Dr. A. Van Hoof Hematology A.Z. St.Jan, Brugge. ASH 2012 Atlanta

Transcription

1 Dr. A. Van Hoof Hematology A.Z. St.Jan, Brugge ASH 2012 Atlanta

2 DLBCL How to improve on R-CHOP What at relapse Mantle cell lymphoma Do we cure patients Treatment at relapse Follicular lymphoma Watch and wait still possible? Do we need chemo? T cel lymphoma First line treatment: need to improve Treatment at relapse Hodgkin lymphoma Early stages: RT yes or no? Advanced stages New drugs

3 How to improve on R-CHOP Dose intensity? R-ACVBP Adding something to R-CHOP Bortezomib (in case of non-germinal center phenotype)? Lenalidomide? Bevacizumab? autosct as consolidation?

4 R-CHOP versus R2CHOP: phase II study

5 Agressive B cell NHL subtypes to treat differently double hit lymphoma Primary mediastinal B cell lymphoma Testicular lymphoma Primary CNS lymphoma Gray zone lymphoma Burkitt lymphoma/leukemia

6 Primary mediastinal B cell NHL R-CHOP Radiotherapy? Retrospective data: no RT if PET negative after R-CHOP Prospective trial ongoing (IELSG-27)

7 Burkitt NHL/leukemia: GMALL : 363 adult patients (15 y+) Overall survival: 15 -< 25 y 91 % 26 - < 55 y 91 % > 55 y 80 %

8 Relapsed DLBCL Is autologous SCT still helpful? Only % of pts benefit from procedure Prognostic markers : worse if Early relapse High secondary IPI score ABC subtype Better conditioning? Radio-chemo maintenance? Rituximab no effect Allo SCT? Alternatives? Ibrutinib: only ABC subtype New antibody/drug conjugates: phase I data CD22 antibody/drug (MMAE) conjugate CD79B antibody/drug (MMAE) conjugate

9 Prognostic markers at relapse Outcome of relapsed DLBCL: GC better with R-DHAP

10 Mantle cell lymphoma Can we cure young patients? Eliminate R-CHOP? What after relapse?

11 MCL younger Protocol Design 4 x R-CHOP 2 x R-CHOP DexaBEAM (stem cell mobilization) Cyclo 120mg/kg + TBI 12 Gray PBSCT PR, CR (2+1) x R- CHOP/R-DHAP alternating stem cell mobilization after course 6 TBI 10 Gray Ara-C 4x1.5 g/m2 Melphalan 140 mg/m2 PBSCT 11

12 Remission Duration after ASCT ARM R-DHAP 81% 76% 74% R-CHOP 67% 53% 44% 12 Update September 26, 2012, European MCL Network, V

13 Remission Duration according to MRD Status after Induction - pooled Arms - n = 142

14 Achievement of MR post Induction is an Independent Prognostic Factor Variable HR 95% CI p Molecular Response 2.4 ( ) MIPI score 1.7 ( ) Treatment arm 0.6 ( ) 0.1 CR 0.9 ( ) 0.68

15 LyMa trial LYMA trial (closed sept 12) Scan MRD BM and PB FDG-PET (option) Scan MRD monitoring BM and PB FDG-PET (option) W1 W4 W7 W10 R-DHAP R-DHAP R-DHAP R-DHAP R-BEAM OBSERVATION Scan MRD monitoring (PB) MRD monitoring (BM) FDG-PET (option): M2 and 12 If < VGPR R-CHOP If > VGPR RITUXIMAB MAINTENANCE every 2 months during 3 years R-DHAP: Rituximab 375mg/m2 d1 (except for C1 where R is to be started at d4); aracytine 2g/m2 x2 IV 3 hours injection 12hours interval; dexamethasone 40mg d1-4; Cisplatin 100mg/m2 d1 (or oxaliplatinum or carboplatinum) R-BEAM: Rituximab 500mg/m2 d-8; BCNU 300mg/m2 d-7; Etoposide 400mg/m2/d d-6 to -3; aracytine 400mg/m2/d d-6 to d-3; melphalan 140mg/m2 d-2

16 MRD Level (RQ-PCR) MRD quantification during the course of treatment MRD during course of treatment Peripheral Blood Bone marrow High level positive 10-5 (+) NEG 9.4% 2.8% 19.8% 19.8% 0% 79.2% 95.3% 0% 64.4% 78.1% Low level positive Negative Diag (n=112) R-DHAP (n=106) Post-ASCT (n= 106) Diag (n= 91) R-DHAP (n=101) Post-ASCT (N= 96) MRD neg : 64.5% in post-induction and 79% after ASCT

17 Response prior/after ASCT in multicentric studies Response prior/after SCT - Response rates after only 4xR-DHAP followed by ASCT (without TBI in the conditioning regimen) compares favorably with other chemotherapy regimens. - Taken together, these results highlight the major roles of HD-Arac and ASCT in disease control in MCL - However, the impact in term of EFS, PFS and/or OS of these results need to be investigated.

18 European MCL network: future plans Young patients: after R-CHOP/R-DHAP Low risk (low MIPI) and MRD negative: Auto-SCT versus Ibrutinib maintenance - Intermediate/high risk MIPI - Auto SCT - Randomisation rituximab versus ibrutinib

19 European MCL network Older patients: Elderly trial published in NEJM in aug 2012: value of rituximab maintenance New trial planned: R-CHOP/R-HAD Randomisation: Rituximab maintenance Rituximab and lenalidomide maintenance Company trial: addition of ibrutinib to Benda- R, with 2 years rituximab maintenance

20 Relapsed MCL: lenalidomide (Emerge study, after bortezomib ) Parameter (n = 134) ORR 28 % CR/CRu 8 % PR 20 % DOR,mo 16.6 TTP 5.4 PFS 4.0

21 Relapsed MCL: ibrutinib efficacy Bortezomibnaive (63) Bortezomibexposed (46) Total (109) ORR 65.1 % CR PR Time to PR: months Time to CR: months (median 3.9) Initial 51 pts: CR 35.3 %

22 Relapsed MCL: GS-1101(idelalisib) Monotherapy In combination with temsirolimus In combination with PD (early G1-arrest by CDK4/CDK6 inhibition)

23 Follicular lymphoma Can we still advise watch and wait? Do we still need chemo? immunochemotherapy immunomodulation only?

24 Rituximab versus Watch and Wait (RWW trial)

25 Time to start new treatment in RWW trial No difference in overall survival

26 Do we still need chemo? Immunochemotherapy: R-CHOP or R-Benda? New monoclonal antibodies and conjugates: ofatumumab obinutuzumab (GA101) GAUDI CD22 antibody/drug (MMAE) conjugate CD79B antibody/drug conjugate Only immunomodulation? Rituximab and lenalidomide (R2)

27 Bright: BR versus R-CHOP or R-CVP

28 GA101-CHOP: GAUDI (first-line FL) Response rate at end of induction: G-CHOP: 95 % G-Benda 92,7 % PR 60% 53.7% CR 35% 39% G-CHOP G-Benda * Unconfirmed CRs were classified as PRs Dyer MJS, et al. ASH 2012; Abstract 3686 (poster).

29 Only immunomodulation: lenalidomide and rituximab Phase III study starting: RELEVANCE ClinicalTrials.gov Identifier: NCT Estimated Enrollment:1000 Start Date:November 2011 Estimated Study Completion Date:June 2024

30 Hodgkin lymphoma Early stages (I/IIa, non bulky): do we need Radiotherapy? Advanced stages: ABVD or BEACOPPesc New drugs

31 Early stages: RAPID trial 602 pts -3 x ABVD % PET neg after 3 x ABVD - Non bulky! - PET negative: Score 1-2

32 Early stages: RAPID trial radiotherapy is unnecessary in 75 % of patients with stage I/IIA who become PET negative after 3 cycles of ABVD

33 Early stages, H10 study (GELA/EORTC) H10F R 2 ABVD 2 ABVD P E T P E T - or ABVD+IN-RT 30 Gy (+6) A: NON - INFERIORITY 2 ABVD 2 BEACOPPesc+IN-RT 30(+6) H10U R 2 ABVD 2 ABVD P E T P E T - or ABVD+IN-RT 30 Gy (+6) B: NON - INFERIORITY 4 ABVD 2 BEACOPPesc+IN-RT 30(+6) Primary endpoint : Progression-free survival

34 Early stages: GELA/EORTC H10 Group A (favourable) Standard Experimental Events 1 9 Relapse 1 9 Death w/o relapse 0 0 Group B (unfavourable) Standard Experimental Events 7 16 Relapses 7 15 Death w/o relapse 0 1

35 Based on this interim analysis of PFS: The objective of non-inferiority of chemotherapy alone as compared to combined therapy has not been met

36 Early stages non bulky I/IIa: meta analysis TTP superior for combined modality therapy vs chemotherapy alone, with similar trend in PFS Greatest benefit for patients who fail to achieve CR after 2 cycles ABVD

37 Hodgkin lymphoma: advanced Meta analysis : BEACOPPesc x 6 is best treatment option for overall survival? 77 publications pts Low number: sec malignancies leukemia

38 Hodgkin lymphoma: advanced Brentuximab vedotin combined with ABVD or ABV in first line treatment - Bleomycin to be avoided: pulmonary toxicitiy - in combination with AVB: mg/m2 per dose - 24/26 pts PET negative after 2 cycles - 92 % complete remission after treatment

39 T- cell NHL First line treatment: better than CHOP? Treatment of relapsed patients

40 T-NHL: first line treatment ACT-1 study: CHOP versus CHOP-campath and autosct: ongoing, extended until end 2013; 110 included ACT-2 study: CHOP versus CHOP-campath: stop mid 2013; 98 included CHOP versus RomidepsinCHOP: starting CHOP and brentuximab vedotin in salcl and other CD30+NHL

41 Proportion Proportion ACT-1 Response rates and time-related end-points Response rates Response rates N (%) ORR 42 (67) CR/CRu 38 (61) PR 4 (6) SD 3 (5) PD 16 (25) Not evaluable 2 (3) Total 63 (100) 15 mo median followup Time-related end-points EFS End-point Primary Months 1-yr (95% CI) EFS 55% (42-67) PFS 54% (42-67) OS 78% (67-88) Secondary PFS Months OS

42 Brentuximab vedotin in first line, high risk salcl and other CD30+ NHL Inclusion: High risk salcl: ALK negative or ALK pos with IPI > 2 (73 %) Other CD30+ T and NK NHL Treatment: Brentuximab (1.8 mg/kg)-chp/3 weeks x 6 Brentuximab maintenance in responders x 8 10 cycles 100 % response rate 88 % CR rate

43 Relapsed T-cell NHL: approved agents in US

44 Update: romidepsin in relapsed T-NHL Single-Agent Romidepsin Associated With Durable Responses in Patients With Relapsed/Refractory Peripheral T-Cell Lymphoma

45 Lenalidomide in relapsed T-NHL

46 Alisertib (MLN8237)

47 Brentuximab vedotin in relapsed salcl Key data: 60 % durable remission No influence of ALK status on PFS

48 Take home messages DLBCL R-CHOP21 still the best, different approach for some subtypes; add something to R-CHOP? relapse: R-DHAP for GC subtype; ibrutinib only for ABC subtype; better solutions needed Follicular lymphoma: Watch and wait still possible R-CHOP with maintenance Rituximab preferred, R-Benda possible equally efficient, less toxic Future is less toxic immunomodulation Mantle cell: High dose AraC essential if tolerated Relapse: ibrutinib? T cell: CHOP not very good; brentuximab first line for CD30+? Alisertib? Hodgkin Early stages, non bulky: RT needed? Advanced stages: BEACOPPesc x 6 preferred Brentuximab in first line?