidi, Biol Blood Marrow Transplant, 2005
No chromosomal or molecular abnormalities have been consistently shown to carryprognostic significance except the t(9;17)(q34;q23) karyotype, which has beenassociated with an aggressive clinical course in children.
Genetics of T-LBL
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