Mantle Cell Lymphoma: Update in Diego Villa, MD MPH FRCPC Medical Oncologist BC Cancer Agency

Transcription

1 Mantle Cell Lymphoma: Update in 2015 Diego Villa, MD MPH FRCPC Medical Oncologist BC Cancer Agency

2 Disclosures Research funding: Roche provides research funding to support the Centre for Lymphoid Cancer Database Honoraria: Roche, Lundbeck, Celgene, Seattle Genetics

3 Common Non-Hodgkin Lymphomas Rummel, JNCCN 2010

4 Epidemiology 1-3 cases / 100,000 people / year Median age Male preponderance (3:1) Evidence of cyclin D1 overexpression Immunohistochemistry PCR: 35-50% sensitivity t(11;14) by FISH: 95% sensitivity, gold standard Presentation Nodal: generalized non-bulky adenopathy Extranodal Bone marrow (~70%) GI (colon ~80%, stomach ~60%) CNS (~4-22%)

5 Natural History Initially responds to treatment; incurable Blastoid transformation Occurs in 35% Median survival 4 months Traditionally, poor survival Median OS 3-4 years 5-yr FFS ~11% Ghielmini, Blood 2009

6 ESMO Guidelines Dreyling, Ann Onc 2014

7 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

8 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

9 Deferred Therapy 97 patients with new MCL diagnosis 31 observed for >3 months before treatment TTT 12 mo (4-128) Age 58 (40-81) ADV stage 75% High MIPI 54% Martin, JCO 2009

10 Deferred Therapy at BCCA 725 patients with MCL first treatment was observation Most excluded: missing data, treatment refusal/frailty, treatment <3 mo s, not MCL 74 (17%) observed 3months 52 (71%) nodal, 16 (22%) non-nodal, 5 (7%) GI tract Median f/u 4 years 10 patients observed for 5 years Median TTT 3 years (range 3 mo-6.6 yr) Abrisqueta, ASH 2015 (we hope!!!)

11 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

12 Phase III trials of standard/conventional dose R- CHEMO Treatment N Med age OR and CR rates, % Median PFS (months) Median OS (months) Reference R-CHOP vs. CHOP (34) 75 (7) 21 (TTF) 14 (TTF) NR 2yr 76% Lenz, JCO 2005 R-CHOP vs. R-FC (± MR) (34) 78 (40) 28 (TTF) 26 (TTF) 4yr 62% 4yr 47% Kluin-Nelemans, NEJM 2012 R-CHOP vs. R-B (30) 93 (40) Not available Rummel, Lancet 2013 (STIL-1 subgr.) R-CHOP/CVP vs. R-B (27) 94 (50) Not available Not available Flinn, Blood 2014 (BRIGHT subgr.)

13 MCL net: Treatment of older patients with MCL 560 MCL patients R-CHOP x8 (n=280) Maintenance IFN-α weekly (n=161) -Age 70 (60-87) -90% advanced stage -50% high-risk MIPI R-FC x6 (n=280) 316 responding patients Maintenance rituximab every 2 months (n=155) Kluin-Nelemans, NEJM 2012

14 MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012

15 German STiL NH1 Trial N=514 Follicular Waldenström s Marginal zone Small lymphocytic Mantle cell (elderly) R Bendamustine-Rituximab - Bendamustine 90 mg/m 2 day Rituximab 375 mg/m 2 day 1 CHOP-Rituximab - Cyclophosphamide 750 mg/m 2 day 1 - Doxorubicin 50 mg/m 2 day 1 - Vincristine 1.4 mg/m 2 day 1 - Prednisone 100 mg days Rituximab 375 mg/m 2 day 1 Rummel, Lancet 2013

16 STIL-1 trial: PFS in the MCL subgroup N=46 N=48 The MAINTAIN trial will evaluate outcomes post BR and maintenance R in patients with FL and MCL. Rummel, Lancet 2013

17 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

18 Maintenance Rituximab 57 patients with relapsed/refractory MCL 1-3 prior therapies (~80% had one therapy) Induction therapy with FCM-R x4 Responding patients randomized to maintenance rituximab weekly x4 at months 3 and 9 Response duration after FCM-R P= year: 45% 2-year: 9% Forstpointer, Blood 2006

19 MCL net: Treatment of older patients with MCL 560 MCL patients R-CHOP x8 (n=280) Maintenance IFN-α weekly (n=161) -Age 70 (60-87) -90% advanced stage -50% high-risk MIPI R-FC x6 (n=280) 316 responding patients Maintenance rituximab every 2 months (n=155) Kluin-Nelemans, NEJM 2012

20 MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012

21 MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012

22 Initial therapy for younger patients: NCCN NHL N= centers Median PFS 3-4 years LaCasce, Blood 2012

23 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

24 Intensive frontline therapy: R-Hyper-CVAD (phase II) Center N OR and CR rates, % PFS OS TRM Reference Single (87) 48% 8yr 56% 8yr 8% Multi (72) 61% 5yr 73% 5yr 6.5% Multi (55) Med 4.8yr Med 6.8yr 2% Romaguera, JCO 2005 (MDACC) Merli, BJH 2012 (GISL) Bernstein, Ann Onc 2013 (SWOG 0213)

25 MDACC: Hyper-CVAD Romaguera, Blood 2005

26 MDACC: Hyper-CVAD Progression-Free Survival Overall Survival 3-year = 64% 3-year = 82% P=0.02 P=0.047 Romaguera, Blood 2005

27 MDACC: Hyper-CVAD Romaguera, Blood 2005

28 First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation

29 Intensive frontline therapy: phase III RCT s Induction Consolidation N OR and CR rates, % Median PFS OS TRM Reference CHOP-like IFN vs. ASCT (37) 98 (81) 1.4 yr 3.3 yr 77% 3yr 83% 3yr 0 Dreyling, Blood 2005 R-CHOP vs. R-CHOP/R- DHAP Cy-TBI ASCT vs. AraC- MEL-TBI ASCT (63) 99 (61) 4 yr 7 yr Med 7yr Med NR 3% 4% Hermine, ASH 2012

30 Intensive frontline therapy: phase II multicenter studies Treatment R-Maxi-CHOP + HD AraC ASCT R-CHOP/ R-DHAP ASCT R-CHOP + MTX + HD AraC ASCT R-CHOP + HD AraC ASCT N OR and CR rates, % (54) PFS OS TRM Reference Med 7.4yr 70% 6yr 5% (78) Med 7yr 75% 5yr 1.5% (69) 56% 5yr 64% 5yr 3% (64) 36% 4yr 66% 4yr 5% Geisler, Blood 2008 (Nordic) Delarue, Blood 2013 (GELA) Damon, JCO 2009 (CALGB 59909) van t Veer, BJH 2009 (HOVON 45)

31 Upfront ASCT in BC 179 transplant-eligible patients Upfront ASCT introduced in 2003 Overall Survival Progression-Free Survival (n=86) (n=86) (n=93) (n=93) Den Brock, ASH 2012

32 MCL net: Adding platinum & AraC to the CHOP-R ASCT standard N=497 Age <65 Stage II-IV Previously untreated CHOP-R alternating with DHAP-R x6 AraC 1.5g/m 2 x4 Melphalan 140mg/m 2 10Gy TBI ASCT CHOP-R x6 Cyclo 60mg/kg x2 12Gy TBI ASCT Primary endpoint: TTF Hermine, ASH 2012

33 MCL net update ASH 2012 ORR pre CR(u) pre ASCT ORR post CR(u) post Med TTF Med OS A 90% 40% 72% 98% 63% 46m 82m B 95% 54% 73% 97% 61% 88m NR p 0.19 < (HR= 0.68) Gr 3/4 heme Hb 9% Lk 50% Pl 10% Hb 30% Lk 75% Pl 74% The authors conclude: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Hermine, ASH 2012 Gr 3/4 renal Gr 3/4 muco TRM 0% 43% 4% 1% 61% 4%

34 ESMO Guidelines Dreyling, Ann Onc 2014

35 Options at Relapse Chemotherapy +/- rituximab Novel Agents Bortezomib Temsirolimus IMIDs: thalidomide, lenalidomide BTK inhibitors PI3K inhibitors Radiotherapy Radioimmunotherapy Allogeneic stem cell transplantation

36 Phase II studies of BR in Rel/Ref MCL Regimen Setting N OR and CR rates, % R-B R/R (38) R-B R-BM (mitoxantrone) R-BAC R/R (inhl +MCL) R/R (inhl + MCL) 1 st line R/R *data for MCL subgroup 63 (16) 57 (18) (50)* 75 (33)* 100 (95) 80 (70) PFS Med 16 months Med 24 months* Med 21 months* 2yr 95% 2yr 70% Reference Czuczman, ASH 2014 Rummel, JCO 2005 Wiede, L&L 2007 Visco, JCO 2013

37 STiL NHL Study Objectives Compare the efficacy and safety profile of BR with that of FR in patients with relapsed follicular, indolent, or mantle cell lymphoma Methodology Phase III, open-label, randomized, parallel group, multicenter study N=114 N=105 FR dose at BCCA: 20 mg/m 2 x3 days or 25 mg/m 2 x5 days Rummel, ASH 2014

38 8-year follow-up of STiL-2 Baseline characteristics balanced Median age 68 (range 38-87) Stage III/IV 90% Median 1 prior therapy (range 1-7) 12% prior bendamustine (+/- rituximab) FL 46%, WM 11%, MCL 43 (21%), Other 21% Protocol amended in 2006 to allow maintenance rituximab 23 BR + 17 FR = 40 patients Unplanned analysis showed PFS and OS Rummel, ASH 2014

39 Progression-Free Survival 8-year follow-up of STiL-2 No information on the MCL subgroup BR (n=114) FR (n=105) p 6 cycles 75% 53% ORR(CR) 84% (39%) 53%(16%) <0.001 Med OS 110 months 49 months SAE rate 17% 22% NS BR FR months Median PFS 11 versus 34 months HR 0.54 (95% CI 0.38, 0.72), p< Rummel, ASH 2014

40 Single agent studies of licensed novel agents in REL/REF MCL Drug N OR and CR rates, % Median DOR (months) Median PFS (months) Median OS (months) Reference Bortezomib (8) Fisher, JCO 2006 Ibrutinib (21) NR Wang, NEJM 2013 Lenalidomide (8) Goy, JCO 2013 Temsirolimus (2) Hess, JCO 2009

41 PINNACLE: Bortezomib in Relapsed/Refractory MCL Phase II study of 155 patients 1.3 mg/m2 (days 1, 4, 8, 11) with rest days ORR 32% (CR 8%) Fisher, JCO 2006; Goy, Ann Onc 2009 (update)

42 Bortezomib combination studies Regimen N OR and CR rates, % PFS Setting CHOPR-V (72) 2y 44% 1 st line VcR-CVAD (77) 3y 63% 1 st line R-HyperCVAD-V (95) Not given 1 st line BEAM-V (ASCT) (?) 5y 57% REL/REF RiBAD+C (59) Med 26m REL/REF RVD (44) Med 12m REL/REF Gem-V (12) Med 11m REL/REF

43 Immunomodulatory Drugs

44 MCL-001 (EMERGE) Study Phase II global, multicenter, single-arm, open-label study 4 median prior therapies: 100% bortezomib 1/3 intensive therapy 72% refractory to the last line of therapy Goy, JCO 2013

45 MCL-001: Most Common AE s Most common AE ( 5% grade 3/4) was myelosuppression, consistent with the known safety profile for lenalidomide in NHL Goy, JCO 2013

46 MCL-001 Responses ORR 28% (CR 8%) Med PFS 4 months 37 responders Goy, JCO 2013

47 MCL-002: SPRINT Study N=170 N=84 Trneny, ASH 2014

48 MCL-002 PFS Len: ORR 40% (CR 5%) Control: ORR 11% (CR 0) Trneny, ASH 2014

49 Targeting pathways downstream of the B-cell receptor B-cell receptor Y CD79 CD20 CD10 CD21 CD22

50 Ibrutinib in Rel/Ref MCL Phase 2 study N=111 with Rel/Ref MCL Median age 68 Median 3 prior Rx (range 1-5) Prior rituximab 89% Prior intensive therapy 41% Refractory last line 45% Ibrutinib 560 mg po daily Median DoR 17.5mo Median PFS 14 mo Wang, NEJM 2013

51 Recommendations for treatment at relapse No standard of care Clinical trial if available Chemo-Rituximab Bendamustine (especially if no prior B) Rituximab re-treatment (if not refractory to 1 st line) Novel agents Ibrutinib (approved for 2 nd line therapy) Bortezomib (coverage challenges) Lenalidomide (not approved but potentially available) Allogeneic stem cell transplant (???)

52 Conclusions MCL remains incurable and challenging to manage First-line therapy is relatively well defined 65 years: intensive therapy +/- maintenance rituximab > 65 years: R-chemo maintenance rituximab Second-line therapy and beyond is not well defined No standard of care R-chemo; many studies support role for bendamustine Novel agents alone or in combination Various emerging novel agents with clinical activity