Double hit lymphomas What are they and how should they be managed? John P. Leonard, M.D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Associate Dean for Clinical Research Vice Chairman, Department of Medicine

Disclosures Consulting advice: Seattle Genetics, Abbott, Sanofi Aventis, Repligen, Johnson and Johnson, Pharmacyclics, Amgen, Biotest, Millenium, Celgene, Helsinn, GSK, Hospira, Boehringer Ingelheim, Genentech, Onyx, Teva, Medimmune, Gilead, Spectrum, Emergent, Cell Therapeutics

What is a “double hit” lymphoma? Recurrent breakpoints activating multiple oncogenes, one being MYC BCL2+/MYC+ most common BCL6, CCND1 and BCL3 may also occur Can also have “triple hit”

B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and Burkitt lymphoma WHO 2008 classification 35-50% of cases have a MYC translocation, 15% have a BCL2 translocation Increasing incidence with age Many are DH

Chromosomal breakpoints in DLBCL Aukema et al, Blood 2011

Chromosomal breakpoints in DLBCL Study N MYC+ total % MYC+ SH % BCL2/ MYC+ DH % BCL6/ MYC+ DH % BCL2/ BCL6/ MYC+ TH % All DH and TH % Barrans 2010 245 14% 2% 8% 1% 3% 12% Obermann 2009 220 4% Yoon 2008 137 7% Tibiletti 2009 74 16% Copie-Bergman 2009 68 Van Imhoff 2006 58 15% 5% Savage 2009 135 9% NA Klapper 2008 117 Aukema et al, Blood 2011

MYC+ B cell lymphomas by histology (Mitelman database) Aukema et al, Blood 2011

Selection biases of series Caveats in understanding clinical characteristics and outcomes in “double hit” lymphoma Selection biases of series Where from? What patients included? Variability in molecular testing Challenges and changes in morphologic/pathologic classification Non-uniform therapy Single vs multicenter Retrospective

Immunophenotype of “double hit” lymphoma CD10+, GCB phenotype Lack MUM1/IRF4 BCL2 + in 95% of cases High proliferative index median 90% Ki67+ Aukema et al, Blood 2011

Clinical features of “double hit” lymphoma Study N DH/ total N (%) DH w prior iNHL % Med age St III/IV % LDH > Nl % BM + % CNS + % > 1 ENS % IPI Hi/HiI % Bertrand 2007 10/17 (59%) 10% 58 70% NA 56% Johnson 2009 54/54 (100%) 46% 62 76% 50% 71% 35% Kanungo 2006 14/14 (100%) None 55 93% 79% 21% 57% Le Gouill 2007 16/16 (100%) 25% 61 100% 94% 88% 81% Macpherson 1999 15/39 (38%) 65 92% 80% 69% 62% 90% Niitsu 2009 19/19 (100%) 84% 63% 89% Snuderl 2010 20/20 (100%) 15% 64 95% 59% 45% 30% 85% Tomita 2009 27/27 (100%) 17% 51 96% 65% 9% 87% Aukema et al, Blood 2011

Treatment and outcome “double hit” lymphoma Study No. of DH/tot (%) Treatment Regimen Overall RR % Median survival, y Bertrand 2007 10/17 (59%) NA 50% < 1 Johnson 2009 54/54 (100%) R-CHOP; HDC +/- SCT; CHOP; P R-CHOP, 1.4; HD, 0.26; CHOP, 0.42 Kanungo 2006 14/14 (100%) CT-NOS; CT and BMT Le Gouill 2007 16/16 (100%) R-CHOP; CHOP; HDC+/- SCT (incl.allo) 75% 0.42 Macpherson 1999 15/39 (38%) CHOP-like; HDC +/- SCT; P 0.21 Niitsu 2009 19/19 (100%) CycloBEAP; CHOP + hi dose MTX; CHOP; R-CHOP 89% 1.5 Snuderl 2010 20/20 (100%) R-ICE/SCT; CHOP; R-CHOP; CODOX-M/IVAC; EPOCH-R 0.38 Tomita 27/27 (100%) CHOP; CODOX-M/IVAC; HyperCVAD 26% 0.5 Aukema et al, Blood 2011

CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL EFS OS Klapper et al, Leukemia 2008 Savage et al, Blood 2009

R-CHOP and MYC rearranged DLBCL 35 (14%) with MYC rearrangements 19 also had t(14;18) 3 also had BCL6 7 “triple hit” Therefore most “MYC+” are “double” or “triple” hit EFS OS Barrans et al, JCO 2010

R-CHOP and MYC rearranged DLBCL Interaction with IPI and age EFS OS Barrans et al, JCO 2010

FISH DH DLBCL and treatment with R-CHOP EFS OS Green et al, JCO 2012

IHC score DH DLBCL and treatment with R-CHOP EFS OS One point for findings above median IHC+ BCL2+ > 70% MYC+ > 40% Green et al, JCO 2012

R-CHOP and MYC+/BCL2+ (IHC) EFS OS Johnson et al, JCO 2012

C-MYC in relapsed DLBCL BioCoral study – relapsed DLBCL Rearrangements noted BCL2 31% BCL6 18% C-MYC 13% C-MYC worse PFS and OS Thieblemont et al, JCO 2011

C-MYC and DH/TH DLBCL and outcomes Generally retrospective analyses Non-comparative studies Less favorable outcome than other DLBCL with R-CHOP Risk seems to be beyond age, IPI Also less favorable at progression Rearrangements noted BCL2 31% BCL6 18% C-MYC 13% C-MYC worse PFS and OS

C-MYC and DH/TH DLBCL and treatment options R-CHOP (nothing to date shown to be better) AutoSCT consolidation Significant number don’t get to SCT Intensive BL type regimens R-EPOCH Less favorable outcome than other DLBCL with R-CHOP Risk seems to be beyond age, IPI Less favorable at progression Rearrangements noted BCL2 31% BCL6 18% C-MYC 13% C-MYC worse PFS and OS

CODOX-M/IVAC and aggressive B cell lymphoma EFS B cell lymphoma, Ki67 >95% Mixture of BL and DLBCL Low and high risk by IPI All 4 DH patients died within 5 mo OS Mead et al, Blood 2008

DA-R-EPOCH and MYC+ DLBCL Similar risk by IPI High RR/PFS in BL How many had DH? EFS OS Dunleavy et al, Lugano 2011

c-MYC+ plasmablastic lymphoma Phase II study of dose adjusted R-EPOCH in previously untreated BL and c-MYC + DLBCL Inclusion criteria Burkitt lymphoma or B-cell lymphoma, unclassifiable, with features intermediate between Diffuse Large B-cell lymphoma and Burkitt Lymphoma c-MYC + DLBCL c-MYC+ plasmablastic lymphoma NCT01092182