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MYC-associated and Double Hit L ymphomas

MYC-associated and Double Hit L ymphomas. 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.

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MYC-associated and Double Hit L ymphomas

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

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

  3. 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”

  4. Immunodeficiency-related BL EBV pos Cooperation with HIV? 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%)

  5. 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

  6. Frequency of MYC-rearrangements in DLBCL Barrans JCO 28:3360-3365; Savage Blood. 2009;114: 3533-3537; Niitsu Ca Sci 2009; Cuccioni Blood 2010

  7. 66% PFS 31% 72% OS 33% Outcome for MYC pos DLBCL Savage Blood 2009

  8. Outcome for MYC+ DLBCL • N=303 de novo DLBCL • All treated with R-CHOP • Med f/u 4 years BarransJ ClinOncol 28:3360-3365, 2010

  9. MYC rearrangement alone may not explain poor prognosis

  10. Frequency of MYC and BCL2-rearrangements in DLBCL + = “DOUBLE HIT LYMPHOMA” MYC BCL2 Anti-apoptosis proliferation Barrans JCO 2010; Savage Blood 2009; Niitsu

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

  12. 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

  13. 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

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

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

  16. Relative frequency of MYC via IHC Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013

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

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

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

  20. 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

  21. 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

  22. Are more intensive regimens better? MDACC experience Oki BJH 2014

  23. MDACC: SCT in patients achieving CR Oki BJH 2014

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

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

  26. 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?

  27. 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

  28. Thank you!

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