This document summarizes key information about double hit lymphomas and other molecularly defined large B-cell lymphomas. It discusses how approximately 40% of B-cell lymphomas involve chromosomal translocations involving oncogenes like MYC and BCL2. Double hit lymphomas specifically involve recurrent breakpoints activating both MYC and another oncogene like BCL2. These tumors have a germinal center B-cell phenotype and poor response to standard R-CHOP chemotherapy, with median survival usually less than 1 year. More intensive chemotherapy regimens like dose-adjusted EPOCH show promise for improving outcomes in double hit lymphoma and other MYC-rearranged large B-cell lymphomas.

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

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

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

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

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

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. 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. 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

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