Medizinische Klinik und Poliklinik III Direktor: Prof. Dr. W. Hiddemann Aktuelle Behandlungsstrategien Studien des European MCL net Prof. Dr. Martin Dreyling Medizinische Klinik III LMU München
Disclosures Research Support (institution) Celgene, Janssen, Mundipharma, Pfizer, Roche Employee - Major Stockholder - Speakers Bureau - Speakers Honoraria Scientific Advisory Board Celgene, Janssen, Gilead, Mundipharma, Pfizer, Roche Bayer, Celgene, Janssen
MCL: a spectrum of disease indolent MCL (15%) classical MCL (80%) transformed (5%) Dreyling, ASCO Educational 2014
Dreyling, ESMO CR MCL 2014
MRD at end of induction Effect of ASCT 100 R-CHOP * * p = 0.08 p = 0.007 ns R-DHAP * p = 0.03 % MRD negative 75 50 25 58% * 70% 37% * 60% 83% 79% 70% 85% Hermine (in submission) 0 PB BM PB BM
MCL younger Time to treatment failure Hermine (in submission)
Dreyling, ESMO CR MCL 2014
Immuno-chemotherapy in MCL Progression-free survival Rummel, Lancet 2013
MCL elderly Remission duration (R-CHOP) Kluin-Nelemans, NEJM 2012
MCL elderly Overall survival (R-CHOP) Kluin-Nelemans, NEJM 2012
DGHO: MCL Guidelines 2015
Targeted therapy in relapsed MCL ASCO Educational 2014
New Bortezomib Ibrutinib Temsirolimus Lenalidomide copyright G. Hess
MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice
VR-CAP vs R-CHOP: Progression-free survival Patients alive and progression-free, % 100 80 60 40 20 R-CHOP VR-CAP R-CHOP VR-CAP Events, n 165 133 Median PFS, months 14.4 24.7 (95% CI) (12.0, 16.9) (19.8, 31.8) HR (95% CI) 0.63 (0.50, 0.79) P-value <0.001 0 0 6 12 18 24 30 36 42 48 54 60 66 Months from randomization Number of patients at risk: R-CHOP 244 181 116 79 55 36 22 16 9 3 0 0 VR-CAP 243 187 146 122 94 66 42 28 17 8 1 0 Median follow-up 40 months; 298 (61%) PFS events 59% improvement with VR-CAP vs R-CHOP (hypothesized: 40% improvement) Median PFS by investigator was 16.1 vs 30.7 months with R-CHOP vs VR-CAP; 307 (63%) events; HR 0.51, p<0.001; 96% improvement with VR-CAP Presented by: Franco Cavalli, MD
Hematologic AEs and Clinical Significance R-CHOP N=242 VR-CAP N=240 Any-grade thrombocytopenia, % 19 72 Grade 3 thrombocytopenia, % 6 57 Any-grade bleeding AEs, % 5 6 Grade 3 bleeding AEs, % 1.2 1.7 Platelet transfusions, % 3 23 Cycle delays due to thrombocytopenia, % 2 5 R-CHOP N=242 VR-CAP N=240 Any-grade neutropenia, % 74 88 Grade 3 neutropenia, % 67 85 Any-grade infection AEs, % 46 60 Grade 3 infection AEs, % 14 21 Systemic antibacterial use, % 65 81 Colony stimulating factor use, % 61 78 Cavalli, ASCO 2014
Study design Ara-C dose: 1gr/m 2 In patients > 65 years Or previous ASCT
MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice
Progression-free survival (ITT) Hess, JCO 2009
BeRT: Benda/Rituximab/Temsirolimus Bendamustin 90 mg/m² Be Be Be Be Rituximab 375 mg/m² R R Temsirolimus 25/50/75 mg T T T G-CSF T d1 Hess, Leukemia 2015 (in press) d8 d15 d22 d29
BeRT phase I Responses Hess, Leukemia 2015 (in press)
MCL studies 2015 Proteasome inhibition mtor inhibition Immune modulation R-CHOP+/-Bortezomib NLG-MCL4 BR-Lenalidomide R-HAD +/-Bortezomib BeRT BR-Temsirolimus T3 protocol chemotherapy+ Temsirolimus LENA-BERIT BR-Lenalidomide MCL 3001 Ibrutinib vs Temsirolimus SPRINT Lenalidomide vs investigator s choice
Study design Rituximab 375 mg/m 2 Lenalidomide 20 mg* Days 1-21 q 28 * Dose escalation to 25 mg allowed Induction (cycles 1-12) 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Rituximab 375 mg/m 2 Lenalidomide 15 mg Days 1-21 q 28 Maintenance (cycle 13 - POD) 13 14 15 16 17 18 19 20 21 22 23 24 POD Ruan, ASH 2014
Efficacy: Progression-free Survival Probability of progression free survival 0.00 0.25 0.50 0.75 1.00 Progression-Free Survival 24-month PFS OS = 84.6% 92.4% (95% CI = 66.6%, 72.3%, 93.4%) 98.1%) Median follow-up = 26 26 months (range 5-38) 0 10 20 30 40 Months from Treatment Number at risk 36 27 21 8 0 Ruan, ASH 2014
European MCL Network MCL R2 elderly 1 st line induction: 8x R-CHOP PR/CR ~80% Rituximab maintenance + Lenalidomide 15 mg daily d1-21, q28 days Treatment: max. 2 years 1 st line induction: 6x R-CHOP/Ara-C Rituximab maintenance sponsor: LYSARC central pathology: W. Klapper MRD diagnostics: M. Ladetto, C. Pott, MH Delfau
Mantle cell lymphoma B-cell receptor pathway
BTK inhibitor Ibrutinib Adverse events (>15%) Wang, NEJM 2013, ASH 2014
BTK inhibitor Ibrutinib Non-hematological grade III/IV toxicities Wang, NEJM 2013, ASH 2014
BTK inhibitor Ibrutinib Response rates Wang, NEJM 2013, ASH 2014 57
BTK inhibitor Ibrutinib Duration of response median 26.7-month follow-up Wang, NEJM 2013, ASH 2014
Ibrutinib and Rituximab in relapsed MCL Rituximab: Ibrutinib: Cycle 1 4 x weekly 375 mg/m² i.v. 560 mg daily p.o. Cycle 3 8: 375 mg/m² i.v. day 1 Cycle >9 375 mg/m² i.v. every 2nd cycle Wang, ASH 2014 Up to 2 years
Best Response 100 90 80 70 60 % 50 40 30 20 10 0 50% Wang, ASH 2014 42% p = 0.0001 8% p = 0.006 100% 44% 56% 88% 48% 12 5 1 34 1 19 50 2 20 Ki67 50% Ki67 < 50% Total N = 50 40% ORR PR CR
Median Follow up 11 months Progression-free survival Overall PFS (n=50) PFS by Ki67 1.0 1.0 0.8 0.8 Probability 0.6 0.4 Probability 0.6 0.4 0.2 0.2 <50% ( E / N = 2 / 34 ) >=50% ( E / N = 6 / 12 ) P-value <.0001 0.0 0 3 6 9 12 15 Months 0.0 0 3 6 9 12 15 Months Wang, ASH 2014
A: R-CHOP/ R-DHAP x 3 ASCT Observation A + I: R R-CHOP + I/ R-DHAP x 3 ASCT 2 yrs I-maintenance Observation I: R-CHOP + I/ R-DHAP x 3 2 yrs I-maintenance Observation superiority/non-inferiority: time to treatment failure HR: 0.60; 65% vs. 77% vs. 49% at 5 years
European MCL Network Study generation 2015 < 65 years > 60 years > 65 years MCL younger: R-CHOP/DHAP =>ASCT R-CHOP/DHAP+I =>ASCT => I R-CHOP/DHAP + I => I MCL elderly R2: R-CHOP vs R-CHOP/Ara-C => Rituximab M +/-Lenalidomide 1. Relapse MCL elderly I: BR +/- Ibrutinib => Rituximab M +/- Ibrutinib R-HAD +/- Bortezomib 2. Relapse (or not qualifying for R-HAD) Ibrutinib vs BeRT BR-Temsirolimus
www.european-mcl.net
Dreyling, ESMO CR MCL 2014