How to incorporate new therapies into the treatment algorithm of patients with mantle cell lymphoma Dr. Guillermo Rodríguez García Hospital Universitario Virgen Macarena Hospital Universitario Virgen del Rocío Seville
Index - INTRODUCTION - FIRST LINE TREATMENT: * Fit patients * Non-Fit patients - REFRACTORY / RELAPSE TREATMENT - TAKE HOME MESSAGES
Mantle cell lymphoma Real world data Nordic Lymphoma Group observational study 5 % Years 2001-2011: 1389 patients 3,6% 2,4% 2 : 1 Abrahamsson et al Blood. 2014;124(8):1288-1295
A subgroup of patients with MCL may be SAFELY OBSERVED from diagnosis Asymptomatic patients Non-nodal presentation Nodal low burden Low proliferative rate Abrisqueta et al, Ann Oncol. 2017 Oct 1;28(10):2489-2495
Treatment FIT PATIENTS (Autologous-SCT) NON- FIT PATIENTS (Comorbidities/Age)
Randomized trial INTERFERON vs ASCT after CHOP induction Progression free survival 17 m. 39 months ( CR 46 m. PR 33 m. ) Dreyling et al, Blood 2005 105: 2677-2684
Pretransplant Induction Clinical trial Chemotherapy N RG / RC SG / SLP Geisler (NLG) (2008) Damon (CALGB) (2009) Maxi-CHOP x 3 + HADx 3 + R cycles 4º,5º,6º + AUTO-TPH (BEAM) Rituximab if PCR(+) R-CHOP-Mtx x 2 + VP16-AraC x 1 + CBV x 1 + AUTO-TPH + Rituximab x 2 160 96% / 54% 70% / 66% at 6 years 78 88% /69% 64% / 56% at 5 years Delarue (GELA) (2013) R-CHOP x 3 + R-DHAP x 3 + AUTO-TPH 60 82% / 78% 75% / 64% at 5 years - ALL seem to have SIMILAR TOXICITY (high, mainly Hematologic) and OUTCOME (1) - HyperCVAD-R probably is the most effective induction regimen (2), but toxicity seems to be higher (3) and is associated with higher rates of hematopoietic progenitor cell mobilization failure despite Plerixafor rescue (4) - BENDAMUSTINE-R could be a good induction regimen (5) (1) Bude et al, JCO 2011;29:3023 3029. (2) Romaguera et al JCO 23:7013-7023 (3) Merli et al British Journal H 56, 346 353 (4) Salhotra et al, BBMT 23 (2017) 1264 1268 (5) Chen et al BJH 2017, 176(5), 759-769
Autologous SCT Clinical Trials After CHOP: INTERFERON AUTO-SCT PreAUTO-SCT CHOP CHOP/DHAP PostAUTO-SCT Watch - Wait 2005 2015 2016 2017 Consensus EBMT / European MCL Network INDUCTION must include CYTARABINE and RITUXIMAB Consolidate ALL candidates with AUTOLOGOUS Stem Cell Transplantation Robinson et al, Leukemia (2015) 29, 464 473
Hermine et al, 2016 PFS 5 years median PFS R-CHOP x 6 R-CHOP x 3 / DHAP-R x 3 AUTO - SCT AUTO - SCT n = 234 n = 232 Follow up 6 years 44 % 65 % 4,3 years 9,1 years No difference in OVERALL SURVIVAL Similar Bone Marrow Transplant-related Mortality > GRADE 3-4 TOXICITY with DHAP-R: Mainly Hematologic 65 % 4,3 y 9,1 y. 40 %
DHAP-R x 4 AUTO-TPH n = 299 n = 257 R n = 120 Observation n = 120 Follow up 4 years PFS: 83% OS: 89% PFS: 64% OS: 80% Progression-free Survival Overall Survival N Engl J Med 2017;377:1250-60
Treatment for FIT patients Hiper-CVAD MTX-AraC-R CALGB regimen Maxi-CHOP AraC-R CHOP-R DHAP-R AUTOLOGOUS SCT
NON-FIT PATIENTS (Comorbidities/Age)
1º Line Randomized Clinical Trials Overall Survival TTF PFS FCM FCM CHOP CHOP > OR > CR > TTF FC CHOP y INTERF V CHOP -CAP 2004 2005 2012 2013 2014 2015 BENDA CHOP INCOMPLETE DATA SAFETY WARNING MAINTENANCE NECCESARY? FCM vs FCM-R. Forstpointner et al, Blood. 2004;104:3064-3071 CHOP vs CHOP-R. Lenz et al, J Clin Oncol 23:1984-1992. CHOP-R vs FC-R +/- R Kluin-N et al, N Engl J Med 2012;367:520-31 CHOP-R vs BENDA-R Rummel et al, Lancet 2013; 381: 1203 10 CHOP-R vs VR-CAP Robak et al, N Engl J Med 2015;372:944-53
Bendamustine results in 1º line Rm 2013 R- BENDA R-CHOP Phase 3 NO INFERIORITY Trial. INDOLENT lymphomas and MCL (n 541 patients) MANTLE CELL LYMPHOMA: 94 / 541 patients PFS TOXIC EFFECTS: - Less INFECTIONS - Less Peripheral neuropathy - Less Stomatitis, etc. 22,1 months 35,4 months Conclusion: Bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP CHOP-R vs BENDA-R Rummel et al, Lancet 2013; 381: 1203 10
BENDA CHOP CVP R O R O R O MORTALITY TRIAL NOT DESIGNED to detect DIFFERENCES between the 3 chemotherapy INDUCTION regiments. Marcus et al, N Engl J Med 2017;377:1331-44
Cross study comparison Number of patients (n) Rate of randomized patients Stil NHL-7-2008 n = 122 (of 168) 73% Kluin-Nelemans et al n = 184 (of 280) 66% Remission duration B - R B R + R CHOP- R CHOP-R + R Median (months) since randomization Rate at 72 months (estimated) 57 63 23 n.y.r. 49% 40% 12% 50% Overall Survival Median (months) since randomization Rate at 72 months (estimated) n.y.r n.y.r 64 n.y.r. 70% 66% 50% 71% After a median observation time of 4.5 years, the results are yet inconclusive Simon Rule, ASH 2016
R - CHOP vs R - CAP 1 4 8 11 CFM ADR PRED RITUX Each 21 days 14,4 m (1) Inv: 16,1 m Inv: 30,7 m 24,7 m (1) 487 patients randomized (NO AUTO-SCT candidates) Median follow up 40 months (1) Investigator assestment: 30,7 vs 16,1 months Robak et al, N Engl J Med 2015;372:944-53
R-CHOP n 244 V R-CAP n 243 CR 42 % (p=0,007) CR 53 % PR 42 % PR 38 % Increased Hematologic Toxicity CHOP-R VR-CAP Platelets transfusion 3 % 23 % Grade 3 Neutropenia 67 % 85 % Grade 3 Infeccion 14 % 21 % MORE DAYS IN HOSPITAL TREATMENT Robak et al, N Engl J Med 2015;372:944-53
Untreated Patients 120 MEDIAN PROGRESSION FREE SURVIVAL (months) 110 100 90 80 50 40 30 20 10 HD-ARA-C + AUTO-SCT CHOP +/- + AUTO-SCT CHOP +/- V IS IT POSSIBLE TO IMPROVE THIS RESULTS WIH BAC 500 OR LENALIDOMIDE? - CAP BENDA CHOP
Bendamustine results in 1º line Visco 2017 BENDA-R + ARA-C 500 (R-BAC500) MANTLE CELL LYMPHOMA: 57 patients COMPLETE REMISSION 91%, PROGRESSION 4%, Toxicity 5%. PROGRESSION FREE SURVIVAL at 35 months: 76% R-BAC500, Visco et al Lancet Haematol 2017; 4: e15 23
+ 9 cycles Maintenance 36 cycles Phase 2. n = 38 patients Median follow-up: 30 months 85% ORR 92% (CR 64%) Grade 3 4 Adverse Events - Neutropenia (50%) - Rash (29%) - Thrombocytopenia (13%) - Anemia (11%) - Tumor flare (11%) - Fatigue (8%) months Ruan et al, N Engl J Med 2015;373:1835-44.
Treatment V R-CAP CHOP-R BENDA-R RELAPSE
REFRACTORY / RELAPSE MCL
Chemo-Immunotherapy (R/R) Treatment n Previous Lines OR / RC (%) Median response duration Progression Free Survival BENDA-R (Phase III) Rummel et al (2016) 24 1-2 --- / --- --- 17,6 months GemOx-Rituximab Obrador-Hevia et al (2016) 20 1-2 80 % (RC 60%) --- 22 months EPOCH-Rituximab Jermann et al (2004) 7 1-2 68 % (RC 28%) --- 15 months HiperCVAD-R Romaguera et al (2005) 21 -- 95 % (RC 43%) --- 18 months Rummel et al (2016) Lancet Oncol 2016; 17: 57 66 Obrador-Hevia et al (2016) Br J Haematol. 2016 Sep;174(6):899-910 Jernmann et al (2004) Ann Oncol. 2004 Mar;15(3):511-6 Romaguera et al (2005) ASH Annual Meeting Abstracts; 106 [abstract 2446]
Old New Drugs for Relapse / Refractory n = 155 PT : 1-2 n = 54 PT : 3-4 n = 69 PT : 2-3 CR 8 % PR 25 % CR 1 % PR 20 % CR 18 % PR 41 % BORTEZOMIB TEMSIROLIMUS TEMSIROLIMUS 2004 2009 2010 2011 DOR : 9,2 months PFS : 6,2 months DOR : 7,1 months PFS : 4,8 months DOR : 11 months PFS : --- months BORTEZOMIB - GEMCITABINE BORTEZOMIB - - DXM BORTEZOMIB - CHOP
New Drugs for Relapse / Refractory LENALIDOMIDE + / - RITUXIMAB 2012 2013 2014 2015 2016 IBRUTINIB + / - RITUXIMAB
Lenalidomide (R/R) More than 400 MCL included in clinical trial Good Toxicity profile. Median time to response : 2 MONTHS. TRIALS OR (%) CR/CRu (%) R. duration months Median PFS months NHL-002 (N = 15) 53 % 20 % NR NR NHL-003 (N = 57) 35 % 12 % 16.3 m 8.8 m MCL-001 (N = 134) 28 % 7% 16.6 m 4.0 m MCL-002 (N = 170) 40 % 5 % 16.1 m 8.7 m NHL-002: Wiernik et al, Journal of Clinical Oncology, 2008,26, 4952 4957. NHL-003: Witzig et al, Annals of Oncology 22: 1622 1627, 2011. MCL-001 (EMERGE TRIAL): Goy et al, Journal of Clinical Oncology 31, 2013, 3688-3695. MCL-002 (SPRINTTRIAL): Trněny, et al, Lancet Oncol 2016; 17: 319 31.
Wang et al. UNTIL PROGRESSION Previous lines: 2 Phase 1 MTD : 20 mgrs/day Phase 2 (n=44) : ORR 57% (CR 36%, PR 21%) 19 months 11 months Wang et al, Lancet Oncol 2012; 13: 716 23.
n = 111 patients Median previous lines: 3 560 mgrs daily ORAL. CR 21 % PR 47 % Median response duration: 17 months Median time to response : 2 months Wang et al, N Engl J Med 2013;369:507-16
Median previous lines: 2 Median follow up: 20 months 6.2 months 14.6 months Wang 2016 50 patients. Median previous lines: 3 ORR: 88% (44% CR. 44% PR).
Refractory / Relapse MCL MEDIAN PROGRESSION FREE SURVIVAL (months) 40 30 20 10 First Line 2º-3º Line 4º Line V - CAP BENDA CHOP BENDAMUSTINE GemOx EPOCH HiperCVAD IBRUTINIB LENALIDOMIDE IBRUTINIB LENALIDOMIDE TEMSIROLIMUS BORTEZOMIB TEMSIROLIMUS
Allogeneic Stem Cell Transplantation 2611 CIBMTR patients (62% non myeloablative) 500 MANTLE CELL LYMPHOMA. UNIQUE POTENTIALLY CURATIVE THERAPY ( 35 65% ) Urbano-Ispizua et al. Biol Blood Marrow Transplant. 2015 Oct;21(10):1746-53
Take Home Messages - Fit patients treatment should include rituximab, cytarabine, autologous stem cell transplantation and rituximab maintenance. - There is no Gold Standard treatment for Unfit patients: R-CHOP with maintenance VR-CAP, probably with maintenance Bendamustine-R, probably without maintenance Promising results from R-BAC and Lenalidomide-Rituximab regimens - Relapsed/refractory: Immunochemotherapy (Bendamustine-R, GemOx-R, etc) IBRUTINIB +/- Rituximab Lenalidomide - Rituximab
Take Home Messages New therapies are NOW improving life expectancy and quality of live of this patients
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