ESMO DOUBLE-HIT LYMPHOMAS

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1 ESMO DOUBLE-HIT LYMPHOMAS Professor Dr. med. Georg Lenz Director Department of Hematology and Oncology Universitätsklinikum Münster, Germany

2 OVERVIEW Definition of double-hit lymphomas Introduction in the biology of MYC Impact on the prognosis of affected patients Therapeutic implications Summary

3 WHAT ARE DOUBLE HIT LYMPHOMAS? Definition: aggressive lymphomas with MYC and BCL2 or less frequently BCL6 translocations However, some studies have not even looked for BCL6 translocations Currently it does not refer to lymphomas in which MYC translocations occur with other chromosomal translocations The term double hit implies that these lymphomas harbour only two genetic aberrations

4 MYC IS DEREGULATED IN DIFFERENT CANCERS Squamous cell carcinoma Ovarian cancer Pancreatic cancer Malignant lymphoma Slide courtesy of German Ott

5 BIOLOGIC ROLE OF MYC MYC regulates roughly 15% of all genes

6 BIOLOGIC ROLE OF MYC MYC regulates roughly 15% of all genes MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes

7 BIOLOGIC ROLE OF MYC MYC regulates roughly 15% of all genes MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes MYC can activate or repress gene expression

8 MYC CONTROLS DIFFERENT BIOLOGIC PROCESSES Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Nat Rev Cancer, Analysis of genomic targets reveals complex functions of MYC. Patel JH, et al., Copyright 2004.

9 BIOLOGIC ROLE OF MYC MYC regulates roughly 15% of all genes MYC dimerizes with MAX to bind specific DNA sequences known as E-boxes MYC can activate or repress gene expression Different genetic aberrations deregulate MYC expression

10 DIFFUSE LARGE B-CELL LYMPHOMA

11 8 10% OF ALL DLBCLs ARE CHARACTERISED BY MYC TRANSLOCATIONS Hecht JL, et al., J Clin Oncol, 18(21), 2000: Reprinted with permission American Society of Clinical Oncology. All rights reserved

12 GENE EXPRESSION PROFILING DIFFERENTIATES BURKITT LYMPHOMA FROM MOLECULAR DLBCL SUBTYPES From N Engl J Med, Dave SS, et al., Molecular diagnosis of Burkitt's lymphoma, 354: Copyright 2006 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

13 DLBCLs WITH MYC TRANSLOCATIONS SHOW A GENE EXPRESSION PROFILE OF DLBCLs From N Engl J Med, Dave SS, et al., Molecular diagnosis of Burkitt's lymphoma, 354: Copyright 2006 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

14 DLBCLs WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL AFTER R-CHOP p=0.006 p=0.016 Republished with permission of American Society of Hematology, from Blood, Savage K, et al., , 2009, permission conveyed through Copyright Clearance Center, Inc.

15 DLBCLs WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL AFTER R-CHOP Incidence 8.8% p=0.006 Characterised by high proliferation Increased risk of CNS relapse p= /12 cases with MYC rearrangement had concurrent t(14;18) Republished with permission of American Society of Hematology, from Blood, Savage K, et al.;114-17, 2009, permission conveyed through Copyright Clearance Center, Inc.

16 DLBCLs WITH MYC AND BCL2 TRANSLOCATIONS ARE CHARACTERISED BY INFERIOR SURVIVAL Reprinted by permission from Springer Customer Service Centre GmbH: Springer Nature, Leukemia, Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations, Niitsu N, et al.,copyright 2009.

17 DLBCLs WITH SINGLE MYC OR DOUBLE HIT ARE CHARACTERISED BY INFERIOR SURVIVAL Republished with permission of American Society of Hematology, from Blood, Copie-Bergman C, et al., 126, 22; 2015, permission conveyed through Copyright Clearance Center, Inc.

18 DLBCLs WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL AFTER R-CHOP Barrans S, et al., J Clin Oncol, 28(20), 2010: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

19 DLBCLs WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL AFTER R-CHOP 74% of cases with MYC rearrangement had concurrent t(14;18) 26% of cases with MYC rearrangement had a BCL6 translocation Barrans S, et al., J Clin Oncol, 28(20), 2010: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

20 RELAPSED DLBCL CASES WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL Progression free survival Overall survival Republished with permission of American Society of Hematology, from Blood, Cuccuini W, et al., 119, 20; 2012, permission conveyed through Copyright Clearance Center, Inc.

21 RELAPSED DLBCL CASES WITH MYC REARRANGEMENT ARE CHARACTERISED BY INFERIOR SURVIVAL Progression free survival Overall survival 17% (28/161) of patients have MYC rearrangement 75% (21/28) harbour one or more concurrent translocation (BCL2, BCL6) MYC+ patients have advanced aaipi, elevated LDH Republished with permission of American Society of Hematology, from Blood, Cuccuini W, et al., 119, 20; 2012, permission conveyed through Copyright Clearance Center, Inc.

22 TRANSLOCATION PARTNERS MIGHT IMPACT PROGNOSIS Pedersen MO, et al., Eur J Haematol 2014;92(1): John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

23 MYC EXPRESSION IS DETECTABLE IN A RELATIVELY HIGH FRACTION OF DLBCL CASES RICOVER DATA MYC FISH R 36/407 (8.8%) MYC only 14/35 (40%) MYC/additional break 21/35 (60%) MYC IHC+ (>40%) 90/283 (31.8%) Horn H, et al., Blood 2013;121(12): Courtesy of German Ott

24 DLBCL REPRESENTS A HETEROGENEOUS DISEASE WITH DISTINCT MOLECULAR SUBTYPES Nogai H, et al., J Clin Oncol, 29(14), 2011: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

25 ABC AND GCB DLBCL HAVE SIGNIFICANTLY DIFFERENT SURVIVAL RATES FOLLOWING R-CHOP From N Engl J Med, Lenz G, et al., Stromal gene signatures in large-b-cell lymphomas, 359, Copyright 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

26 GCB ABC MYC-R Slide courtesy of Kieron Dunleavy.

27 GCB ABC Double-hit lymphomas High BCL-2 expression BCL-2-R MYC-R High MYC expression Slide courtesy of Kieron Dunleavy.

28 DLBCL CASES THAT EXPRESS BOTH MYC AND BCL2 ARE CHARACTERISED BY ADVERSE PROGNOSIS Johnson NA, et al., J Clin Oncol, 30(28), 2012: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

29 DLBCL CASES THAT EXPRESS BOTH MYC AND BCL2 ARE CHARACTERISED BY ADVERSE PROGNOSIS Johnson NA, et al., J Clin Oncol, 30(28), 2012: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

30 DOUBLE EXPRESSERS ARE CHARACTERISED BY INCREASED CNS RELAPSE RISK Republished with permission of American Society of Hematology, from Blood, Savage KJ, et al., 127, 18; 2016, permission conveyed through Copyright Clearance Center, Inc.

31 THERAPEUTIC IMPLICATIONS

32 ARE MORE INTENSIVE REGIMENS BETTER THAN R-CHOP?

33 DOSE-ADJUSTED-EPOCH-R Dose-Adjusted EPOCH-R Chemotherapy Dose mg/m 2 /day Treatment Days Infusional Agents Etoposide Vincristine Doxorubicin Bolus Agents Prednisone Cyclophosphamide BID 750 Days 1-4 Days 1-4 Day 5 Biologic Agents Rituximab 375 Day 1 Filgrastim 5 (mg/kg) Days 6! ANC recovery Pharmacodynamic Dose Adjustment

34 Progression-free survival (%) DA-EPOCH-R IN MYC-R AND MYC DLBCL 100 Total samples FISH: N=108 MYC-R MYC- 9 (8%) 99 (92%) MYC-R MYC-neg Low IPI 4 (44%) 56 (57%) High IPI 5 (56%) 43 (43%) *P= P=0.59 Median f/up 4 years Time (years) *Fisher s Exact Test Dunleavy K, et al. Lugano, 2011.

35 DA-EPOCH-R IN MYC-R DLBCL Untreated patients Age 18 years De-novo DLBCL (transformed excluded) or BCL-U MYC-R + by FISH or cytogenetics Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.

36 DA-EPOCH-R IN MYC-R DLBCL N=52 Characteristics % Median (range) age (years) 61y (29-80y) Male sex 71% Stage III or IV 73% High LDH 59% CNS disease 6% IPI score Histology DLBCL BCL-U MYC+ by FISH or cytogenetics BCL2+ by FISH BCL2 High by IHC 35% 65% 86% 14% 100% 45%* 56% *Of 31 cases tested. Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.

37 Survival (%) PROGRESSION-FREE SURVIVAL ALL PATIENTS Median f/up 14 months Time (months) Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.

38 Survival (%) PFS IMPACT OF BCL2-R (DHL) P=0.23 Median f/up 14 months BCL2-R Cases that underwent a consolidative transplant were censored Time (months) Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.

39 Survival (%) PFS IMPACT OF BCL2 IHC P=0.044 Median f/up 14 months BCL2+ BCL2 Cases that underwent a consolidative transplant were censored Time (months) Dunleavy K, et al., Blood 2014;124:395. Presented at American Society of Hematology Annual Meeting 2014.

40 META-ANALYSIS ON DOSE INTENSIFICATION IN DOUBLE HIT LYMPHOMAS Howlett C, et al., Br J Haematol 2015;170(4): Reprinted with permission 2015 John Wiley & Sons Ltd.

41 META-ANALYSIS ON DOSE INTENSIFICATION IN DOUBLE HIT LYMPHOMAS Howlett C, et al., Br J Haematol 2015;170(4): Reprinted with permission 2015 John Wiley & Sons Ltd.

42 INTENSIFICATION MIGHT IMPROVE OUTCOME OF PATIENTS WITH DOUBLE HIT LYMPHOMA Landsburg DJ, et al., J Clin Oncol, 35(20), 2017: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

43 ASCT DOES NOT SEEM TO IMPROVE OUTCOME OF PATIENTS WITH DOUBLE HIT LYMPHOMA Landsburg DJ, et al., J Clin Oncol, 35(20), 2017: Reprinted with permission American Society of Clinical Oncology. All rights reserved.

44 CONCLUSIONS Double hit lymphomas are still not completely defined and understood MYC-positive and double hit lymphomas seem to be characterised by adverse survival DA-EPOCH-R might overcome therapeutic dilemma of MYC-positive and double hit lymphomas Incorporation of novel agents into molecularly defined subsets of DLBCL is crucial to improve prognosis of affected patients

45 THANK YOU!