Is there still a role for autotransplant with follicular lymphoma in the rituximab era. Pr. Christian Gisselbrecht Hôpital Saint Louis Paris, France

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1 COSTEM Berlin September Is there still a role for autotransplant with follicular lymphoma in the rituximab era. Pr. Christian Gisselbrecht Hôpital Saint Louis Paris, France

2 World Health Organization (WHO) Classification of Lymphoid Neoplasms: B-Cell Neoplasms Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) Mature (peripheral) B-cell neoplasms B-cell CLL/SLL B-cell PLL Lymphoplasmacytic lymphoma Plasmacytoma, plasma cell myeloma HCL Marginal zone B-cell lymphoma Marginal zone B-cell lymphoma of MALT Nodal marginal zone lymphoma (+/- monocytoid B-cells) (Jaffe et al. Oncol. 1998;9 zone (suppl 5):S25). Ann Splenic marginal B-cell FL Follicular : 22% Grade 1, -5 centroblasts/hpf Grade 2, 6-15 centroblasts/hpf Grade 3, >15 centroblasts/hpf 3a, >15 centroblasts, but centrocytes still present 3b, centroblasts from solid sheets with no residual centrocytes Variants Cutaneous follicle center MCL Mantle cell DLCL Diffuse Large Cell Mediastinal (thymic) large B-cell lymphoma Intravascular lymphoma Primary effusion lymphoma

3 FOLLICULAR LYMPHOMA REQUIRING TREATMENT Prog 1 Diagnosis Prog 2 Auto Follow up Interval smaller Nb of phases Other treatments Nb of Chemo High tumor burden Cross over make analysis of survival benefit related to treatments almost impossible Histologic transformation Time in years 3-5%

4 Each recurence is associated Impaired quality of life Diminution of quality of response Diminution of duration of remission Diminution of life expectancy Basis for consolidation therapy

5 TREATMENT OF LYMPHOMA NHL Consolidation Options Poor Risk Chemo + Rituximab CR PR ASCT Ibritumomab Tiuxetan No treatment Rituximab

6 Before Rituximab CUP Trial for Follicular Lymphoma Progression-Free Survival 1. Probability.8 Chemotherapy Unpurged Purged Events Total EBMT registry.4 First CR n= Patients at: Chemotherapy Unpurged Purged Schouten HC et al. J Clin Oncol. 23;21: Months Other responses n=

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8 RELAPSES GELF 86 (111pts)- GELF 94 (144pts) SALVAGE WITH OR WITHOUT AUTOLOGOUS STEM CELL TRANSPLANTATION Rohatiner et al. Gela studies 11.5 y 13 y AZS Rohatiner et al. Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma at the Time of Second or Subsequent Remission: Long-Term Follow-Up. J Clin Oncol 27;25:2554 Sebban et al

9 Does Rituximab make a difference at relapse? What is the Impact of first line Treatment? Poor Risk Chemo + Rituximab salvage with rituximab Maintenance after chemo ASCT after response to salvage CR PR ASCT Ibritumomab Tiuxetan No treatment Rituximab

10 Intergroup phase III trial: study design NO first line RITUXIMAB R A N D O M I Z E D CHOP every 21 days maximum 6 cycles Rituximab + CHOP every 21 days maximum 6 cycles CR PR R A N D O M I Z E D Observation Rituximab maintenance* 2 EORTC Data Center *375mg/m every 3 months for 2 years or until relapse 25 Van Oers MHJ, et al.november (Blood. 26;18:3295-

11 Progression-free survival (%) Intergroup phase III trial: PFS from second randomization all patients MabThera maintenance median: 51.6 months Overall log-rank test: p<.1 Hazard ratio:.4 O N Years Number of patients at risk EORTC Data Center 1 2 Observation median: 15. months Treatment Observation MabThera 25 Van Oers MHJ, et al.november (Blood. 26;18:3295-

12 Intergroup phase III trial: PFS from second randomization by induction regimen Progression-free survival after CHOP Median 42. months Median 11.6 months Overall log-rank test: p<.1; HR:.3 O N Years Number of patients at risk : EORTC Data Center 4 Progression-free survival (%) Progression-free survival (%) Subgroups according to induction treatment Progression-free survival after R-CHOP Median 51.9 months Median 23.1 months Overall log-rank test: p=.4; HR: Years 1 4 Treatment Observation MabThera O N Number of patients at risk : Treatment Observation MabThera 25 Van Oers MHJ, et al.november (Blood. 26;18:3295-

13 Intergroup phase III trial: PFS from second randomization by response to induction Progression-free survival after CR Progression-free survival (%) Progression-free survival (%) Subgroups according to response quality after induction Median 51.6 months Median 14.5 months Overall log-rank test: p=.9; HR:.38 1 O N Number of patients at risk : Years EORTC Data Center Median 45.4 months Median 15.6months Overall log-rank test: p<.1; HR: Progression-free survival after PR Treatment Observation MabThera O N Years Number of patients at risk : Treatment Observation MabThera 25 Van Oers MHJ, et al.november (Blood. 26;18:3295-

14 GELF-86 & GELF-94 Design CHVP arm months CHVP+Ifn arm Interferon alpha 5MU S.C. 3 times a week for 18 months PBSC reinjection 94 CHVP regimen TBI Adriamycine 25mg/m2 J1 Endoxan 6mg/m2 J1 Teniposide 6mg/m2 J1 Prednisone 4mg/m2 J1 à J5 6 CHOP+ASCT arm Sebban et al CHOP regimen Cyclophosphamide + Etoposide

15 Treatments according to Studies Gelf-86 Gelf % 92% 1% 1% 11% 1% Yes 2% 47% Alone With chemotherapy No Unknown 1% 1% 98% - 9% 38% 52% 1% Yes 38% 39% No Unknown 57% 5% 59% 1% Number of patients Salvage chemotherapy Yes No Unknown Rituximab: no maintenance High-dose therapy with ASCT

16 RELAPSES GELF 86 (111pts)- GELF 94 (144pts) SALVAGE WITH OR WITHOUT AUTOLOGOUS STEM CELL TRANSPLANTATION Sebban et al Bertrand Coiffier et al ASH 27

17 Survival after Relapse or PD

18 Rituximab at time of Salvage Van Oers et al. Our study R-CHOP M. van Oers M, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 26;18:

19 EBMT LYM1 <3 <3 <21 28 <3 Days FL in CR/VGPR 2, 3 2 MabThera 375mg/m weekly x 4 2 R No treatment PBPC collection After any treatment CR or VGPR n=46 MabThera 375mg/m q 2 month x4 High-dose therapy BEAM R Observation alone

20 EBMT GELA GOELAMS study in FL: EBMT LYM1 R purging + RR maintenancemaintenance Pts Nb 69 Median PFS NR@ 6.4 y 69 R purging No R y 4.3 y 3.34 y 5y PFS 62.9 % 56 % 46 % 37.6 % 5y OS 79.5 % 8.5 % 84.8 % 78.4 % Ruth Pettengell et al: Blood (ASH) : Abstract 3567

21 Does rituximab maintenance in first line will change the place of autotransplantation?

22 P R IMA : s tu dy de s ig n INDUCTION MAINTENANCE Rituximab maintenance 375 mg/m2 every 8 weeks for 2 years Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM CR/CRu PR PD/SD off study Random 1:1* Observation * Stratified by response after induction, regimen of chemo, and geographic region Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up Salles G et al Lancet 211; 377: 42 51

23 P rim a ry e n dpo in t (P F S ) m e t a t th e pla n n e d in te rim a n a ly s is Rituximab maintenance significantly reduced the risk of progression by 5% Progression-free rate 1. 82% Rituximab maintenance N= Observation N=513 66%.4 stratified HR=.5 95% CI.39;.64 p< Time (months) Patients at risk Salles G et al Lancet 211; 377: 42 51

24 B e n e fit s o f ritu x im a b m a in te n a n c e s e e n in a ll m a jo r s u b -g ro u ps e v a lu a te d Category N Hazard ratio* All < FLIPl R-FCM CR/CRu PR Subgroup All Age FLIPl Index Hazard ratio FLIPl = 2 FLIPl 3 Induction Chemotherapy Response to Induction R-CHOP R-CVP 2 1 Favors maintenance Favors observation 95% CIs 3 Salles G et al Lancet 211; 377: * Non-stratified analysis

25 R e s po n s e s t a tu s a t e n d o f m a in te n a n c e Observation n = 398 * Rituximab n = 389 * 162 (4.7%) 79 (2.3%) Stable disease (SD) 1 (.3%) (%) Partial response (PR) 29 (7.3%) 28 (7.2%) 19 (47.7%) 26 (66.8%) n = 19 n = 258 Patients remaining in CR/CRu 153 (56%) 29 (75%) Patients converting from PR/SD to CR/CRu 37 (3%) 49 (45%) Progressive disease (PD) Complete response (CR/CRu) Response: end of Induction Maintenance The quality of response remains a major parameter * Patients not evaluated/missing data: respectively 16 and 22 pts not evaluated in the rituximab maintenance arm: 2 pts Salles G et al Lancet 211; 377: 42 51

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27 Post treatment PET-CT is predictive of patient outcome in follicular lymphoma Analysis of PET-CT in PRIMA study Trotman J et al JCO 211 on line

28 After first line therapy Bachy E, Brice P et al. JCO 29 GELF 86

29 FL2 study design CR : 6% EFS: 63% Arm A 6 months R 12 months Staging including CT-scan and bone marrow biopsy CR : 75% EFS: 78% Arm B D1 Cyclophosphamide 6 mg/m2 D1 Doxorubicin 25 mg/m2 D1 Etoposide 1 mg/m2 D1-D5 Prednisone 4 mg/m2 every month for 6 months (arm A & B) then every 2 months in arm A α-ifn 2b, 4.5 MU tiw for 18 months (3MU if aged 7 yr) Rituximab: 375 mg/m2 Salles G, et al. Blood 28; 112:

30 FL2 study Response to treatment After first line in rituximab treated patients Salles G, et al. Blood 28; 112: Bachy E, Brice P et al. JCO 29

31 FL 2: Patient outcome according to transplantation at first progression: ----transplanted patients (n=42); non-transplanted patients(n=111). Event free survival (P=.5). Overall survival (P=.3) transplantation in follicular lymphoma Steven Le Gouill et al Haematologica 211,

32 FL 2: Patients outcome according to frontline therapy and use of transplantation at first progression (---- transplanted patients and non-transplanted patients Event free survival for patients who fail R-CHVP-I (P=.52). Overall survival for patients who fail R-CHVP-I (P=.52). transplantation in follicular lymphoma Steven Le Gouill et al Haematologica 211,

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34 Conclusion ASCT is still the best therapy after 1st relapse for most patients with follicular lymphoma, in each situation: before and during rituximab era. Best treatment if histologic transformation Consolidation with ASCT is even more appropiate for patients failing rituximab treatment and can be selected earlier with PET-SCAN. It can be challenged by new therapy or new monoclonal antibodies ASCT is also challenged by RIC allo for survival But improving progression free survival is the first step for: THE LONG WAY FOR CURE

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36 Allogeneic BMT for Low-Grade Lymphoma Disease-Free Survival After BMT Percentage 1 High Treatment-Related Mortality Low Probability of Relapse van Besien K et al. Blood. 1998;92: Years After BMT 5 6

37 Adjusted Probability, % LYMPHOME FOLLICULAIRE AUTO/ ALLO SURVIE SANS RECHUTE REGISTRE ABMTR 1 8 Allogeneic (n = 175) 6 4 Auto-unpurged (n = 596) Auto-purged (n = 13) years (K. Van Besien et al., Blood, 23)

38 CONCLUSION We have new tools To improve survival A reasonable objective Survival has improved over the last 25 years as a result of sequential application of effective therapies even before monoclonal antibodies era. The chance for long term cure an idealistic goal.

39 Basis for a maintenance therapy Sustain the disease in ongoing remission Delay disease progression Improve the extent of response attained Extend the interval until next therapy Improve the QOL Improve the survival

40 Response to treatment After first line therapy Bachy E, Brice P et al. JCO 29

41 The Follicular Lymphoma International Prognostic Index (FLIPI): Overall survival Solal-Céligny P, et al. Blood 24; 14: Probability of survival 1. Good ( 1).8 Intermediate (2).6 Poor (3 5).4.2 P <.1 N = 1,795 Risk group Months AGE < 6 vs. 6 No. of factors Patients (%) 5-year (%) 1-year (%) Relative risk HEMOGLOBIN 12g/dL vs. < 12g/dL Intermediate vs. > ULN 1 SERUM LDH36LEVEL ULN91 2 ANN ARBOR37STAGE I II vs. 78III IV Poor 3 Good NUMBER OF NODAL SITES INVOLVED 4 vs. >

42 IMPROVEMENT OF SURVIVAL IN FOLLICULAR LYMPHOMA PATIENTS Swenson et coll. JCO 25

43 LOW GRADE LYMPHOME - Treatment Options? Wait and watch RIC Allograft Radiotherapy Radio immuntherapy Relapse Autograft Monochemotherapy? New drugs Polychemotherapy CT CT +/- Monoclonal Antibodies CT + IFN CT + RT Immunomodulator agents Vaccines

44 LYMPHOMA : HISTOLOGIC TYPES (adapted from the Non-Hogkin s classification project, 1997) Indolent lymphoma (low risk) Small lymphocytic (CLL) Lymphoplasmocytoid Marginal zone B-cell, MALT Marginal zone B-cell, nodal Follicular all grades Aggressive lymphoma (intermediate risk) Mantle cell Diffuse large B-cell Primary mediastinal large B-cell 6. % 3.6 % 2.4 % Peripheral T-cell, all types Anaplastic large T / null cell Very aggressive lymphomas (high risk) Burkitt s High grade B-cell, Burkitt like Precursor T-lymphoblastic % % % % % 7. % 2.4 % < 1 % 2.1 % 1.7 %

45 LYMPHOMES FOLLICULAIRES EN RECHUTE RÉPONDEURS AU TRAITMENT DE SAUVETAGE CHOP: RITUXIMAB D ENTRETIEN VERSUS OBSERVATION: SURVIE SANS PROGRESSION 1 Median PFS: Maintenance = 38 months Observation = 15 months P <.1 Percentage 8 6 Maintenance 4 2 O Observation P <.1 N Number of patients at risk: Years 5 Observation Rituximab maintenance Van Oers MHJ, et al. (Blood. 26;18:3295-

46 Rituximab en traitement d entretien (1/3) EORTC 2981 : Survie Sans Progression 1 Réduction de 45 % du risque de rechute à 6 ans Entretien Rituximab 6 Hazard ratio:, ms 1 44 ms Observation p<,1 (années) O O N N Nombre Nombrede depatients patients à risque à risque : : Observation Observation Rituximab Rituximab Van Oers / Etude EORTC 2981: Blood 26; Van Oers / Etude EORTC 2981: ASH 28

47 Rituximab en traitement d entretien (2/3) EORTC 2981 : Survie Sans Progression Analyse par sous-groupes : traitement d induction 1 CHOP induction Hazard ratio:.37 5 R-CHOP induction 1 médiane: 52,7 ms Médiane : 36,8 ms 2 2 p<,1 Hazard ratio =,37 1 O N Médiane : 11,6 ms Nombre de patients à risque : (années) 8 Observation Rituximab A 6 ans : réduction de 63 % du risque de rechute 1 O N p=,43 Hazard ratio =,69 Médiane : 23, ms Nombre de patients à risque (années) Observation Rituximab A 6 ans : réduction de 31 % du risque de rechute Van Oers / Etude EORTC 2981: Blood 26; Van Oers / Etude EORTC 2981: ASH 28

48 Rituximab en traitement d entretien (3/3) EORTC 2981 : Survie sans progression depuis la 2ème randomisation Analyse par sous-groupes : réponse à l induction 1 RC après induction 9 RP après induction Médiane : 52,7 ms Médiane : 41,8 ms Médiane : 14,4 ms p=,3 (années) O N Nombre de patients à risque : Observation Rituximab A 6 ans : + 38 mois de SSP et réduction de 64% du risque de rechute p=,6 O N Médiane : 15,6 ms Nombre de patients à risque : (years) Observation Rituximab A 6 ans : + 26 mois de SSP et réduction de 54 % du risque de rechute Van Oers / Etude EORTC 2981: Blood 26; Van Oers / Etude EORTC 2981: ASH 28

49 Event-free survival after relapse/pd

50 Rituximab treated No maintenance

51 FL2 study design Arm A 6 months R 12 months Staging including CT-scan and bone marrow biopsy Arm B D1 Cyclophosphamide 6 mg/m2 D1 Doxorubicin 25 mg/m2 D1 Etoposide 1 mg/m2 D1-D5 Prednisone 4 mg/m2 every month for 6 months (arm A & B) then every 2 months in arm A α-ifn 2b, 4.5 MU tiw for 18 months (3MU if aged 7 yr) Rituximab: 375 mg/m2 Salles G, et al. Blood 24; 14:Abstract 16.

52 FL 2: Outcome of patients calculated from the time of first progression (n=175). Event free survival; the 3 and 5 year EFS rates are 5% (95%IC; 42-58%) and 26% (95%IC; 14-39%), respectively Overall survival; the 3 and 5 year OS rates are 72% (95%IC;64-78%) and 52% (95%IC; 36-66%). transplantation in follicular lymphoma Steven Le Gouill et al Haematologica 211,

53 FL 2: Patients outcome according to frontline therapy and use of transplantation at first progression: ---- transplanted patients and non-transplanted patients 3a: Event free survival for patients who fail CHVP-I (P=.2). 3b: Overall survival for patients who fail CHVP-I (P=.5) transplantation in follicular lymphoma Steven Le Gouill et al Haematologica 211,

54 4. Patient outcome according to the period of progression and use of transplantation at first progression (---- transplanted patients and non-transplanted patients). 4a: Event free survival of primary refractory patients (P=.2). 4b: Event free survival of patients who progressed or relapsed after completion of their first-line treatment: (P=.11). transplantation in follicular lymphoma Steven Le Gouill et al Haematologica 211,

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