Traitement des lymphomes diffus à grandes cellules B

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1 Traitement des lymphomes diffus à grandes cellules B Corinne HAIOUN Unité Hémopathies Lymphoïdes- CHU Henri Mondor Université Paris Est Créteil DES Hématologie Février 2012 On February 10th, the merging of the GELA and the Goelams lymphoma groups resulted in the birth of the new group Lysa. Lysa, The Lymphoma Study Association

2 Don t miss the first line treatment Lessons from CORAL trial, Pts<60 yr, salvage treatment According to prior rituximab According to prior rituximab Failure <12 mo after diagnosis Gisselbrecht C et al. JCO 2010;28:

3 CHOP-21 was a Gold Standard It was associated with a good efficacy It was easy to use It gave reproducible results But long terms results are insufficient and improvements were needed Overall survival (%) CHOP MACOP-B ProMACE-CytaBOM m-bacod Years R. Fisher N Engl J Med 1993;328:1002

4 Aggressive lymphoma: International Prognostic Index overall survival by IPI risk group The International Non-Hodgkin s Lymphoma Prognostic Factors Project, NEJM 1993 adverse parameters: age > 60y PS >1 III-IV stage LDH >1N EN sites >1 age-adjusted IPI (<60y or >60y): PS>1 III-IV stage LDH >1N L LI HI years H FR

5 Did me made any progress since 1990? Attempts to improve the therapeutic results achieved with CHOP:. Before dose dense therapy - high dose therapy. After combine chemo with anti-cd20

6 Some regimens were able to demonstrate superiority over CHOP Dose dense (CHVmP-VB, CHOP-14, CHOEP) Dose intense (ACVBP) Consolidation with High Dose Therapy supported by ASCT Education Book, EHA 2008

7 n= 635; 60-70y aa-ipi 1= 35% aa-ipi 2= 43% aa-ipi 3= 23% The LNH 93-5 Study: ACVBP compared to CHOP ACVBP R CHOP MTX IFM - VP16 ARA-C week week % survival 100 % survival DFS 80 Survival 60 ACVBP 60 ACVBP CHOP p= years 20 CHOP p= years Tilly et al, Blood 2003

8 Randomized study of CHOP-21 / CHOP-14 / CHOEP-21 / CHOEP-14 Young patients Elderly patients Multivariate analysis for overall survival P = NS P < M Pfreundschuh Blood 2004 & 2004

9 Superiority of autotransplant in patients with HI/High IPI risk index. aa-ipi 2-3 : n = 236 aa-ipi 2 : n = 105 % survival N =49 Auto (BEAM) 74% % CBV + auto chemotherapy 49% P =.04 p = CHOP 44% Months Overall survival Overall survival Haioun C. et al J Clin Oncol 16:3025, 2000 Milpied N, et al. New Engl J Med 2004; 350:1287

10 Since 2000, a major change: R-CHOP as a new standard

11 Rituximab plus CHOP versus CHOP in elderly patients with DLBCL LNH 98.5 study: Design Rituximab: 375 mg/m 2 on day 1 Cyclophosphamide: 750 mg/m 2 on day 1 Doxorubicin: 50 mg/m 2 on day 1 Vincristine: 1.4 mg/m 2 (up to 2 mg/m 2 ) on day 1 Prednisolone: 40 mg/m 2 /d days 1 5 DLBCL Age years No prior treatment PS 0 2 Stage II IV R A N D O M I Z A T I O N Rituximab + CHOP q3wk x 8 CHOP q3wk x 8 Coiffier B, et al. N EnglJ Med2002; 346:235.

12 LNH 98.5 study: Treatment responses P = patients 202 patients Coiffier B, et al. N EnglJ Med2002; 346:235.

13 LNH98-5: median follow-up 7 years EFS PFS DFS OS

14 MInT: trial design CD20 + DLBCL years IPI 0, 1 Stages II IV, I with bulk * CHOP-21 (n = 396) CHOEP-21 (n = 362) MACOP-B (n = 33) PMitCEBO (n = 32) Randomization 6 x CHOP-like* Gy (Bulk, E) 6 x CHOP-like* + rituximab Gy (Bulk, E) M Pfreundschuh Lancet Oncol 2006;7:379

15 MInT study Event-Free Survival Progression-Free Survival Overall Survival M Pfreundschuh Lancet Oncol 2006;7:379

16 R-CHOP: reproducibility of the benefit Probability 1.0 MInT study British Columbia R-chemotherapy Chemotherapy Post-rituximab Pre-rituximab p= p= Months Years Survival TTF CHOP R-CHOP ECOG study 3 Maintenance Observation Years MInT = MabThera International Trial ECOG = Eastern Cooperative Oncology Group TTF = time-to-treatment failure FFS = failure-free survival FFS p= RiCOVER study 4 R-CHOP-14 CHOP Months 1 Pfreundschuh M, et al. Lancet Oncol 2006;7: Sehn LH, et al. J Clin Oncol 2005;23: Habermann T, et al. J Clin Oncol 2006;24: Pfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of print

17 Optimizing the use of anti-cd20 monoclonal antibodies Risk adapted treatment in the R-CHOP era

18 Optimizing the use of anti-cd20 monoclonal antibodies Patients with localized disease Do we still need radiation therapy in the R-CHOP context?

19 GOELAMS clinical trial yrdlbcl witha I-II, no bulk(<7cm) and adjustedipi 0-2 Days DIAGNOSIS Biological protocols RANDOMIZATION Granocyte + Neorecormon C C C C EVALUATION PET Scan positive PET IPI 1 C C C C Radiotherapy40Gy initial site STOP STOP At diagnosis : 1) IPI scoring 2) One initial randomization ( IR ) CR PETneg IPI = 0 IR Radiotherapy40Gy initial site STOP C STOP R-CHOP 14

20 LNH93-1 study: ACVBP ACVBP ACVBP Metho Ifosf+Eto AraC ACVBP regimen versus CHOP plus radiotherapy R CHOPCHOP CHOP RADIOTHERAPY involved field Weeks Weeks 90 n = 318 IPI=0, age < 60 y median f-up: 6.3 y. event-free survival stratified log rank p = n = 329 ACVBP arm Reyes F. et al NEJM CHOP arm Years

21 LNH03-1B aaipi=0, <60 yr R-ACVBP + sequential consolidation, no radiotherapy 3 yr= 93% (CI 87-97) 3 yr= 98% (CI ) PFS OS Ketterer N, ICML Lugano 2011

22 LNH 93-4 study: IPI=0; >60y R CHOP X 4 CHOP X 4 + IF RT - Identical CR rates - More secondary cancers with RT C Bonnet, J Clin Oncol 2007 Probability of Event Free Survival Probability of Overall Survival y EFS: 64% 5y EFS: 61% P = 0.5 median f-up= 7y CHOP plus radiotherapy CHOP n=299 n= Years after Randomization P = 0.5 5y OS: 72 % 5y OS: 68 % median f-up= 7y CHOP n=277 CHOP plus radiotherapy n= Years after Randomization

23 LNH03-1B aaipi=0, <60 yr R-ACVBP + sequential consolidation, no radiotherapy 3 yr= 93% (CI 87-97) 3 yr= 98% (CI ) PFS OS

24 420 patients needed LNH 09-1B < 80 yr, aa-ipi = 0 NEG POS 2 RCHOP21 2 RCHOP21 2 RCHOP21 R 2 RCHOP21 STOP withdrawal 2 RCHOP21 withdrawal 2 RCHOP21 2 RCHOP21 PET C0 PET C2 PET C4 PI: Bologna S, JN Bastie

25 Optimizing the use of anti-cd20 monoclonal antibodies Young patients with favorable characteristics Is dose intensity an option?

26 GELA-LNH 03-B program Trials according to age and age-adjusted IPI Inclusions from 2003 to 2009 age aa-ipi LNH03-1B R-ACVBP vs LNH03-2B R-ACVBP vs LNH03-3B R-ACVBP+PBSCT ACVBP R-CHOP LNH03-6B >80 LNH03-7B

27 LNH 03-2B study <60 yrs, aaipi = 1 MTX R-IFM-VP16 Ara-C R-ACVBP 14 R Wks 4 IT-MTX No radiotherapy Wks R-CHOP 21 RecherC et al. Lancet 2011

28 R-ACVBP INDUCTION R-ACVBP (every two weeks) PDN: 60 mg/m 2 ; d1-d5 Rituximab: 375 mg/m 2 ; d1 MTX R-IFM-VP16 Ara-C Doxo:75 mg/m 2 ; d1 CPM: 1200 mg/m 2 ; d1 Vindesine: 2 mg/m 2 ; d1 & d5 Bleomycin10 mg ; d1 & d5 G-CSF 5 µg/kg/d; d6-d Wks R-ACVBP 14 Dose Intensity mg/m 2 per week Doxo: 37,5 CPM: 600 Rituximab: 187 R-ACVBP x 2.25 x 2.4 x 1.5 Doxo: 16.7 CPM: 250 Rituximab: 125 R-CHOP

29 Hematological toxicity (grade 3) R-ACVBP R-CHOP

30 Progression-Free Survival R-ACVBP R-CHOP p=0.0015, HR The 3-y PFS was 87% (95% CI, 81-91) in the R-ACVBP arm and 73% (95% CI, 66-79) in the R-CHOP arm

31 Overall Survival R-ACVBP R-CHOP p=0.0071, HR The 3-y OS was 92% (95% CI, 87-95) in the R-ACVBP arm and 84% (95% CI, 77-89) in the R-CHOP arm

32 Optimizing the use of anti-cd20 monoclonal antibodies Young patients with unfavorable characteristics Still a real challenge!

33 Superiority of autotransplant in patients with HI/High IPI risk index. aa-ipi 2-3 : n = 236 aa-ipi 2 : n = 105 % survival N =49 Auto (BEAM) 74% % CBV + auto chemotherapy 49% P =.04 p = CHOP 44% Months Overall survival Overall survival Haioun C. et al J Clin Oncol 16:3025, 2000 Milpied N, et al. New Engl J Med 2004; 350:1287

34 GELA-LNH 03-B program age aa-ipi LNH03-1B R-ACVBP vs LNH03-2B R-ACVBP vs LNH03-3B R-ACVBP+PBSCT R-ACVBP R-CHOP LNH03-6B >80 LNH03-7B

35 Role of chemotherapy dose intensity in the context of immunochemotherapy? Improving ASCT upfront with Rituximab pre transplant LNH 03-3B Rituximab R R R R Doxorubicin 75mg/m² d1 Cyclophosphamide 1 200mg/m² d1 Vindesine 2mg/m² d1, d5 Bleomycin 10mg d1, d5 Prednison 60 mg/m² d1 to d5 MTX intra-thecal 15mg d2 G-CSF 5µg/kg d6 to d13 wk A C V B P A C V B P A C V B P A C V B P PBPC collection MTX 3g/m² BEAM + ASCT Fitoussi 0, Belhadj K, Hematologica 2011

36 LNH 03-3B Survival analysis 75% 81% PFS OS Fitoussi 0, Belhadj K, Hematologica 2011

37 Matched control study : Progression free survival 75% R-ACVBP 60% ACVBP PFS study N Median Min Max Follow-up (months) LNH Follow-up (months) LNH

38 Optimizing the use of anti-cd20 monoclonal antibodies Other option: risk adapted treatment

39 PET-scan in DLBCL:.. a tool for response assessment 2 cycles 4 cycles Value of interim PET in DLBCL.. 2 cycles 4 cycles.. Good responder Poor responder Haioun C, et al. Blood 2005; 106(4):

40 Role of PET to individualize treatment? Interim PET after 2 cycles may help stratify patients? Probability Event-free survival PET (n = 54) PET+ (n = 36) p < Overall survival PET (n = 54) PET+ (n = 36) p = Years after randomisation Years after randomisation Pprobability Haioun C, et al. Blood 2005

41 Visual vs. quantitative analysis 2 cycles, n=92 Visual analysis (Créteil, MRU) Quantitative analysis (% reduction SUVmax) Probability of EFS PET2 (-) PET2 (+) P =.009 > 65.7% ROC analysis yielded an optimal cutoff value of 65.7% SUVmax reduction after 2 cycles for predicting EFS. 65.7% P <.0001 Months after inclusion Months after inclusion Lin, Itti et al. J Nucl Med 2007;48:

42 To be applicable, quantitative criteria requires a baseline PET Which threshold acceptable for minimal residual uptake?

43 Five-point scale (Deauville and Menton workshops) 1. no uptake 2. uptake mediastinum 3. uptake > mediastinumbut liver 4. uptake > liver at any site 5. uptake >>liver ±new sites of disease Meignan, et al. Leuk Lymphoma 2009 Barrington, et al. Eur J Nucl Med Mol Imaging 2010 Meignan Eur J Nucl Med Mol Imaging 2010

44 LNH B DLBCL: y, aaipi=2-3 PET Results 2± / 4+ Salvage therapy R-ACVBP14 + MTX IT + G-CSF A1 MTX iv R - IFOSFAMIDE-VP AraC SC Arm A A2 2- / 4- MTX iv Z-BEAM + ASCT PET 0 R PET 2 PET 4 2+ / 4- Arm B B2 2- / 4- R-CHOP14 + MTX IT + G-CSF B1 R-CHOP14 + G-CSF 2± / 4+ Salvage therapy RO Casasnovas, Blood 2011

45 End Treatment Evaluation

46 LNH B PET review Planned real time central PET review: PET0, PET2 and PET4 mandatory Central PET review by 2 experts PET Interpretation according to IHP criteria (M.Juweid et al, J.Clin.Oncol 2007; 25: 571) Additional exploratory PET analysis using quantitative criteria (SUVmax reduction) Comparison of visual and quantitative PET results

47 LNH B SUVmax for interim PET assessment Baseline PET (PET0): SUVmax in the most active lesion Interim PET: If (+): SUVmax in the most active lesion If (-): SUVmax in the area of PET0 tumor Calculation of % of SUVmax reduction (Lin et al J. Nucl Med 2007; 48: ) Optimal cut-off determined by ROC 66% for SUVmaxPET0-2 70% for SUVmaxPET0-4

48 LNH B PFS according to PET2 results Visual Analysis (IHP) PET2- SUVmax PET0-2 SUV>66% PET2+ SUV 66% P = 0.59 P <0.03

49 LNH B OS according to PET2 results Visual Analysis (IHP) PET2- PET2+ SUVmax PET0-2 SUV>66% SUV 66% P = P <0.0001

50 GOELAMS 075

51 Survival according to the Tx Arm (Intent to treat) 1,0 0,8 R-CHOP 0,6 R-HDT Survie cumulée 0,4 3 y OS R-CHOP: 87 % (+/-3 %) 3 y OS R-HDT: 80 % (+/-4%) 0,2 p= ,0 0,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 Mois Milpied et al. ASH 2010

52 Optimizing the use of anti-cd20 monoclonal antibodies How to improve further such results? risk adapted treatment Other anti-cd20 mabs?

53 GA101: A glycoengineered anti-cd20 antibody Type II antibody Low CDC Low fucose content ADCC Elbow hinge substitution Cell death Clone B-Ly1 ADCC = antibody-dependent cellular cytotoxicity; CDC = complement-dependent cytotoxicity. Umaña P, et al. Ann Oncol 2008; 19:Abstract 098. Umaña P, et al. Blood 2006; 108:Abstract 229.

54 GA In NEwly Diagnosed DLBCL GAINED LNH B DLBCL, 18-60y, aaipi= 1-3: Phase III 2 arms CHEMO14 according to center decision: - ACVBP14 - CHOP14 R Arm A Arm B Induction R-CHEMO14 C1 C2 C3 C4 GA101-CHEMO14 C1 C2 C3 C4 PET results SUV0-4 70% 4+ SUV0-4 >70% 4- SUV 0-2 > 66% 2-/4- A B consolidation Salvage therapy Accordingto randomization arm and CHEMO14 regimen R-CHOP-14 x 4 MTX / R-VP-IFOSFAMIDE / Arac MTX / GA101-VP-IFOSFAMIDE / Arac GA101-CHOP-14 x 4 GA101: 1000mg by injection D1-D8 cycles 1-2 PET 0 PET 2 PET 4 SUV % 2+/4- MTX BEAM + ASCT

55 Optimizing the use of anti-cd20 monoclonal antibodies patients over 60 years How can we improve R-CHOP results?

56 LNH98-5: Overall survival according to age years years years year OS (%) CHOP R-CHOP

57 R-CHOP benefit to low and high risk patients > 60 y. Low-risk Progression-free survival High-risk Low-risk High-risk Overall survival

58 RICOVER 60: trial design 80% with DLBCL 60% IPI x CHOP Gy (Bulk, E) CD20 + DLBCL stages I IV years Random 2x2 Factorial design 8 x CHOP Gy (Bulk, E) 6 x CHOP Gy (Bulk, E) + 8 x rituximab 8 doses of rituximab regardless of number of cycles of chemotherapy 8 x CHOP Gy (Bulk, E) + 8 x rituximab Pfreundschuh M, Lqncet Oncol 2008

59 RICOVER-60: results Event-free survival Overall survival Proportion x CHOP x R 8 x CHOP x R 8 x CHOP x CHOP x R 8 x CHOP x R 8 x CHOP-14 6 x CHOP x CHOP Months Months Pfreundschuh Lancet Oncol 2008

60 LNH 03-6B years, IPI > 0 4 MTX IT Rituximab R-CHOP-21 CHOP Week R * Additional randomisation for darbepoetin prophylaxis Week R-CHOP-14 4 MTX IT Delarue R et al, ASCO 2012 submitted

61 Progression-free survival 3y-PFS : 60% vs 62% HR: 0.99 (95%CI: ); p=0.94

62 Overall survival 3y-OS : 69% vs 72% HR: 0.93 (95%CI: ); p=0.76

63 REMARC - Design Induction Maintenance Registration R- CHOP x 8/ y - aaipi 1 - PR after 6 or 8 cycles of R-CHOP 14 or 21 SD, PD Off study S T R A T I F I C A T I O N R A N D O M I Z A T I O N Lenalidomide 25mg / day Placebo C Thieblemont, B Coiffier

64 Optimizing the use of anti-cd20 monoclonal antibodies patients over 80 years How can we improve results?

65

66 N = 131, primary de novo DLBCL +13 % / 10 ans

67 Rationale in DLBCL after the age of 80 10,00 9,00 8,00 7,00 6,00 5,00 4,00 3,00 2,00 1,00 0,00 Life expectancy regarding age in western E(x) europe E(x) age Rate of Patients aged over 80 in western europe 2010: 7.8% 2030: 12% 2050: 15.6% To conduct a large prospective phase II study to assess the efficacy and safety of the association of a standard dose of rituximab with a reduced dose of chemotherapy in this population

68 LNH 03-7B Phase II R-miniCHOP Age > 80 years Diffuse large B-cell lymphoma No previous treatment All stages and IPI Performance status 0 to 2 R - minichop Prednisone Rituximab Doxorubicin Cyclophosphamide Vincristine GCSF OPTIONAL Dose 40 mg/m² 375 mg/m² 25 mg/m² 400 mg/m² 1 mg DT R-miniCHOP R-miniCHOP Inclusion 3 w 3w 3 w 3 w 3 w 4 w 3 months C1 C2 C3 C4 C5 C6 FU0 FU1 FUn RESPONSE RESPONSE Primary endpoint: overall survival F Peyrade, Lancet Oncol 2011

69 Response at the end of the treatment Intent-to-treat population RESPONSE N (149) % Complete response Unconfirmed complete response Partial response Stable disease 2 1 Progression during treatment 8 2 Death Not evaluated 3 2 According to Cheson 1999

70 Primary endpoint: Overall survival Intent-to-treat population Median FU: 20 months Median OS: 29 months At two years: 59%( CI: 49-67) F Peyrade, Lancet Oncol 2011

71 Univariate Analysis / Overall Survival Albumin level >35 g/l <=35 g/l P = Albumin is the single statistically significant prognostic factor in a multivariate analysis

72 LNH 09-7B OmCHOP phase II PRE-PHASE INDUCTION PHASE (for PS 1,2 patients) CONSOLIDATION PHASE 9 weeks 10 weeks Oncovin Prednisone O-miniCHOP O-miniCHOP Tout stades Tout IPI I 1 w 3 w 3 w 3 w 3 w 3 w 4 w C1 C2 C3 C4 C5 C6 FU0 3 months FU1 FUn Clinical evaluation RESPONSE RESPONSE PS 3,4 PS 1,2 Patient withdrawal

73 The next challenges in aggressive lymphoma 1. A marked and reproducible improvement has been achieved with rituximab: R-CHOP is a standard Is it possible to maximize its benefit through adaptations of doses, schedule, chemo regimen, etc? 2. Other promising molecules are coming in clinical trials: Dedicated multi-centric clinical trials are important 3. Tools to further delineate molecularly defined disease may soon become available: To Identify patients subgroups that may benefit from targeted therapies