MCL: Should all Eligible patients with MCL receive HDT-ASCT upfront? Andre Goy, MD Cancer Center Director Lymphoma Division Head John Theurer Cancer Center @ HUMC, NJ Chief Science Officer Research / Innovation RCCA Professor of Medicine at Georgetown agoy@hackensackUMC.org

MCL – Clinical Course – EU MCL Network CR-CRu 20-25%

MCL: High-Dose Therapy as Consolidation CHOP-> ASCT >CHOP-IFN 69 / 75 pts Response IFN arm ASCT arm p value Med DOR 3.7y 1.6 y 0.0004 ITT med TTF 1.4y 2.6y 0.0001 OS 5.4 y 7.5 0.075 Dreyling M, et al. Blood. April 2005 3 3 3

MCL – Management – 4 Phases BEFORE Induction Consolidation Maintenance Salvage More chemo…? Very short response to salvage chemo even with HDT-ASCT CVP, CHOP, FC, CBL Nothing or HDT-ASCT Nothing or IFN Frequent chemoresistance

MCL – Management – 1st Challenge Decide when to treat and recognize “indolent” MCL MIPI Ki-67 Indolent? Hoster, Blood Jan 2008 Determann, Blood Dec 2007

MCL – Management – 1st Challenge Decide when to treat and recognize “indolent” MCL Fernandez, Can Res, Feb 2010

MCL – Management – 1st Challenge Recognize “indolent” MCL iMCL vs. cMCL Fernandez, Can Res, Feb 2010

MCL – Important Steps – Induction Therapy Geisler, Leuk Lymphoma, Aug 2009

MCL – Important Steps – Rituximab Impact Meta analysis showed > OS with R-chemo Elderly “real world” / TTNT med 11 ms, med OS 27 vs 37 ms Schulz, J Natl Cancer Inst, May 2007 Griffith et al, Blood 2011; SEER data

MCL – Important Steps- Rituximab / R-chemo Response CHOP R-CHOP p ORR 74% 94% 0.005 CR 7% 34% 0.00024 TTF 14 ms 21 ms 0.01 59 / 62 pts PFS TTNT OS Rituximab increases ORR, CR rate but med PFS @2y 25%!!! Lenz, JCO, March 2005; Hoster ASH 2008 Schulz, J Natl Cancer Inst, May 2007; Griffith et al, Blood 2011; SEER data

MCL: ASCT remains Relevant in R-chemo Era ASCT vs. Maint IFN in R-chemo era Pooled younger / older HDT /vs. stand + maint IFN ASCT remains relevant in the R-chemo era Hoster, ASH 2008 11 11 11

DIT/ASCT Have Also an Impact Outside of Clinical Trials 167 MCL pts NCCN database – frontline R-chemo - NOT on trial PFS OS 3y PFS R-CHOP 18% 3 times < to any dose-intensive strategy (56-58%) OS K-M p R-HyperCVAD vs R-CHOP P < .04 R-CHOP/ASCT vs R-CHOP P < .20 R-HyperCVAD vs R-CHOP/ASCT TP = .64 When pooling DI-HDT pts / R-CHOP >>> PFS and OS (p=0.001) LaCasce A, et al. Blood, 2012 Mar 1;119(9):2093-9

MCL - Important Steps - Induction Impact Prior to ASCT EFS (R)-CHOP-DHAP  ASCT OS Tripled CR rate after R-DHAP (12% vs. 61%) Med EFS: 84 ms vs. 51 ms prior to rituximab Delarue, Blood Jan 2013 13 13 13

MCL – Important Steps- Induction Impact Prior to ASCT MCL 2: 55% CR-CRu post induction < 60y vs. > 60y / same benefit Geisler, Blood, July 2008

MCL – Important Steps- Induction Impact Prior to ASCT Median follow-up of 6·5 years More than 70% of patients with low-intermediate MIPI-B were alive at 10 years Geisler, Br JnlHeamatol, Aug 2012 Geisler, Blood Feb 2010 Geisler, Br JnlHeamatol, Aug 2012

MCL - Important Steps - Induction Impact Prior to ASCT Multicenter setting Med age 56 y (32-65) Median OS and median response duration BOTH not reached at 10 years Geisler, Blood Feb 2010

MCL - Important Steps - R/AraC Induction Impact Study Therapy 5-Yr EFS, % GITIL[2] (R) HDS-ASCT* 61% MDACC [3,4] R-HyperCVAD 60% / FFS CALGB R-Maxi CHOP-MTX / VP16-AraC/ CBV- ASCT 56% / PFS EU (GELA) R-CHOP/DHAP- TAM ASCT 65% / TTF R-CHOP 2y PFS 25% !! 1. Cortelazzo S, et al. ASH 2007. Abstract 1282. 2. Romaguera JE, et al. J ClinOncol. 2005;23:7013-7023. 4. Fayad L, et al. Clin Lymphoma Myeloma. 2007;8, Delarue, Blood Jan 2013

MCL - Important Steps - R/AraC Induction Impact AraC benefit confirmed in randomized trial MCL Younger < 65 years R Dexa BEAM Cyclo TBI + Autograft P B S C harvest Ara-C, Melphalan 3-monthly follow-up 1 9 5 13 17 week R-CHOP/R-DHAP alternating 3-weekly R-CHOP 3-weekly MRD MRD 2-3 monthly intervals Hermine et al, ASH 2010 abst # 110

MCL - Important Steps - R/AraC Induction Impact 212 pts R-CHOP/ 208 pts R-CHOP/DHAP No diff between arms in pts characteristics or % pts going ASCT (77% / 79%) months TTFT (Primary endpoint) Remission Duration after ASCT w/ med follow up 51 ms, TTF 46 vs 88 ms, p0.038 w/ med follow up 51 ms, remission duration 49 vs 84 ms, p 0.0001 Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

MCL - Important Steps - R/AraC Induction Impact HD AraC translates into > OS as well Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

MCL – Important Steps Benefit in all MIPI groups: TTF ITT Ki67 in low MIPI Hermine O, et al. ASH 2012. Abst # 151

MCL – Important Steps Hermine O, et al. ASH 2012. Abst # 151

Remission duration based on clinical and mol response after induction MCL – Important Steps Remission duration based on clinical and mol response after induction Hermine O, et al. ASH 2012. Abst # 151

EU - MCL Younger Pts - Results Impact of ASCT on MRD status R-CHOP R-DHAP PB BM 25 50 75 100 % MRD negative 54% 70% p = 0.04 p = 0.01 36% 60% 82% 73% 87% ns * Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

MCL – Younger Pts – Frontline Summary Arm R-CHOP-DHAP leads to > outcome TTF, DOR and now OS Due to higher and earlier rate of CR-CRu and molecular CR in HD AraC arm POST induction ++ Med OS AraC arm NR vs 82 ms, p 0.045 Parameter R-CHOP/R-DHAP R-CHOP p CR-CRu 55% 40% p=0.0028 Mol CR 83% 51% p < 0.0001 Post ASCT similar CR-CRu (79/82%) Hermine et al, ASH 2010 abst # 110 / ASH 2012 abst # 151

MCL – Important Steps – ASCT remains relevant in the R-chemo Era TTF w/ R-CHOP vs. R-CHOP/R-DHAPASCT Hoster, AH 2008

MCL – Important Steps – DIT/ASCT remains relevant in the R-chemo Era “Longest mileage” Cost

MCL - DIT/HDT-ASCT - Summary Med OS improvement recognized mostly due to long unprecedented PFS > 5y with DIT and /or HDT-ASCT (40% MCL are <60y) Achieving a deep and early response in MCL matters A CR  translates into >> outcome Molecular CR ++ might become new surrogate endpoint

MCL – DIT-ACST Remains the Best Option in R-Chemo Era Clearly subset of MCL that are more indolent (nonnodal leukemic phase, hypermutated & SOX11 -ve) Novel therapies very promising Platform for combinations (improve mol CR) and /or maintenance post therapy Alternative to chemotherapy (in elderly)

MCL – Management – DIT/ASCT Fit Pts NOW and FORWARD Induction Induction: R-chemo with cytarabine Mol CR as a new endpoint? Beyond standard chemo in MCL Consolidation Still longest PFS Will MOL CR early still need ASCT? Maintenance Still late relapses Novel therapies? PCR based? Salvage Role of HDT/ASCT debated Novel therapies combos? Mini allo? CAR?

Thank you! agoy@HackensackUMC.org