Treatment Strategies for Double Hit/Double Protein Lymphoma. Adam M. Petrich, MD Northwestern University

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1 Treatment Strategies for Double Hit/Double Protein Lymphoma Adam M. Petrich, MD Northwestern University October 24, 2015

2 Courtesy: Kieron Dunleavy, MD Double-protein lymphomas (DPL)

3 DPL=double protein lymphoma= DEL=double expression lymphoma DLBCL*: ~30,000 DPL: ~7,500 MYC aberrancy MYC plus BCL2 aberrancy DHL: ~2,500 IHC 37% 26% FISH 12% 8% *Estimated new cases in the USA % of DLBCL cases Petrich AM, et al. Cancer, 2014.

4 Reference/Year N # MYC + % MYC + # DHL % DHL Van Imhoff, Yoon, Copie-Bergman, NR NR Tibiletti, NR NR Obermann, NR NR Stasik, NR NR Barrans, Tapia, NR NR Kluk, NR NR Johnson, Green, Cuccuini, Valera, Horn, Caponetti, NR NR Wang, Howlett, NR NR Tsai, NR NR 34 6 Landsburg, Totals Petrich, et al, Cancer, 2014

5 MYC rearrangement (RA) in DLBCL: R-CHOP MYC positive DLBCL PFS 66% 31% OS 72% 33% Savage Blood 2009 & Barrans et al, JCO, 2010

6 BCL2 RA among those with MYC RA R-CHOP DA-EPOCH-R Johnson, et al. Blood 2009 Dunleavy, et al. Proc ASH 2014

7 MYC Amplification/Gain of Copy vs. Rearrangement N=224 Amp=amplification in copy number SH=single hit DH=double or triple hit Landsburg, et al, Proc ASH, 2015 (under submission)

8 DHL: IHC vs FISH definition OS *Patients treated with R-CHOP or similar Johnson, et al. J Clin Oncol 2012; 30: 3452

9 % of Patients Double Hit Lymphoma Response rates by induction regimen 100 * * * N=311 Petrich, et al, Blood, PD SD PR CR 20 0 * p<0.05 for CR rate by Fisher s exact test, two-tailed.

10 N=311 Petrich, et al, Blood, 2014

11 N=129 Oki, et al, BJH, 2014

12 Courtesy: Kieron Dunleavy, MD

13 BCL2: Could IHC detection be a better Discriminator of outcome than FISH? DA-EPOCH-R Dunleavy, et al. Proc ASH 2014

14 CNS involvement/progression Petrich, et al, Blood, 2014 Oki, et al, BJH, 2014

15 SCT in first CR Petrich, et al, Blood, 2014 Oki, et al, BJH, 2014

16 Prognostic scoring A B C (A) a novel prognostic score (B) the original international prognostic index (IPI) (C) the revised IPI (DLBCL in the rituximab era) Novel prognostic score: 1. Leukocytosis 2. LDH>3x ULN 3. AA stage 3 or 4 disease 4. CNS involvement *Intensified regimens were NOT associated with improved outcomes among those with 0-1 RF. Petrich, et al, Blood, 2014

17 Relapsed/refractory DHL Petrich, et al, Blood, 2014

18 Relapsed/refractory DEL -Rel/ref DLBCL isenriched for DEL -Difference between PFS and OS suggests better overall salvage rates than DHL -Relapsed/refractory DLBCL/Grade 3 FL treated with R-IVAD -HDT/ASCT or HD MTX in responding patients -MYC IHC cutoff: >40% -BCL2 IHC cutoff: >50% Miura K, et al, Leuk Lymphoma, 2015 Oct 22:1-7. [Epub ahead of print]

19 Remember what it means to give Hyper CVAD Oki, et al, BJH, 2013

20 What is the best approach to DHL? Every patient with DLBCL should be tested for MYC by FISH; BCL2/BCL6 testing can be reserved for only those who are MYC+ BCL2/BCL6 are of limited prognostic value in MYC-negative/unselected DLBCL Those with MYC+ by FISH are more likely than not to have concurrent BCL2 and/or BCL6 rearrangement I would ignore MYC amplification/gain of copy Most patients with DHL should be treated with escalated induction Exceptions include the frail and those with 0-1 prognostic risk factors The aggregate of data pushes me to favor an EPOCH backbone, but hyper CVAD and R-CHOP can still be considered Transplant for DHL in first CR should be a consideration My personal practice is to offer/recommend SCT for those NOT in CR after 2-3 cycles of induction, but who achieve CR at any other point. DHL patients have very little chance at ANY salvage upon relapse progression Any rel/ref DHL patient should be enrolled in a clinical trial of novel agents +/- chemotherapy

21 What is the best approach to DPL/DEL? Patients with DLBCL should have MYC and BCL2 expression evaluated by IHC MYC >40% BCL2 >70% Escalated induction should be considered for DPL/DEL This is based on poor outcomes with R-CHOP, rather than any good data suggesting other combinations are any better The role of transplant in first CR for DPL/DEL is not well studied My personal practice is to offer/recommend SCT for those NOT in early CR Unlike DHL, those with DPL/DEL patients probably have better outcomes with standard multi-agent salvage upon relapse progression This is based on limited data, and clinical trials should always be a consideration at time of relapse

22 MYC Nair SK, Burley SK. Cell, 2003: 112,

23 MYC

24 Preclinical evidence that BET inhibitors downregulate MYC and BCL2

25 Other agents that target MYC and/or BCL2 Ventoclax (ABT-199; GDC-0199) Selinexor (selective inhibitor of nuclear export) Davids MS, et al. Proc EHA 2014; Kuruvilla, et al. ICML 2015

26 Acknowledgments Northwestern University Mitul Gandhi, MD Leo Gordon, MD Jane Winter, MD University of Chicago Chadi Nabhan, MD Sonali Smith, MD NCI Kieron Dunleavy, MD MGH/Dana Farber Jeremy Abramson, MD Weill/Cornell John Leonard, MD