DOUBLE HIT AND OTHER MOLECULARLY
DEFINED LARGE CELL LYMPHOMAS
Morton Coleman, M.D.
Director, Center for Lymphoma and Myelo...
Chromosomal translocations in
lymphoma and MYC
• 40% of B cell lymphomas have recurrent
reciprocal translocations
– May be...
Chromosomal breakpoints in DLBCL
Aukema et al, Blood 2011
Chromosomal breakpoints in DLBCL
Aukema et al, Blood 2011
Study N
MYC+
total %
MYC+
SH %
BCL2/
MYC+ DH
%
BCL6/
MYC+
DH %
B...
What is a “double hit” lymphoma?
• Recurrent breakpoints activating multiple
oncogenes, one being MYC
• BCL2+/MYC+ most co...
B cell lymphoma, unclassifiable, with
features intermediate between diffuse
large B cell lymphoma and Burkitt
lymphoma
• W...
Immunophenotype of “double hit”
lymphoma
• CD10+, GCB phenotype
• Lack MUM1/IRF4
• BCL2 + in 95% of cases
• High prolifera...
Clinical features of “double hit” lymphoma
Aukema et al, Blood 2011
Study
N DH/
total N
(%)
DH w
prior
iNHL
%
Med
age
St I...
Treatment and outcome “double hit” lymphoma
Aukema et al, Blood 2011
Study
No. of
DH/tot (%)
Treatment Regimen
Overall
RR ...
CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL
Klapper et al, Leukemia 2008
EFS
OS
Savage et al, Blood 2009
BCL-2 and MYC rearranged “double hit”
lymphomas
Johnson et al, Blood 2009
EFS
OS
55 cases (BCCA) out
of 1260
57% C-MYC + a...
R-CHOP and MYC rearranged DLBCL
Barrans et al, JCO 2010
EFS
OS
35 (14%) with MYC
rearrangements
19 also had t(14;18)
3 als...
R-CHOP and MYC rearranged DLBCL
Interaction with IPI and age
Barrans et al, JCO 2010
EFS
OS
C-MYC in relapsed DLBCL
• BioCoral study – relapsed DLBCL
• Rearrangements noted
– BCL2 31%
– BCL6 18%
– C-MYC 13%
• C-MYC...
C-MYC and DH/TH DLBCL and
treatment options
• R-CHOP (nothing to date shown to be
better)
• AutoSCT consolidation
– Signif...
CODOX-M/IVAC and aggressive B cell lymphoma
Mead et al, Blood 2008
EFS
OS
B cell lymphoma,
Ki67 >95%
Mixture of BL
and DLB...
DA-R-EPOCH and MYC+ DLBCL
Dunleavy et al, Lugano 2011
EFS
OS
9 MYC+ DLBCL
99 MYC- DLBCL
Similar
risk by IPI
High RR/PFS in...
Phase II study of dose adjusted R-
EPOCH in previously untreated BL and
c-MYC + DLBCL
• Inclusion criteria
– Burkitt lymph...
Approach to “variant” DLBCL
• GCB vs non-GCB
– R-CHOP is standard
– Various randomized trials underway
• MYC+, DH, TH
– Co...
Acknowledgment
Clinical Research
Jia Ruan, M.D., Ph.D.
Richard Furman, M.D.
John P. Leonard, M.D.
Peter Martin, M.D.
Maure...
DOUBLE HIT AND OTHER MOLECULARLY DEFINED LARGE CELL LYMPHOMAS
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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

  1. 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. 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
  3. 3. Chromosomal breakpoints in DLBCL Aukema et al, Blood 2011
  4. 4. Chromosomal breakpoints in DLBCL Aukema et al, Blood 2011 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% 3% 0 0 0 1% Yoon 2008 137 7% 7% 1% 1% 1% 3% Tibiletti 2009 74 16% 4% 7% 7% 1% 12% Copie- Bergman 2009 68 3% 3% 0 0 0 0 Van Imhoff 2006 58 15% 8% 5% 2% 0 7% Savage 2009 135 9% 7% 2% NA NA NA Klapper 2008 117 8% NA NA NA NA NA
  5. 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. 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. 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. 8. Clinical features of “double hit” lymphoma Aukema et al, Blood 2011 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 NA NA NA 56% Johnson 2009 54/54 (100%) 46% 62 76% 50% 71% NA 35% 70% Kanungo 2006 14/14 (100%) None 55 NA 93% 79% 21% 57% NA Le Gouill 2007 16/16 (100%) 25% 61 100% 100% 94% 50% 88% 81% Macpherson 1999 15/39 (38%) 46% 65 92% 80% 69% NA 62% 90% Niitsu 2009 19/19 (100%) None 61 100% 100% 84% 21% 63% 89% Snuderl 2010 20/20 (100%) 15% 64 95% 100% 59% 45% 30% 85% Tomita 2009 27/27 (100%) 17% 51 96% 93% 65% 9% 65% 87%
  9. 9. Treatment and outcome “double hit” lymphoma Aukema et al, Blood 2011 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 NA R-CHOP, 1.4; HD, 0.26; CHOP, 0.42 Kanungo 2006 14/14 (100%) CT-NOS; CT and BMT NA < 1 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 NA 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 50% 0.38 Tomita 2009 27/27 (100%) CHOP; CODOX-M/IVAC; HyperCVAD 26% 0.5
  10. 10. CHOP/CHOEP/R-CHOP and MYC rearranged DLBCL Klapper et al, Leukemia 2008 EFS OS Savage et al, Blood 2009
  11. 11. BCL-2 and MYC rearranged “double hit” lymphomas Johnson et al, Blood 2009 EFS OS 55 cases (BCCA) out of 1260 57% C-MYC + at dx 43% at transformation
  12. 12. R-CHOP and MYC rearranged DLBCL Barrans et al, JCO 2010 EFS OS 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
  13. 13. R-CHOP and MYC rearranged DLBCL Interaction with IPI and age Barrans et al, JCO 2010 EFS OS
  14. 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. 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
  16. 16. CODOX-M/IVAC and aggressive B cell lymphoma Mead et al, Blood 2008 EFS OS B cell lymphoma, Ki67 >95% Mixture of BL and DLBCL Low and high risk by IPI All 4 DH patients died within 5 mo
  17. 17. DA-R-EPOCH and MYC+ DLBCL Dunleavy et al, Lugano 2011 EFS OS 9 MYC+ DLBCL 99 MYC- DLBCL Similar risk by IPI High RR/PFS in BL
  18. 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. 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
  20. 20. 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 Biostatistician Ken Chueng, Ph.D. (Columbia) Madhu Mazumdar, Ph.D. (Cornell) Translational Core Maureen Lane, Ph.D. (Cornell) Maureen Ward Laboratory Research Ari Milneck, M.D., Ph.D.(Cornell) Katherine Hajjar, M.D. (Cornell) Shahin Rafii, M.D. (Cornell) Lymphoma Research Foundation ASCO Foundation (YIA, CDA) NIH / NHLBI

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