Les Ateliers Lymphomes et LLC octobre 2009 Le Moulin de la Forge Le Vaumain (60)

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1 Les Ateliers Lymphomes et LLC octobre 2009 Le Moulin de la Forge Le Vaumain (60)

2 4 ème session : Lymphomes indolents Modérée par Guillaume CARTRON

3 Programme de la session 4 ème session : Lymphomes indolents Modérée par G. Cartron Anatomopathologie Facteurs pronos8ques cliniques Facteurs pronos8ques biologiques Maladie résiduelle Stratégies thérapeu8ques Cas clinique interac8f Pathogénie et traitement des MZL Cas clinique interac8f N. Brousse Ph. Solal Céligny F. Jardin G. Salles Présenté par G. Cartron C. Thieblemont Présenté par Ph. Solal Céligny 3

4 Stratégies thérapeu8ques Gilles Salles Service Hématologie Clinique, Hospices Civils de Lyon

5 Traitements des lymphomes folliculaires La décision thérapeutique en première ligne Standards et options pour les patients avec faible masse et les stades localisés Standards et options pour les patients de forte masse Quelles voies de progrès? Les choix thérapeutiques en rechute Que veut-on obtenir? Quels outils, quels bénéfices?

6 Traitements des lymphomes folliculaires La décision thérapeutique en première ligne

7 1.0 The Follicular Lymphoma International Prognostic Index (FLIPI): Overall survival Solal-Céligny P, et al. Blood 2004; 104: Probability of survival Good (0 1) Intermediate (2) Poor (3 5) N = 1,795 P < Months Risk group No. of AGE factors < 60 vs. Patients 60 (%) 5-year (%) 10-year (%) Relative risk Good HEMOGLOBIN g/dL vs. < 91 12g/dL Intermediate SERUM 2 LDH LEVEL 37 ULN vs. 78 > ULN Poor ANN 3 ARBOR STAGE 27 I II vs. 53 III IV NUMBER OF NODAL SITES INVOLVED 4 vs. > 4

8 Questions regarding the FLIPI index Age has a major impact Number of nodal areas involved are not really easy to evaluate Will 18- FDG PET help? Young patients with large tumor mass may be considered as low risk even with one factor (LDH, bone marrow)

9 The tumor burden criteria GELF 86 GELF 94 FL2000 PRIMA B symptoms presence ECOG PS > Compression / Seric effusion / Spleen Tumor > 7 cm Nodes or more > 3 cm Cytopenia + LDH > N β2-micro > 3 mg/l + + +

10 Clinical criteria to start a cytotoxic treatment GELA criteria High tumor bulk defined by either: - a tumor > 7 cm - 3 nodes in 3 distinct areas each > 3 cm - symptomatic splenic enlargement - organ compression - ascites or pleural effusion Presence of systemic symptoms Serum LDH or β2-microglobulin above normal values BNLI criteria Rapid disease progression in the preceding 3 months Life threatening organ involvement Renal or liver infiltration Bone lesions Systemic symptoms or pruritus Hb<10 g/dl or WBC< /L or Plat.< /L ; related to marrow involvement

11 First line treatment of follicular lymphoma in the 90 s: the wheel of fortune? Watch and wait Fludarabine Radiation therapy Chlorambucil Autotransplant CHOP Allotransplant CVP CHVP+IFN FC/FM

12 Traitements des lymphomes folliculaires Standards et options pour les patients avec faible masse et les stades localisés

13 1.0 GELF-86 OVERALL SURVIVAL 0.8 P = 0.88 Proportion Low Tumor Burden 0.2 No Treatment Prednimustine Years Interferon a At risk Brice et al., 1997, JCO

14 Retarder la mise en route d un traitement: surveillance armée Le Watch and Wait est une option acceptable sur le plan scientifique: chez des patients à faible risque 3 études randomisées temps médian pour début du traitement ~ 2 ans mais 15 à 20% des patients ne seront pas traités pendant 10 ans Oui, cependant Pas toujours facile à accepter pour le patient et sans doute pas à l origine de progrés

15 Radiothérapie dans les stades localisés (I-II) Study Nb of patients (% stage II) 10 years results (%) DFS OS BNLI 82 (57) BNLI 208 (0) Princess Margar 190 (45) 53 (12a) 58 (12a) Standford 177 (58) MD Anderson 80 (59) 41 (15a) 43 (15a) Royal Marsden 58 (31) DFS : Disease free survival OS : Overal survival

16 Ces patients irradiés sont-ils guéris? Barcelona data:. Continuous risk of relapse. FLIPI as a prognostic parameter in these patients Plancarte F at al., 2005

17 L irradiation est-elle supérieure au Watch and Wait? Advani et al, JCO, 2004

18 Rituximab as single agent in untreated low tumor burden FL patients 100 Response to treatment (n=49) 4 weekly infusions 375 mg/m Cheson d78 Best response Percentage ORR CR/Cru PR SD PD Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585)

19 Rituximab as single agent in untreated low tumor burden FL patients Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585)

20 100 USA maintenance schedule: progression-free survival Progression-free survival (%) Follicular/small cleaved Median PFS = 52.1 months Months Updated from Hainsworth J et al. J Clin Oncol 2002;20:4261 7

21 SAKK 35/98 study design FL = 202 MCL = 104 FL = 151 MCL = 61 Observation R Rituximab 375mg/m² weekly x 4 SD,PR,CR Prolonged Rituximab 375mg/m² every 2 months x 4 PD off study

22 SAKK 35/98: event free survival for FL (only randomised patients) 1.0 p-value: Standard (median: 12 m) Prolonged (median: 23 m) Event-free survival Ghielmini et al, Blood 103: , 2004

23 Tositumomab ( 131 I-B1) as first line treatment of FL patients CR rate : 75% Kaminski MS, NEJM 2005

24 Autres options chez des patients de faible risque? 1) Anti-CD20: - ttt d entretien: 3 essais en attente (RESORT, RWW, and SAKK) - doses élevées de rituximab? Autres anti-cd20? 2) Radio-immunotherapie: - disponibilité? Risques à long terme? 3) Associer le rituximab avec des cytokines, d autres Mabs, ou des agents immunomodulateurs? - IFN, GM-CSF, IL-2 (Davis 2000 ; Sacchi 2001 ; Kimby 2002 ; Bosly 2004, Cartron 2007) - Anti-CD22, -CD40, -CD80, etc - Lenalidomide = R2 regimen?

25 Traitements des lymphomes folliculaires Standards et options pour les patients de forte masse

26 Traitements des lymphomes folliculaires Ce que nous savons des essais menés avant les anticorps monoclonaux: Bénéfice des anthracyclines non démontré Place des analogues de purines discutée Effet positif de l interféron-α Pas de bénéfice évident de l autogreffe Peut-être un contrôle de la maladie meilleur pour les patients les plus graves Mais au prix d une toxicité peu acceptable

27 Cependant, l obtention d une RC au premier traitement semble importante Long term results of the GELF-86 trials Bachy et al, JCO in press

28 Immunochemotherapy in first-line indolent NHL: Four randomized trials Study name and author Randomized Patients Treatment M39021; Marcus et al FL CVP vs R-CVP GLSG; Hiddemann et al. 2,3 557 FL CHOP vs R-CHOP * M39023; Herold et al FL, MCL, LC MCP vs R-MCP ** FL2000; Salles et al FL CHVP IFN vs R-CHVP IFN * autotransplant or */ ** interferon as consolidation FL = follicular lymphoma MCL = mantle cell lymphoma LC = lymphoplasmacytic lymphoma 1. Marcus R, et al. Blood 2005; 105: Hiddemann W, et al. Blood 2005; August 25 (Epub). 3. Hiddemann W, et al. Blood 2004; 104:Abstract Herold M, et al. Blood 2004; 104:Abstract Salles G, et al. Blood 2004; 104:Abstract 160.

29 CVP versus R-CVP : time to treatment failure median follow-up 42 months Event-free probability R-CVP: median 27 months p< CVP: median 7 months Study month Patients at risk: CVP R-CVP

30 FL2000 study design Arm A R 6 months 12 months Staging including CT-scan and bone marrow biopsy Arm B D1 Cyclophosphamide 600 mg/m 2 D1 Doxorubicin 25 mg/m 2 D1 Etoposide 100 mg/m 2 D1-D5 Prednisone 40 mg/m 2 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 70 yr) Rituximab: 375 mg/m 2 Salles G, et al. Blood 2004; 104:Abstract 160.

31 FL2000: Event-free survival median follow-up 60 months Event-free survival Response duration Confirmation of the primary endpoint with 5 years of follow-up: improved outcome despite less chemotherapy Salles G, Blood 2008

32 Immunochemotherapy in first-line FL: Effect on overall survival Overall survival (%) Study name and author Follow-up Control Rituximab P M3902; Marcus et al. 1 4 years GLSG; Hiddemann et al. 2 5 years M39023; Herold et al. 3 4 years FL2000; Salles et al. 4 5 years (high risk pts) Cochrane analysis: HR=0.63 [ ] Schulz H et al. Cochrane Database Syst Rev Oct 17;(4):CD Marcus R, JCO Hiddemann W, ASH Herold M, JCO Salles G, Blood 2008

33 Fortes masses: Quelles voies de progrès?

34 Follicular lymphoma : the next steps? Other chemotherapy drugs? Fludarabine? Bendamustine? Combine with other Mab or cytokines 6 8 x R-CVP or R-CHOP Maintenance with rituximab? PRIMA study Intensify with high-dose or Rx-Ab? Ri-CHOP study ; SWOG study

35 Radio-immunotherapy consolidation after chemotherapy Progression-free and overall survival of 90 patients with bulky stage II to stage IV FL having received CHOP followed by tositumomab 131 I-B1 CR rate after CHOP+RIT : 69% Press O, JCO 2006

36 EU/Canada: FIT First line Indolent Trial 1st line follicular lymphoma Phase III consolidation study Newly diagnosed follicular NHL Stage III - IV Remission induction Chemotherapy* Start of Study CR /PR Ibritumomab 90 Y No further Treatment NR PD No inclusion * Left to the discretion of the treating physician, e.g. CLB, CHOP, CVP, Fludara etc. (incl. Rituximab after last protocol amendment) This study included MRD monitoring and QoL assesment

37 FIT Primary End Point: Median PFS in All Patients* Proportion remaining progression free (%) Control: median 13.5 mo n = 206 Zevalin: median 37 mo n = PFS time from randomization (months) Log rank P < HR Morchhauser et al, JCO 2008

38 Rationale fo rituximab maintenance Maintenance therapy against lymphoma more efficient in a state of minimal residual disase Long half life of the antibody in vivo Target level of 25 µg/ml 95% will have this level if the drug is given every 3 months Gordan et al, JCO 23: , 2005 Rituximab immunological mediated actions? ADCC Antigen presentation by dendritic cells?? Good safety profile of the antibody

39 PRIMA study Untreated Follicular NHL High tumour burden R-CVP x 8 or R-CHOP x 6 + 2R or R-FCM x 6 + 2R R CR/PR Rituximab maintenance: 1 dose every 8 weeks for 24 months 1018 patients 1217 patients Observation PD/SD off study An international Intergroup study conducted by the GELA

40 PRIMA: An international collaborative effort

41 Résultats de PRIMA? Soumis à l ASH 2009 : RITUXIMAB MAINTENANCE FOR 2-YEARS SIGNIFICANTLY IMPROVES THE OUTCOME OF PATIENTS WITH UNTREATED HIGH TUMOR BURDEN FOLLICULAR LYMPHOMA AFTER RESPONSE TO IMMUNOCHEMOTHERAPY: RESULTS OF THE PRIMA STUDY.

42 Maintenance : questions to be solved? Optimal scheme? How long should rituximab maintenance be given? Safety of rituximab maintenance? Characteristics of patients relapsing during / after rituximab maintenance? Re-treatment after maintenance?

43 Other chemotherapy (purine analogues?) German study Follicular lymphoma: next steps? Other drugs? Targeted therapies? Combine with cytokines (lenalidomide, bortezomib, ) (IFN, GM-CSF) Vaccines 6-8 R-CVP or R-CHOP Intensify using ASCT Ri-CHOP study Role of PET?? Maintenance with rituximab? PRIMA study Consolidate using RIT? next generation FIT anti-cd20?

44 Traitements des lymphomes folliculaires Les choix thérapeutiques en rechute Que veut-on obtenir? Quels outils, quels bénéfices? Quelles voies de progrès?

45 Au moment de la rechute, le choix thérapeutique devient complexe Possibilités thérapeutiques: Ne rien faire et surveiller (W&W) Le rituximab en monothérapie Les Ac radiomarqués Les agents alkylants en monothérapie Les combinaisons de type (FCM, DHAP, MIV ) L autogreffe Entretien par rituximab après une seconde ligne L allogreffe Essais thérapeutiques et nouvelles drogues Bendamustine Nouveaux anticorps (anti-cd20, autres) Immunoconjugués (CMC542) Inhibiteurs du protéasome Immunomodulation, Anti-BCL2.

46 Le cas particulier des transformations histologiques Bachy et al, JCO 2009 in press

47 Faut-il réadministrer du rituximab? First treatment 9.8 months Davis TA, et al. J Clin Oncol 2000;18: Second treatment 16.3 months Time (months) Pas d études publiées «démonstratives» - Suggestion d un bénéfice sur cohortes historiques (Johnson et al.) - Pas de bénéfice évident dans rechutes FL2000 (Le Gouill et al.)

48 Phase II prospective R-FM study in relapsing FL patients ORR 84% ; CR/CRu 68% Progression Free Survival (median = 33 months) Overall Survival Morschhauser et al, submitted

49 Intergroup phase III trial: study design 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* *375mg/m 2 every 3 months for 2 years or until relapse

50 EORTC Intergroup phase III trial PFS from 2nd randomization Subgroups according to induction treatment 100 Progression free survival CHOP induction After response to CHOP induction 100 Progression free survival R-CHOP induction After response to R-CHOP induction Overall Logrank test: p< Hazard ratio: 0.37 median: 36.8 months median: 52.7 months med months 10 0 (years) O N Number of patients at risk : Treatment Observation Rituximab med months 10 Overall Logrank test: p= Hazard ratio: 0.69 (years) O N Number of patients at risk : Treatment Observation Rituximab

51 EORTC Intergroup phase III trial Overall survival from 2nd randomization R-maintenance 5 yrs 74% observation 5 yrs 65 % Overall Logrank test: p= (years) O N Number of patients at risk : Treatment Observation Rituximab

52 Autogreffe en rechute dans le GELF-86 E Bachy et al. In press

53 Autogreffe et rechutes FL2000 Event Free Survival Overall Survival Après CHVP I P=.002 Après R CHVP I P= % [30% ; 65%] vs 75 % [41% ; 91%]

54 The Role of Autologous and Allogeneic Transplantation for Follicular Lymphoma I favor using autologous transplantation for patients with high-risk disease who have early relapse following conventional therapy Low NRM (<5%) Risk of MDS/AML with TBI regimens May provide long term disease free survival Conditioning regimens including immunotherapy (radioimmunotherapy or Rituximab) promising Nonmyeloablative allogeneic transplantation provides a potentially curative therapy NRM is significant (15-25%) May provide salvage even following failed autologous transplant D Maloney 4 th Eur Cong Hematol Malignancies

55 A marked improvement in FL patients outcome pre 1990 Median OS post Years NR SEER 1 Stanford 2 MDACC 3 pre 1990 Probability of OS post 1990 SWOG (4-year) 4 MDACC (5-year) 3 GELA (10-year) % patients 1. Swenson, J Clin Oncol 2005; 23: Tan, Blood 2007; 110:3428A. 3. Liu, J Clin Oncol 2005; 24: Fisher, J Clin Oncol 2005; 23: Sebban, J Clin Oncol 2008; 26:

56 Follicular lymphoma: What do we want to achieve? Patient wishes Palliation Chronic disease Repeat treatments Healthcare costs Quality of life High response rate Prolonged response Long disease-free intervals Histological transformation Long-term side effects Improved survival

57 Les Ateliers Lymphomes et LLC octobre 2009 Le Moulin de la Forge Le Vaumain (60)