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DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS

DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS. Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma New York-Presbyterian Hospital Weill Cornell Medical Center Clinical Professor of Medicine Weill Cornell Medical College Chairman, Medical Affiliates Board

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DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS

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  1. DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS Morton Coleman, M.D. Director, Center for Lymphoma and Myeloma New York-Presbyterian Hospital Weill Cornell Medical Center Clinical Professor of Medicine Weill Cornell Medical College Chairman, Medical Affiliates Board Lymphoma Research Foundation

  2. Chromosomal translocations in lymphoma and MYC • 40% of B cell lymphomas have recurrent reciprocal translocations • May be subtype specific • Often oncogene plus Ig loci enhancer • t(8;14)(q24;q32) – lymphoma initiating in BL • MYC breakpoints may be secondary events in other lymphomas • At diagnosis or at progression • In MYC+ DLBCL and DH lymphoma, often non Ig-MYC breakpoints • “Double hit”

  3. Chromosomal breakpoints in DLBCL Aukema et al, Blood 2011

  4. Chromosomal breakpoints in DLBCL Aukema et al, Blood 2011

  5. 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”

  6. 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

  7. 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

  8. Clinical features of “double hit” lymphoma Aukema et al, Blood 2011

  9. Treatment and outcome “double hit” lymphoma Aukema et al, Blood 2011

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

  11. BCL-2 and MYC rearranged “double hit” lymphomas EFS 55 cases (BCCA) out of 1260 57% C-MYC + at dx 43% at transformation OS Johnson et al, Blood 2009

  12. 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

  13. R-CHOP and MYC rearranged DLBCLInteraction with IPI and age EFS OS Barrans et al, JCO 2010

  14. 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

  15. 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

  16. 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

  17. DA-R-EPOCH and MYC+ DLBCL 9 MYC+ DLBCL 99 MYC- DLBCL Similar risk by IPI High RR/PFS in BL EFS OS Dunleavy et al, Lugano 2011

  18. 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

  19. Approach to “variant” DLBCL • GCB vs non-GCB • R-CHOP is standard • Various randomized trials underway • MYC+, DH, TH • Consider FISH for MYC, BCL2, BCL6 • Less favorable with R-CHOP • Unclear if other approaches better • Prospective studies underway • Analysis needs incorporation in clinical trials • 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

  20. Wayne Tam, M.D. Amy Chadburn, M.D. (Northwestern) Elizabeth Hyjek, M.D., Ph.D. Acknowledgment Clinical Research Jia Ruan, M.D., Ph.D. Richard Furman, M.D. John P. Leonard, M.D. Peter Martin, M.D. Maureen Joyce, R.N. Patricia Glenn, R.N. Jamie Ketas Jessica Hansen Karen Weil Jennifer O’Loughlin Rebecca Elstrom Translational Core Maureen Lane, Ph.D. (Cornell) Maureen Ward Biostatistician Ken Chueng, Ph.D. (Columbia) Madhu Mazumdar, Ph.D. (Cornell) Lymphoma Research Foundation ASCO Foundation (YIA, CDA) NIH / NHLBI Laboratory Research Ari Milneck, M.D., Ph.D.(Cornell) Katherine Hajjar, M.D. (Cornell) Shahin Rafii, M.D. (Cornell)

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