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
 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
Chromosomal breakpoints in DLBCL
Aukema et al, Blood 2011
Chromosomal breakpoints in DLBCL
BCL6/
MYC+
DH %
BCL2/
BCL6/
MYC+ TH
%
All DH
and TH %
Study
N
MYC+
total %
MYC+
SH %
BCL2/
MYC+
DH %
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%
CopieBergman
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
Aukema et al, Blood 2011
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
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%
Study
Aukema et al, Blood 2011
Treatment and outcome “double hit” lymphoma
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
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
Macpherson
1999
Aukema et al, Blood 2011
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
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
EFS
35 (14%) with MYC
rearrangements
19 also had t(14;18)
3 also had BCL6
OS
7 “triple hit”
Therefore most
“MYC+” are “double”
or “triple” hit
Barrans et al, JCO 2010
R-CHOP and MYC rearranged DLBCL
Interaction with IPI and age
EFS
OS
Barrans et al, JCO 2010
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
CODOX-M/IVAC and aggressive B cell lymphoma
EFS
B cell lymphoma,
Ki67 >95%
Mixture of BL
and DLBCL
OS
Low and high
risk by IPI
All 4 DH patients
died within 5 mo
Mead et al, Blood 2008
DA-R-EPOCH and MYC+ DLBCL
9 MYC+ DLBCL
EFS
99 MYC- DLBCL
Similar
risk by IPI
OS
High RR/PFS in
BL
Dunleavy et al, Lugano 2011
Phase II study of dose adjusted REPOCH 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
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
Laboratory Research
Ari Milneck, M.D., Ph.D.(Cornell)
Katherine Hajjar, M.D. (Cornell)
Shahin Rafii, M.D. (Cornell)
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