Double Hit Lymphoma 3/2016

Transcription

1 Double Hit Lymphoma 3/2016

2 Thomas M. Habermann et al. JCO 2006;24: View from the Rear View Mirror: FFS and OS after CHOP vs RCHOP

3 MYC-expressing lymphomas Burkitt Lymphoma Positive by definition in BL (100%) Translocation partner usually IGH (14q21) less common variant IGK and IGL MYC rearrangements sole abnormality Target genes involve cellular proliferation DLBCL Occurrence variable (5-16%) Translocation partner is often a non-immunoglobulin gene (i.e. PAX5, BCL6, BCL11A, IKarosZincFinger1) Rearrangements are part of a complex karyotype with 3+ abnormalities Featured genes involved in NFκB pathway and antiapoptotic cascades

4 Aukema S M et al. Blood 2011;117: Distribution of morphologies according to breakpoints.

5 Relationship between BCL-u, DLBCL, BL, double expression and DHL Double expression of mcy/bcl2 by IHC have inferior survival, though their outcome may not be as poor as cytogenetic DHL All pts IHC for MYC and BCL2?all DLBCL FISH for MYC? Test all following by FISH for myc BCLU Immunoblastic DLBCL + by fish + by IHC Up to 1/3 70% ABC Transformed indolent lymphoma British Journal of Haematology Volume 168, Issue 6, pages , 22 DEC 2014

6 MYC, BCL2 and Double Hit Lymphomas Approximately 10% of DLBCL cases harbor an MYC rearrangement, associated with an inferior outcome following RCHOP chemotherapy. Patients with MYC rearrangement without additional breaks in BCL2 or BCL6 : single hit lymphoma Cases that harbor an additional BCL2 (or BCL6) translocation have been termed double hit lymphomas (DHL) and have a particularly poor outcome with standard therapy Most of these are of GCB derivation. Optimal therapy has not been defined, and there is no definite role for upfront transplantation.

7 Single Hit Lymphoma Author Year #pts prognosis Aukema et al (German Molecular Mechanisms in Lymphoma Network) 2014 DHL47/ SHL31 Valera pts DHL4% SHL 3% No difference in survival MYC gains did not adversely affect survival, Amplification, SHL and DHL negative Green 2012 Myc breaks did not confer adverse prognosis unless bcl2 also present Johnson 2012 same

8 Double Hit Lymphoma are more likely to present with extranodal involvement high LDH CNS+ higher IPI scores Worse KPS Increased advanced stage disease

9 OS and PFS of DLBCL treated with RCHOP according to presence of concurrent expression of MYC and BCL2 proteins (DEL) and/or translocations (DHL) Nathalie A. Johnson et al. JCO 2012;30: by American Society of Clinical Oncology

10 Johnson et al, JCO 2012 OS DHL vs. DEL vs. All remaining cases

11 Prognostic impact of MYC/BCL2 coexpression in DLBCL. (A-B) OS (A) and PFS (B) of patients with DLBCL with MYC/BCL2 coexpression (MYC+BCL2+) in the training set. Hu S et al. Blood 2013;121: by American Society of Hematology

12 Prognostic impact of MYC/BCL2 coexpression in DLBCL risk-stratified according to clinicopathologic parameters. Hu S et al. Blood 2013;121: by American Society of Hematology

13 Frequency of BCL2 and MYC expression in COO subtypes of DLBCL. (A) Relative frequency of the ABC vs GCB subtype in DLBCL positive for BCL2 expression, MYC expression, or MYC/BCL2 coexpression in the training set. Hu S et al. Blood 2013;121: by American Society of Hematology

14 MYC/BCL2 coexpression contributes to the inferior prognosis of ABC-DLBCL. Hu S et al. Blood 2013;121: by American Society of Hematology

15 Prognostic impact of MYC/BCL2 coexpression in DLBCL is independent of MYC/BCL2 corearrangement and TP53 mutation status. Hu S et al. Blood 2013;121: by American Society of Hematology

16 Response rates by induction regimen 32% 21% 14% Multicenter retrospective analysis from 23 N.A. centers, , BCL2 or BCL6 + MYC by FISH. 311 pt 2/3 Stage IV 45% B symptoms 10% CNS+ (1/3 no baseline) 41% marrow + 59% extranodal disease 50%DLBCL, 48% BCLU Petrich A M et al. Blood 2014;124:

17 Comparison of long-term, progression-free, and overall survival. PFS/OS ALL PFS/OS by induction regimen Petrich A M et al. Blood 2014;124: RCHOP vs. any more intensive 2014 by American Society of Hematology

18 Overall survival by novel prognostic score, IPI, and R-IPI. IPI 1 point each WBC >10 LDH 3x>ULN Stage 3-4 CNS+ RCHOP vs. more intensive R-IPI LOW 0 points 7% 2yr OS91% INT 1 point 33% 2yr OS 59% HIGH 2+point 60% 2yr OS 41% Petrich A M et al. Blood 2014;124:

19 Overall survival by SCT versus observation in first complete remission. If CR, observation vs. SCTx no difference CNS + prognosis dismal, CNS prophylaxis admin assoc. with better outcome Petrich A M et al. Blood 2014;124: by American Society of Hematology

20 All myc+ PFS Myc-positive VS DHL Bcl2- Untreated, de novo DLBCL or BCLU FISH + for myc No AutoSCT in CR1 Bcl2+ OS Cohen, et al. Cancer Volume 120, Issue 11, pages , 27 FEB 2014 DOI: /cncr cncr.28642/full#cncr28642-fig-0001

21 Myc+ AND DHL, evaluated for PFS and OS based on whether CR1 achieved no autosct in CR1 Cancer Volume 120, Issue 11, pages , 27 FEB 2014 DOI: /cncr

22 MYC + diffuse large B-cell lymphoma is not salvaged by classical R-ICE or R-DHAP followed by BEAM plus autologous stem cell transplantation by Wendy Cuccuini, Josette Briere, Nicolas Mounier, Hans-Ullrich Voelker, Andreas Rosenwald, Christer Sundstrom, Sergio Cogliatti, Edouard Hirchaud, Loic Ysebaert, Dominique Bron, Jean Soulier, Philippe Gaulard, Remi Houlgatte, Christian Gisselbrecht, and Catherine Thieblemont Blood Volume 119(20): May 17, 2012

23 PFS and OS according to the presence (MYC+) or the absence (MYC ) of MYC aberration. 477 pt in CORAL study (R/R DLBCL, compare RICE vs. RDHAP with autohct, and to test maintenance rituximab) 161 had adequate FISH analysis to determine DHL status 28 (17%) were DHL by criteria. ORR to salvage (either) worse, 25% vs. 45% Fewer went to autosctx (43% vs. 60%) Cuccuini W et al. Blood 2012;119:

24 PFS and OS according to the treatment and the presence (MYC+) or absence (MYC ) of MYC aberration. Cuccuini W et al. Blood 2012;119:

25 Double hit lymphoma: Survival by baseline characteristics British Journal of Haematology Volume 166, Issue 6, pages , 18 JUN 2014 DOI: /bjh /bjh.12982/full#bjh fig-0001

26 British Journal of Haematology Volume 166, Issue 6, pages , 18 JUN 2014 DOI: /bjh wiley.com/doi/ /bjh.12982/full# bjh12982-fig-0002 Double hit lymphoma: Survival by prognostic scores

27 Double hit lymphoma: Survival by treatment British Journal of Haematology Volume 166, Issue 6, pages year data 68 vs53% not sig Both 70%

28 Double hit lymphoma: Cumulative incidence of CNS disease British Journal of Haematology Volume 166, Issue 6, pages , 18 JUN 2014 DOI: /bjh

29 Prognostic impact of MYC/BCL2 coexpression in DLBCL. (A-B) OS (A) and PFS (B) of patients with DLBCL with MYC/BCL2 coexpression (MYC+BCL2+) in the training set. Hu S et al. Blood 2013;121: by American Society of Hematology

30 Prognostic impact of MYC/BCL2 coexpression in DLBCL risk-stratified according to clinicopathologic parameters. Hu S et al. Blood 2013;121: by American Society of Hematology

31 Frequency of BCL2 and MYC expression in COO subtypes of DLBCL. (A) Relative frequency of the ABC vs GCB subtype in DLBCL positive for BCL2 expression, MYC expression, or MYC/BCL2 coexpression in the training set. Hu S et al. Blood 2013;121: by American Society of Hematology

32 MYC/BCL2 coexpression contributes to the inferior prognosis of ABC-DLBCL. Hu S et al. Blood 2013;121: by American Society of Hematology

33 Prognostic impact of MYC/BCL2 coexpression in DLBCL is independent of MYC/BCL2 corearrangement and TP53 mutation status. Hu S et al. Blood 2013;121: by American Society of Hematology

34 Double Expressing (MYC/BCL2) and Double Hit Diffuse Large B-cell Lymphoma Have Inferior Survival After Autologous Stem Cell Transplantation Alex F. Herrera, Matthew Mei, Lawrence Low, Reid W. Merryman, Joo Y. Song, Victoria Bedell, Heather Sun, Tanya Paris, Tracey Stiller, Jennifer R. Brown, Elizabeth Budde, Robert Chen, Matthew S. Davids, Arnold Freedman, David C. Fisher, Eric D. Jacobsen, Caron A. Jacobson, Haesook T. Kim, Ann S. LaCasce, Joyce Murata-Collins, Auayporn P. Nademanee, Joycelynne Palmer, German A. Pihan, Tanya Siddiqi, Aliyah R. Sohani, Leslie Popplewell, Jasmine Zain, Larry W. Kwak, David M. Weinstock, Stephen J. Forman, Dennis D. Weisenburger, Young Kim, Scott J. Rodig, Amrita Krishnan, and Philippe Armand City of Hope (COH) and Dana-Farber Cancer Institute (DFCI) American Society of Hematology Annual Meeting 2015

35 Relapsed/Refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL) ~25-40% of DLBCL patients SOC is salvage chemotherapy followed by autologous stem cell transplantation (ASCT) in chemosensitive patients Pre-ASCT PET status, time to relapse, and prognostic indices (e.g. saaipi) associated with outcome (Hamlin et al. Blood 2003, Dickinson et al. BJH 2010, Alousi et al. BJH 2008, Derenzini et al. Cancer 2008, Armand et al. BJH 2012, Guglielmi et al. JCO 1998, Gisselbrecht et al. JCO 2010)

36 Double-Hit DLBCL (DHL) DLBCL with rearrangement of c-myc and BCL2 and/or BCL6 5-10% of newly diagnosed DLBCL Dismal prognosis with standard R-CHOP (Johnson et al. Blood 2009; Green et al. JCO 2012; Petrich et al. Blood 2014) MYC BCL6 BCL2 FISH with dual color break-apart probes for MYC, BCL2, BCL6. Photos courtesy of V. Bedell, 63x Bioview imaging system.

37 MYC/BCL2 Double Expressing DLBCL (DEL) DLBCL with coexpression of c-myc and BCL2 proteins by immunohistochemistry 21-34% of newly diagnosed DLBCL Poor outcomes after R-CHOP, independent of other factors (Johnson et al. JCO 2012; Green et al. JCO 2012) MYC BCL2 Photos courtesy of S. Rodig, 1000x

38 Rationale ~1/2 of chemosensitive R/R DLBCL pts cured with ASCT (Philip et al. NEJM 1995, Gisselbrecht et al. JCO 2010) MYC-rearranged R/R DLBCL: poor outcome after salvage chemo and ASCT (Cuccuini et al. Blood 2012) No data on R/R DEL and ASCT What is impact of DEL and DHL on ASCT outcome in R/R patients?

39 Cohort and Methods Retrospective study of patients with R/R DLBCL or transformed indolent lymphoma (TIL) who underwent ASCT at COH or DFCI/BWH from All patients with archival tissue included IHC for MYC and BCL2 (Ventana, BOND) 2-3 pathologists at each institution, scored in deciles FISH for MYC; BCL2, BCL6 in MYC-rearranged (dual-color break-apart, Abbott) Abnormal value cutoff 10% nuclei

40 Baseline Characteristics Total 201 (100%) DFCI/BWH COH 116 (58%) 85 (42%) Age (median, range) in years 60 (30-77) Male 120 (60%) DLBCL 148 (74%) Transformed indolent B-NHL 53 (26%) Prior therapy lines (median, range) 2 (2-5) Prior rituximab exposure 198 (99%) Primary Refractory/Early Relapse Relapse > 6 mo 107 (53%) 94 (47%)

41 Baseline Characteristics Disease status at ASCT CR PR SD/PD Conditioning CBV BEAM R/Z-BEAM Other Median follow-up for survivors (median, range) in months 120 (60%) 73 (36%) 6 (3%) 133 (66%) 32 (16%) 20 (10%) 16 (8%) 54 (2-155)

42 Immunohistochemistry Results Myc evaluable Median (range) 186 (93%) 30% (0-100%) Bcl2 evaluable Median (range) 188 (94%) 90% (0-100%) Myc and Bcl2 performed 40%/ 50% (DEL) 50%/ 50% 40%/ 70% 50%/ 70% (40%) 64 (35%) 67 (36%) 58 (31%)

43 DEL (MYC+/BCL2+ by IHC) Associated with Poorer Progression-Free Survival Not DEL, n = 111 4y PFS DEL 37%, (95CI 26-48%) Non-DEL 52%, (95CI 42-61%) DEL, n = 74 p = 0.001

44 DEL (MYC+/BCL2+ by IHC) Associated with Poorer Overall Survival Not DEL, n = 111 DEL, n = 74 4y OS DEL 52%, (95CI 39-63%) Non-DEL 69%, (95CI 59-77%) p = 0.005

45 MYC/BCL2 Co-expression Associated with Poorest Outcome MYC+/BCL2-, n = 17 MYC-/BCL2-, n = 36 MYC-/BCL2+, n = 75 DEL, n = 74 p = 0.004

46 FISH Results FISH Myc evaluable Not rearranged Myc-Rearranged Myc alone Double-hit (DHL) Myc/Bcl2 Myc/Bcl6 Myc/Bcl2/Bcl6 164 (82%) 137/164 (84%) 27/164 (16%) 7 (4%) 20/164 (12%) 9 (5%) 6 (4%) 5 (3%)

47 DHL by FISH Associated with Poorer Progression-Free Survival Non-DHL, n = 144 4y PFS DHL 25%, (95CI 8-48%) Non-DHL 48%, (95CI 39-56%) DHL, n = 20 p = 0.007

48 DHL by FISH Associated with Poorer Overall Survival Non-DHL, n = 144 4y OS DHL, n = 20 DHL 34%, (95CI 13-57%) Non-DHL 63%, (95CI 53-71%) p = 0.003

49 Multivariable Analysis (n = 160) Variable Neither DEL (IHC) DHL (FISH) Disease status CR PR SD/PD (n = 6) OS PFS HR p HR p Ref Ref Ref Ref * No center effect observed

50 DEL, DHL, and Other Factors CR, not DEL PR, not DEL CR, DEL PR, DEL p = 0.007

51 Conclusions Prevalence of DEL and DHL in ASCT population similar to initial diagnosis DEL and DHL status are associated with inferior outcome after ASCT Inferior PFS and OS is independent of other factors including remission status Myc alone appears not to drive outcome Target population for study of relapse reduction strategies ASCT remains a curative approach for subset of R/R DEL and DHL patients

52 Resources for patients