Lymphoma Christophe BONNET Centre Hospitalier Universitaire, Ulg, Liège. 14 th post-ash meeting, January 6 th 2011, Brussels

Transcription

1 Lymphoma Christophe BONNET Centre Hospitalier Universitaire, Ulg, Liège 14 th post-ash meeting, January 6 th 2011, Brussels

2 Hodgkin s lymphoma Follicular lymphoma Diffuse large B-cell lymphoma Mantle cell lymphoma

3 Hodgkin s lymphoma

4 Introduction Last year, E Van Den Neste made an excellent summary of our current knowledge about the treatment of Hodgkin s lymphoma. However, we have to answer some remaining questions: -What place should radiotherapy be given? -Which is the best regimen? more is not always better Moreover, in diseases with high cure rates, a long follow-up of studies is needed before concluding.

5 Old study, long F-up: «the NCIC CTG / ECOG HD 6 lesson» 1994 *: Meyer et al. JCO 2005; **: Meyer et al ASH 2011 # 590

6 Median F.-up: 4.2 y * Rxtherapy Chemo p 5y FFS 93% 87%.006 5y FFS (unf) 95% 88%.004 Median F.-up: 11.3 y** 12y FFS 92% 88%.05 12y OS 87% 94%.04 12y FFS (unf) 94% 86% y OS (unf) 81% 92%.04 Deaths (n) HL / TOX 4 6 Second tumor 9 4 Others 11 2 *: Meyer et al. JCO 2005; **: Meyer et al ASH 2011 # 590

7 NCIC CTG / ECOG HD 6: conclusion Conclusion: With longer F.-up, Radiotherapy < Chemotherapy Take home message: «with competitive risk in different arms, long F.-up is needed to conclude»

8 PET study Random Engert A. #589 What s new for advanced disease? Final results of the GHSG HD15 study A B C 8 x BEACOPP escalated 6 x BEACOPP escalated 8 x BEACOPP 14 (baseline) Yes Residual tumor mass? (>2.5 cm) No PET-study PET positive: RT 30 Gy PET negative: follow up Follow up

9 GHSG HD15: final results RANDOM COMPLETE RESPONSE A B C p 90% 94% 92% TOXICITIES A B C Hematological 92% 92% 80% A B C DEATHS n=53 n=33 n=37 Toxic deaths n=15 n=6 n=6 2d cancers n=13 n=5 n=8 2d MDS + AML n=29 n=2 n=8 Engert A. #589

10 GHSG HD15: conclusions RANDOM: 6 BEACOPPesc. decrease the toxicities of 8 BEACOPPesc. with same efficiency PET study: PFS PR PET- patients = PFS CR patients PET guided radiotherapy decreases the number of irradiated patients:72% (HD9) => 11% (HD15) TAKE HOME MESSAGE: «6 X BEACOPPesc + PET guided Rxtherapy more efficient and less toxic for patients with advanced HL» Engert A. #589

11 Other interesting news Residual mass on CT scan (diam > 4 cm) in post-treatment PET-negative patients has a pejorative prognostic value (5y DFS 89% vs 69%)* Bad prognosis for older relapsing patients: median OS 11 months (2 y after curative 2d line vs 6 m after palliative 2d line)** A(B)VD + SGN35, 1 st line, advanced HL: CRR 100%, sensitive PNP 50% (phase 1 study)*** *: Magagnoli M. et al. #93; **: Böll B. et al. #92; ***: Younes A. et al. #955

12 Follicular lymphoma

13 What do we know today? Localized diseases (I, small II) can be cured by radiotherapy For more advanced disease: Treat if symptomatic* If asymptomatic: no treatment or clinical study FLIPI one and two **: help physicians to choose more / less intensive therapy but don t define the need for treatment *Brice P. et al. JCO 1997; **Solal Celigny P. et al. BLOOD 2004; **Frederico M. et al. JCO 2009; : Salles G. et al The Lancet, Dec 2010.

14 What did we learn last year? *Ardeshna et al. ASH 2010 #6; **Salles G. et al The Lancet, Dec No GELF criteria*: STAGES II to IV 4 x Rituximab 375 mg/m², week + Rituximab TTNT 375 mg/m², Q 3 months For symptomatic patients: New French standard : PRIMA!** + 6 x R-CHOP R 12 x R / 2 months 3y: 74.9%

15 Kahl B et al, #LBA6 What s new for Low Tumor Burden FL?: Rituximab monotherapy +/- maintenance: ECOG E4402 (RESORT) Rituximab 375 mg/m², Q 3 months Maintenance R. 4 x Rituximab 375 mg/m²/week TTTF R Longer time to 1st chemo, but no advantage in TTTF, higher cost! P=0.8 At progression: 4 x Rituximab 375 mg/m²/week R. Retreatment

16 Stages large II, III and IV Other drugs, other maintenance schedules? 4 x R / 2 months 2y: 80% 4 x R-FND R N=234 Median age: 66 years FLIPI I / H: 89% Second malignancies: n=11 NS No maintenance 2y: 68% Take Home Message: Prima design seems to be superior. 8 month maintenance seems to be too short. High rate of sec. malignancies with R-FND Vitolo U. et al. #777

17 Radio Immunotherapy (RIT)?* Background: 1. High FLIPI FL, conventional chemo 50% 2. To improve survival - add Mab to chemotherapy - prolong treatment with rituximab - prolong treatment with RIT 3. R-FND: effective regimen for indolent lymphoma 4 x R-FND 28 + RIT + but: MDS = 7% CR: 91% 5y: 74% 5y: 91% Take Home message: results seem to be better, but, given high rate of MDS, this approach must be reserved for patients with HR-FLIPI *:Fowler et al. #99

18 New monoclonal antibodies (phase II studies) Obinutuzumab (GA 101) GAUSS study (relapsed LG NHL : FL + non FL)* R 4 x 1000 mg GA 101 / w 4 x 375 mg/m² ritux / w 12 x 1000 mg GA 101 / 2 mo 12 x 375 mg/m² ritux / 2 mo ORR: + 4.6% GAUDI study**(relapsed FL) R 6-8 x 1000 mg GA 101- CHOP21 12 x 1000 mg GA 101 / 2 mo 6-8 x 1000 mg GA 101- FC28 12 x 1000 mg GA 101 / 2 mo ORR: 96.4% 92.9% Ofatumumab (first line LG NHL: FL (n=36) + non FL) *** 6-8 x O-bendamustine => ORR 98% / CR 60% *:Sehn L. et al. # 269; **: Radford J. et al. # 270. ***: Fowler N. et al # 778

19 PET Interm. PET Final PET Dupuis J. et al, #877 New prognostic factor: early PET 4 x R-CHOP 21 2 x R-CHOP R N: years 2 years Interm. PET (n=111) Final PET (n=106) Neg (76%) 86% ND Pos (24%) 61% ND Neg (78%) 87% 100% Pos (22%) 51% 88%

20 Diffuse large B-cell lymphoma

21 How do we treat our patients today? Young patients: 6 x R-CHOP21 +/- radiotherapy (if bulky)* if no adverse aaipi factor. more intensive R-chemo (R-ACVBP +/- ASCT) if adverse factor(s).** Old patients: 6-8 R-CHOP 21 -Good results but +/- 30% patients relapse / are refractory -R-CHOP14 = R-CHOP21 is a strange equation *: Pfreundschuh et al., ASH 2010; **Tilly et al., Lancet 2011 and Haioun et al., JCO 2000; : Coiffier et al. Blood 2010; : Delarue et al. ICML 2011;

22 How to improve the results for old patients? SMART E-R-CHOP14 (# 591) RITUXIMAB D-4 D-1 D10 D29 D57 D99 D155 D239 CHOP D1 D15 D29 D43 D57 D71 RICOVER (Older study) RITUXIMAB D1 D15 D29 D43 D57 D71 D85 D99 CHOP D1 D15 D29 D43 D57 D71 RICOVER Δ SMART-E-R-CHOP % 67.5% 78.1% 81.4% 59.9% % 73% OS@3y 67.1% % 77.9% IPI 3-5 Pfreundschuh et al. Lancet 2008; #591; Delarue et al. Lugano 2011; Cunningham et al. JCO 2011.

23 How to improve the results for old patients? Pfreundschuh et al. Lancet 2008; #591; Delarue et al. Lugano 2011; Cunningham et al. JCO SMART E-R-CHOP14 (# 591) RITUXIMAB D-4 D-1 D10 D29 D57 D99 D155 D239 CHOP D1 D15 D29 D43 D57 D71 RICOVER (Older study) 8 x R-CHOP21 RITUXIMAB D1 D15 D29 D43 D57 D71 D85 D99 D148 CHOP D1 D15 D29 D43 D57 D71 RICOVER Δ SMART-E-R-CHOP14 PFS@3y 66.5% 67.5% OS@3y 78.1% 81.4% PFS@3y 59.9% % 73% OS@3y 67.1% % 77.9% IPI 3-5 Take Home Message: Wait for randomized study!

24 Lenz G. et al. NEJM 2008; Hans CP et al. Blood 2004; Friedberg W. ASH 2011 What s new for relapsing patients? Hans algorithm : GCB-like ABC-like Perhaps the most robust single marker in DLBCL is c-myc *** c-myc - + Bad prognostic Good prognostic

25 The CORAL study Rel./Refractory DLBCL < 65 y N=477 R R-ICE x 3 R-DHAP x 3 PR/CR A S C T B E A M SD/PD Off R Rituximab x 6 Observation N=161 MYC + 28 (17%) (Sgle: 7 / Complex: 21) MYC (83%) Thieblemont C. et al. #594

26 Thieblemont C. et al. #594 The CORAL study PROGRESSION FREE SURVIVAL OVERALL SURVIVAL results Multivariate analysis PFS OS MYC +/ R-DHAP/R-ICE p = NS NS GC/nonGC (Hans) NS NS p =

27 *: Govi S. et al #958;**: Telio D. et al. #780 Other interesting findings - Patients with localized gastric HP+ DLBCL can be cured by antibiotics without any other treatment (phase II study, n=16, ORR: 69%, OS@5y: 94%)* - In the rituximab era, testicular localization remains associated with high risk of CNS relapses (retrospective study)**

28 Mantle cell lymphoma

29 How do we treat our patients today? Nearly all patients must be immediately treated* MIPI is a very good prognostic index but doesn t indicate the need for treatment** *: Martin P. et al., JCO 2009 **: Hoster E. et al., Blood 2008

30 Elderly patients 60% of MCL in patients > 60 yrs HD Ara-C and ASCT not feasible R-CHOP => low CRR Almost all patients relapse Median OS: 3-5 years Kluin N H. C. et al ASH 2011 #499

31 What s new? European MCL Network Elderly study: final results Newly diagnosed, >60-65 yrs; PS 0-2, stages II-IV, central PA review 8 x R-CHOP21 PR, CR 6 x R-FC28 IFN-a maintenance (3 x 3 MIU/week) or Peg-IFN (1 mg/kg/week) Rituximab maintenance (every 2 months) Kluin N H. C. et al ASH 2011 #499

32 Results R-CHOP R-FC p CR/Cru/PR 87% 78% Toxicities (all grades) Deaths after progression in first CR Neuropathy Alopecia Infections Mucositis (16%) 8 (13%) WBC Platelets (34%) 25 (26%) Rituximab Interferon p Median remission duration 77 months 26 months Toxicities Infections WBC Platelets Fatigue Kluin N H. C. et al ASH 2011 #499

33 European MCL Network Elderly study: final results Conclusion: The winner is R-CHOP followed by Rituximab maintenance 4years: 87%

34 New drugs R-2CdA-Vorinostat (1st line, phase I/II, n=20)*: ORR: 100% CRR: 79% BTK inh PCI (relapse, phase II, n=48)**: ORR: 67% Vorinostat-bortezomib (relapse, phase II, n=17) : ORR: 47% *: Spurgeon S et al. #441; **: Wang L. et al. #442; : Holkova B. et al. #779

35 Conclusion Hodgkin s lymphoma: Wait for long F-Up Advanced disease: 6 x BEACOPPesc + IFRT for posttreatment PET+ patients Follicular lymphoma: Promising results for RIT and new Mab Diffuse large B-cell lymphoma: Benefit of longer rituximab exposure? c-myc: bad prognostic factor Mantle cell lymphoma: Elderly patients: 8 x R-CHOP21 + rituximab maintenance