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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 - PowerPoint PPT Presentation
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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
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
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
Aukema et al, Blood 2011
Chromosomal breakpoints in DLBCL
Aukema et al, Blood 2011
Study NMYC+ 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
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
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
Aukema et al, Blood 2011
StudyN 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%
Treatment and outcome “double hit” lymphoma
Aukema et al, Blood 2011
StudyNo. 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
200919/19
(100%)CycloBEAP; CHOP + hi dose
MTX; CHOP; R-CHOP89% 1.5
Snuderl 2010 20/20 (100%)
R-ICE/SCT; CHOP; R-CHOP; CODOX-M/IVAC; EPOCH-R
50% 0.38
Tomita
200927/27 (100%)
CHOP; CODOX-M/IVAC; HyperCVAD
26% 0.5
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) outof 1260
57% C-MYC + at dx43% at transformation
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
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 worse PFS and OS
Thieblemont et al, JCO 2011
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
Mead et al, Blood 2008
EFS
OS
B cell lymphoma,Ki67 >95%
Mixture of BL and DLBCL
Low and highrisk by IPI
All 4 DH patientsdied within 5 mo
DA-R-EPOCH and MYC+ DLBCL
Dunleavy et al, Lugano 2011
EFS
OS
9 MYC+ DLBCL
99 MYC- DLBCL
Similarrisk by IPI
High RR/PFS inBL
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 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
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 KetasJessica HansenKaren WeilJennifer O’LoughlinRebecca 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