Who should get what for upfront therapy for MCL? Kami Maddocks, MD The James Cancer Hospital The Ohio State University

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1 Who should get what for upfront therapy for MCL? Kami Maddocks, MD The James Cancer Hospital The Ohio State University

2 Treatment Challenges Several effective options, improve response durations, none curable Less common disease, majority of data smaller phase II trials Treatment decision based on age, co-morbidities, risk factors Several prognostic markers, but unknown correlation to therapy

3 Mantle cell lymphoma International Prognostic Index Age Performance Status LDH Leukocyte Count Eva Hoster et al. Blood 2008;111:

4 Peter Martin et al. JCO 2009;27: Outcomes of Observation at Diagnosis

5 Treatment of MCL Younger Clinical trial, as no standard of care Advanced stage disease RHyper-CVAD +/- transplantation RMCHOP (DAMON) + transplantation RCHOP/RDHAP + transplantation Nordic Regimen R-DHAP + transplantation R-Bendamustine +/- maintenance rituximab Elderly Clinical trial, as no standard of care Advanced stage disease RCHOP + transplantation RCHOP + maintenance rituximab R-Bendamustine +/- maintenance rituximab R-BAC Vr-CAP

6 CR PR PFS R-CHOP R-CHOP CHOP Orion M. Howard et al. JCO 2002;20: Lenz et al. JCO 2005;23:

7 N = 549 ORR CR PFS PFS (MCL) BR R-CHOP N = 447 (74) BR 97 (95) 31 (50) R-CHOP/CVP 91 (85) 25 (27) Hematologic, infections, alopecia, neuropathy vs. hypersensitivity Neuropathy, alopecia, constipation vs. hypersensitivity, N/V Rummel, et al Ian W. Flinn et al. Blood 2014;123:

8 n = 487 CR IR PFS I PFS DOR Median OS 4-yr OS R-CHOP VR-CAP NR 64 Robak T et al. N Engl J Med 2015;372: *Hematologic toxicity

9 Carlo Visco et al. JCO 2013;31:

10 Maintenance European MCL 455 pts not candidates for transplant Randomized to R-CHOP vs R-FC Pts with PR or CR second randomization to INF vs R maintenance until progression 316 pts randomized Remission duration 75 vs 27 mos OS not significant 79 vs 67% Median DOR exceeded 6 years 4 year OS 87% vs 63% Kluin-Nelemans H et al. N Engl J Med 2012;367:

11 BS Kahl et al. Ann Oncol 2006;17:

12 Untreateds tage IV MCL (N=99) Romaguera et al. J Clin Oncol. 2005;23:7013. Cycles 1, 3, 5, 7 Rituximab 375 mg/m 2 d1 Cyclophosphamide 300 mg/m 2 d2-4 Doxorubicin 16.6 mg/m 2 d5-7 Vincristine 1.4 mg/m 2 d5,12 Dexamethasone 40 mg d2-5, Cycles 2, 4, 6, 8 Rituximab 375 mg/m 2 d1 Methotrexate 200 mg/m 2 d2 IVPB Methotrexate 800 mg/m 2 d2 IVCI Cytarabine 3000 mg/m 2 d3-4 (Cytarabine dose reduced by 2/3 for age >60 y or creatinine >1.5 mg/dl) Cycles repeated every 21 days Prophylaxis: Mesna, G-CSF, antifungal, antibacterial, antiviral, leucovorin, prednisone eyedrops A S S E S S Patients without CR after 6 courses offered ASCT Clinical Response (n=97) % of Patients ORR 97 CR/CRu (after first 87 6 cycles) PR 10 3, 7-year OS 82, 60 3, 7-year FFS 64, 43

13 R-Hyper-CVAD Alternating With R-M/A: FFS According to Age 1.0 Survival probability Romaguera et al. J Clin Oncol. 2005;23:7013. % of Patients <65 (E/N = 21/65) 73 >65 (E/N = 18/32) 50 P= Months from start of treatment 29% unable to finish Hematologic toxicity 5 patients died acute toxicity, 4 from AML/MDS

14 Phase II multi-center SWOG study 49 untreated MCL pts age < 70 Treatment per MDACC regimen Only 22 pts completed therapy Grade 4 hematologic toxicity in 87% of pts 1 death, 2 MDS ORR 86% (CR 55%, 31% PR) Median 2, 5-yr PFS 65, 53% 2, 5-yr OS 76, 69% Median f/u 4.8 years, median PFS 4.8 years, 5.5 years < 65 Median OS 6.8 years S. H. Bernstein et al. Ann Oncol 2013;24:

15 CHOP-like induction 4-6 (N=269) CHOP-like consolidation Dreyling et al. Blood. 2005;105:2677.

16 Chemoradiotherapy Followed by Interferon or ASCT in MCL: PFS Probability Years after end of induction 3-y PFS (%) ASCT 54 IFN 25 = Dreyling et al. Blood. 2005;105:2677.

17 Chemoradiotherapy Followed by Interferon or ASCT in MCL: OS Survival probability y OS ASCT 83 IFN 77 P= Dreyling et al. Blood. 2005;105:2677. Years after end of induction 5% mortality ASCT

18 Lloyd E. Damon et al. JCO 2009;27:

19 Phase II 78 untreated MCL pts age < 70 86% completed planned therapy ORR 88% (CR 69%, 19% PR) 2, 5-yr PFS 75, 56% 2, 5-yr OS 87, 64% Median f/u 4.7 years, median PFS and OS not reached CALGB BM (4 weekly q8 for 18 months) vs BC (1,4,8,11 for 4 cycles) 2-year PFS 84 vs 89% 3-year PFS 67% 28% BC withdrew for toxicity 2 treatment related mortalities Lloyd E. Damon et al. JCO 2009;27: ARF issue prior to DR of MTX

20 Nordic data N = 160 ORR 96% CR 54% 6-year PFS 66% 6-year OS 70% Median OS > 10 yrs 6 relapses Updated MCL2 outcomes 8 deaths (5%) 1 MDS

21 European MCL younger Protocol Design (< 65 yrs old) N = 455 Hermine, ASH 2010, abstrac t110 Control 4 x R-CHOP 2 x R-CHOP DexaBEAM (stem cell mobilization) Myeloablative regimen Cyclo 120mg/kg + TBI 12 Gray PBSCT PR, CR PR, CR PRIMARY ENDPOINT: TTF (2+1) x R- CHOP/R-DHAP alternating stem cell mobilization after course 6 Myeloablative regimen TBI 10 Gray Ara-C 4 x 1.5 g/m2 Melphalan 140 mg/m2 PBSCT

22 Time to treatment failure ORR 90 vs 95% prior ASCT CR 54 vs 50% ORR 98 vs 97% post ASCT CR 63 vs 61% ORR 88% (CR 69%, 19% PR) TTF 88 vs 46 months OS not reached vs 82 months Median f/u 51 months Hazard Ratio 0.68 p= (one sided sequential test) Update November 19, 2010, European MCL Network, V

23 French GELA N = 60 After 3 (R)-CHOP, no. (%) After 3 R-DHAP, no. (%) CR/Cru 7/60 (12) 34/60 (57) PR 48/60 (80) 18/60 (30) SD 3/60 (5) 0/60 (0) Progression 1/60 (2) 4/60 (7) NE 1/60 (2) 4/60 (7) Median DFS 78 months Median PFS 84 months Median OS not reached 5-year OS 75% Richard Delarue et al. Blood 2013;121:48-53

24 First line MCL treatment, age 65 and under Q2 mo x 3 yrs CR/PR CR/PR

25 N=299 enrolled 257 (86%) got AutoHCT 238 (80%) randomized Median f/u 30 mo after randomization CR 81.4, 92 3 yr PFS 83% for maint rituximab arm (vs. 73% for obsv) 2 yr OS 93% (rituximab) vs. 94% (obsv)

26 MCL-2: Survival according to MIPI 70% low MIPI, 23% high MIPI alive at 10 years CALGB 75% low MIPI, 25% high MIPI at 6 years Geisler, et al BJH, 2012, 158,

27 Hongtao Liu et al. Haematologica 2012;97: CALGB MRD Data

28 Christiane Pott et al. Blood 2006;107: Christiane Pott et al. Blood 2010;115:

29 MRD(+) predicted shorter PFS, independent of MIPI, Rx arm, or protocol PB MRD predicted clinical relapse 87% of the time If MRD(-) at 1 year, 3 yr PFS about 80% and 4 yr PFS about 70%

30 Frontline Regimen Age (years) ORR PFS/FFS OS R-HyperCVAD 81 97% 3-year 64% ( 65 3-year 73%) 3-year 82% R-HyperCVAD < 70 86% 5-year 49% 5-year 63% R-HyperCVAD 70 83% 5-year 61% 5-year 73% CALGB < 70 88% 5-year 56% 5-year 64% CALGB < 70 81% 3-year 67% NLG MCL % 6-year 66% 6-year 70% GELA 66 95% 5-year 64% 5-year 75% European MCL 65 95% Median TTF 88 months Median OS not reached

31 Treatment of MCL Younger Intensive treatment prolongs PFS Ara C is important component Transplant benefit unclear in low risk MIPI and MRD? just good biology Elderly Observation is reasonable in select cases Several effective chemoimmunotherapies R-HyperCVAD increased toxicities, inferior outcomes R maintenance role in R-CHOP and possibly others

32 Newly Diagnosed Stage II-IV Mantle Cell Lymphoma Observation in highly selected cases Age < and transplant eligible RHyperCVAD/ methotrexate + cytarabine X 8 cycles *must be < 65 Clinical Trial OR R-methotrexate, augmented CHOP x 2-3 cycles + EAR (or any rituximab and cytarabine containing regimen Age > or nontransplant eligible Clinical Trial OR VrCAP, B-RAC, R- benadmustine or RCHOP followed by maintenance R Observation in highly selected cases Autologous Transplant? Rituximab Maintenance

33 Ongoing 4 arm Phase II Intergroup trial ECOG BR vs. BVR, R vs. R-Len Phase III randomized, double-blind, placebo controlled trial to evaluate BR+R vs. BR+ RI Triangle Study RCHOP/RDAHP + ASCT vs. RCHOP/RDAHP + ASCT + I vs. RCHOP/RDAHP + I + I maintenance

34 Future Directions Novel therapeutics Use of prognostic markers to guide therapy decisions MRD based approaches

35 THANK YOU!