MYC-associated and Double Hit Lymphomas Lisa G Roth, MD Division of Hematology/Oncology Weill Cornell Medical College New York, NY

Overview How to define double hit lymphoma FISH IHC Prognostic relevance of MYC and BLC2 aberrations Management challenges

What is a “double hit” lymphoma? Recurrent oncogene rearrangements, one being MYC MYC and BCL2 rearrangements most common BCL6, CCND1 and BCL3 may also occur Can also have “triple hit”

Burkitt Lymphoma (BL) clinical variants Endemic BL Sporadic BL EBV pos children sub-Saharan Africa MYC/IG breakpoints (somatic hypermutation) EBV +/- adults MYC/IgH locus 8q24 MYC rearrangement 14q32 (80%) 2p11 (15%) 22q11 (5%) Immunodeficiency-related BL EBV pos Cooperation with HIV?

MYC translocation is not specific for Burkitt Lymphoma Diffuse large B-cell lymphoma B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCL, U) Follicular lymphoma

Frequency of MYC-rearrangements in DLBCL Reference N Treatment MYC rearranged Outcome UK 245 R-CHOP 35/245 (14%) 2-yr OS 35% BCCA 135 12/135 (9%) 5-yr OS 33% Japan 252 CHOP 28/252 (11%) 5-yr OS 44% France 161 R-CHOP, R-CVP, R-FCM 28/161 (17%) NR Barrans JCO 28:3360-3365; Savage Blood. 2009;114: 3533-3537; Niitsu Ca Sci 2009; Cuccioni Blood 2010

Outcome for MYC pos DLBCL 66% 31% PFS OS 72% 33% Savage Blood 2009

Outcome for MYC+ DLBCL N=303 de novo DLBCL All treated with R-CHOP Med f/u 4 years Barrans J Clin Oncol 28:3360-3365, 2010

MYC rearrangement alone may not explain poor prognosis

Frequency of MYC and BCL2-rearrangements in DLBCL Ref. N MYC rearr. MYC and BCL2 rearr. Comments Barrans 245 35 (14%) 19 (7.7%) MYC as sole abnl was rare (2%) BCCA 135 12 (9%) 3 (2%) Japan 394 24 (6%) 19 (4.8%) Only looked at pts with cytogenetic abnl + = “DOUBLE HIT LYMPHOMA” MYC BCL2 Anti-apoptosis proliferation Barrans JCO 2010; Savage Blood 2009; Niitsu

Double hit lymphoma: BCL2 expression associated with inferior prognosis Overall Survival Johnson Blood 2009 Johnson Blood 2009

Immunophenotype of Double hit Lymphoma DLBCL and BCL, U histology CD10+, GCB phenotype BCL2 + in 95% of cases High proliferative index median 90% Ki67+ Aukema et al, Blood 2011

Clinical Characteristics of Double hit Lymphoma Higher IPI Worse PS Higher LDH Increased advanced stage disease Increased extranodal sites Increased CNS disease Petrich, Cancer 2014

How to detect MYC aberrations Routine karyotyping FISH break-apart Rearrangement Increased copy number Images courtesy of Dr. Gordana Raca, The University of Chicago

NEW: Immunohistochemistry for MYC Images courtesy of Dr. Girish Venkataraman, The University of Chicago Hematopathology

Relative frequency of MYC via IHC Ref. N Subtype MYC rearr MYC IHC BCL2 rearr BCL2 IHC BCL2 and MYC IHC Horn 2013 442 DLBCL (RICOVER) 8.8% 32% (>40%) 13.5% 80% (>0%) Johnson 2012 167 DLBCL (training) 11% 29% 18% 44% 18% overall (vs. 5% with DHL) 140 (validation) 13% 37% 30% 62% Hu 2013 466 DLBCL (training) NR 64% 50% (>70%) 34% (vs. 3% with DHL) Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013

IHC expression of BCL2 and MYC is associated with poor prognosis Overall survival EFS Perry BJH 2014

Prognosis of classic double hit lymphoma vs Prognosis of classic double hit lymphoma vs. MYC/BCL2 expressing lymphomas OS and PFS for classic DHL (MYC/BCL2 rearranged) OS and PFS for MYC/BCL2 expression 75% 73% 30% 27% Hu Blood 2013

Clinicopathologic features lymphoma expressing MYC and Bcl2 Age, PS, B sx, stage IPI CR, COO, Ki67 Hu Blood 2013

Prognostic relevance of COO and MYC/Bcl2 protein expression Co-expression of BCL2 and MYC is 2-fold higher in ABC DLBCL Hu, et al., Blood. 2013;121(20):4021-4031 Co-expression of BCL2 and MYC drives the negative outcomes in ABC DLBCL

How should we treat double hit lymphoma? Questions: R-CHOP vs. intensified treatment? If intensified treatment – which regimen? Upfront SCT? Considerations: All data to date is retrospective All data to date is on DHL defined by FISH/cytogenetics not IHC

Are more intensive regimens better? MDACC experience Oki BJH 2014

MDACC: SCT in patients achieving CR Oki BJH 2014

Are more intensive regimens better? Petrich et al, Blood 124 (15), 2014

What is the role of SCT in patients who achieve a CR? Petrich et al, Blood 124 (15), 2014

Treatment of double hit lymphoma in 2014: Many questions, no answers What is the best initial treatment? Should patients with DHL and IHC-DHL be approached similarly? Should autologous stem cell transplant be offered as consolidation? How should relapsed disease be treated?

Ongoing trials and new agents Phase II trial of DA-EPOCH-R (NCI) Phase I/II trial of lenalidomide plus DA-EPOCH-R New agents: Bromodomain inhibitors Direct inhibitors of BCL2 Dasatinib

Thank you!