Mantle Cell Lymphoma: Update in 2015 Diego Villa, MD MPH FRCPC Medical Oncologist BC Cancer Agency
Disclosures Research funding: Roche provides research funding to support the Centre for Lymphoid Cancer Database Honoraria: Roche, Lundbeck, Celgene, Seattle Genetics
Common Non-Hodgkin Lymphomas Rummel, JNCCN 2010
Epidemiology 1-3 cases / 100,000 people / year Median age 60-65 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%)
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
ESMO Guidelines Dreyling, Ann Onc 2014
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
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
Deferred Therapy at BCCA 725 patients with MCL 1998-2015 286 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!!!)
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
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 112 61 94 (34) 75 (7) 21 (TTF) 14 (TTF) NR 2yr 76% Lenz, JCO 2005 R-CHOP vs. R-FC (± MR) 485 70 86 (34) 78 (40) 28 (TTF) 26 (TTF) 4yr 62% 4yr 47% Kluin-Nelemans, NEJM 2012 R-CHOP vs. R-B 94 70 91 (30) 93 (40) 22 35 Not available Rummel, Lancet 2013 (STIL-1 subgr.) R-CHOP/CVP vs. R-B 74 60 85 (27) 94 (50) Not available Not available Flinn, Blood 2014 (BRIGHT subgr.)
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
MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012
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 1+2 - 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 1-5 - Rituximab 375 mg/m 2 day 1 Rummel, Lancet 2013
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
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
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=0.049 2-year: 45% 2-year: 9% Forstpointer, Blood 2006
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
MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012
MCL net: Treatment of older patients with MCL Kluin-Nelemans, NEJM 2012
Initial therapy for younger patients: NCCN NHL N=167 2000-2008 7 centers Median PFS 3-4 years LaCasce, Blood 2012
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
Intensive frontline therapy: R-Hyper-CVAD (phase II) Center N OR and CR rates, % PFS OS TRM Reference Single 97 97 (87) 48% 8yr 56% 8yr 8% Multi 60 83 (72) 61% 5yr 73% 5yr 6.5% Multi 49 85 (55) Med 4.8yr Med 6.8yr 2% Romaguera, JCO 2005 (MDACC) Merli, BJH 2012 (GISL) Bernstein, Ann Onc 2013 (SWOG 0213)
MDACC: Hyper-CVAD Romaguera, Blood 2005
MDACC: Hyper-CVAD Progression-Free Survival Overall Survival 3-year = 64% 3-year = 82% P=0.02 P=0.047 Romaguera, Blood 2005
MDACC: Hyper-CVAD Romaguera, Blood 2005
First-Line Options Observation R-CHEMO Maintenance rituximab Hyper-CVAD Autologous stem cell transplantation
Intensive frontline therapy: phase III RCT s Induction Consolidation N OR and CR rates, % Median PFS OS TRM Reference CHOP-like IFN vs. ASCT 122 99 (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 455 98 (63) 99 (61) 4 yr 7 yr Med 7yr Med NR 3% 4% Hermine, ASH 2012
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, % 160 96 (54) PFS OS TRM Reference Med 7.4yr 70% 6yr 5% 60 82 (78) Med 7yr 75% 5yr 1.5% 77 88 (69) 56% 5yr 64% 5yr 3% 87 70 (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)
Upfront ASCT in BC 179 transplant-eligible patients 1990-2010 Upfront ASCT introduced in 2003 Overall Survival Progression-Free Survival (n=86) (n=86) (n=93) (n=93) Den Brock, ASH 2012
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
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 <0.001 0.038 (HR= 0.68) 0.045 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%
ESMO Guidelines Dreyling, Ann Onc 2014
Options at Relapse Chemotherapy +/- rituximab Novel Agents Bortezomib Temsirolimus IMIDs: thalidomide, lenalidomide BTK inhibitors PI3K inhibitors Radiotherapy Radioimmunotherapy Allogeneic stem cell transplantation
Phase II studies of BR in Rel/Ref MCL Regimen Setting N OR and CR rates, % R-B R/R 45 82 (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) 20 20 75 (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
STiL NHL-2 2003 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
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
Progression-Free Survival 8-year follow-up of STiL-2 No information on the MCL subgroup 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 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 0.013 SAE rate 17% 22% NS BR FR 0 12 24 36 48 60 72 84 months Median PFS 11 versus 34 months HR 0.54 (95% CI 0.38, 0.72), p<0.0001 Rummel, ASH 2014
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 155 33 (8) 9 7 24 Fisher, JCO 2006 Ibrutinib 111 68 (21) 18 14 NR Wang, NEJM 2013 Lenalidomide 134 28 (8) 17 4 19 Goy, JCO 2013 Temsirolimus 54 22 (2) 7 5 13 Hess, JCO 2009
PINNACLE: Bortezomib in Relapsed/Refractory MCL Phase II study of 155 patients 1.3 mg/m2 (days 1, 4, 8, 11) with rest days 12-21 ORR 32% (CR 8%) Fisher, JCO 2006; Goy, Ann Onc 2009 (update)
Bortezomib combination studies Regimen N OR and CR rates, % PFS Setting CHOPR-V 32 91 (72) 2y 44% 1 st line VcR-CVAD 30 90 (77) 3y 63% 1 st line R-HyperCVAD-V 20 100 (95) Not given 1 st line BEAM-V (ASCT) 23 95 (?) 5y 57% REL/REF RiBAD+C 39 79 (59) Med 26m REL/REF RVD 16 81 (44) Med 12m REL/REF Gem-V 26 60 (12) Med 11m REL/REF
Immunomodulatory Drugs
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
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
MCL-001 Responses ORR 28% (CR 8%) Med PFS 4 months 37 responders Goy, JCO 2013
MCL-002: SPRINT Study N=170 N=84 Trneny, ASH 2014
MCL-002 PFS Len: ORR 40% (CR 5%) Control: ORR 11% (CR 0) Trneny, ASH 2014
Targeting pathways downstream of the B-cell receptor B-cell receptor Y CD79 CD20 CD10 CD21 CD22
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
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 (???)
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