Double hit and other molecularly defined large cell lymphomas
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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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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

Lymphoma Research Foundation


Chromosomal translocations in lymphoma and myc

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”


Chromosomal breakpoints in dlbcl

Chromosomal breakpoints in DLBCL

Aukema et al, Blood 2011


Chromosomal breakpoints in dlbcl1

Chromosomal breakpoints in DLBCL

Aukema et al, Blood 2011


What is a double hit lymphoma

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”


Double hit and other molecularly defined large cell lymphomas

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


Immunophenotype of double hit lymphoma

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

Clinical features of “double hit” lymphoma

Aukema et al, Blood 2011


Treatment and outcome double hit lymphoma

Treatment and outcome “double hit” lymphoma

Aukema et al, Blood 2011


Chop choep r chop and myc rearranged dlbcl

CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL

EFS

OS

Klapper et al, Leukemia 2008

Savage et al, Blood 2009


Bcl 2 and myc rearranged double hit lymphomas

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


R chop and myc rearranged dlbcl

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

R-CHOP and MYC rearranged DLBCLInteraction with IPI and age

EFS

OS

Barrans et al, JCO 2010


C myc in relapsed dlbcl

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 treatment options

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

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

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


Phase ii study of dose adjusted r epoch in previously untreated bl and c myc dlbcl

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


Approach to variant dlbcl

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


Acknowledgment

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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