1. Double hit lymphomas What are they and how should they be managed?
John P. Leonard, M.D.
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Associate Dean for Clinical Research
Vice Chairman, Department of Medicine

2. Disclosures Consulting advice:
Seattle Genetics, Abbott, Sanofi Aventis, Repligen, Johnson and Johnson, Pharmacyclics, Amgen, Biotest, Millenium, Celgene, Helsinn, GSK, Hospira, Boehringer Ingelheim, Genentech, Onyx, Teva, Medimmune, Gilead, Spectrum, Emergent, Cell Therapeutics

3. 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”

4. 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

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

6. Chromosomal breakpoints in DLBCL
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%
Yoon 2008
137 7%
Tibiletti 2009 74
16%
Copie-Bergman 2009 68
Van Imhoff 2006 58
15% 5%
Savage 2009
135 9% NA
Klapper 2008
117
Aukema et al, Blood 2011

7. MYC+ B cell lymphomas by histology (Mitelman database)
Aukema et al, Blood 2011

8. Selection biases of series
Caveats in understanding clinical characteristics and outcomes in “double hit” lymphoma
Selection biases of series
Where from?
What patients included?
Variability in molecular testing
Challenges and changes in morphologic/pathologic classification
Non-uniform therapy
Single vs multicenter
Retrospective

9. 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

10. Clinical features of “double hit” lymphoma
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
56%
Johnson 2009
54/54 (100%)
46% 62
76%
50%
71%
35%
Kanungo 2006
14/14 (100%)
None 55
93%
79%
21%
57%
Le Gouill 2007
16/16 (100%)
25% 61
100%
94%
88%
81%
Macpherson 1999
15/39 (38%) 65
92%
80%
69%
62%
90%
Niitsu 2009
19/19 (100%)
84%
63%
89%
Snuderl 2010
20/20 (100%)
15% 64
95%
59%
45%
30%
85%
Tomita 2009
27/27 (100%)
17% 51
96%
65% 9%
87%
Aukema et al, Blood 2011

11. 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
R-CHOP, 1.4; HD, 0.26; CHOP, 0.42
Kanungo 2006
14/14 (100%)
CT-NOS; CT and BMT
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
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
0.38
Tomita
27/27 (100%)
CHOP; CODOX-M/IVAC; HyperCVAD
26%
0.5
Aukema et al, Blood 2011

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

13. 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

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

15. FISH DH DLBCL and treatment with R-CHOP
EFS OS
Green et al, JCO 2012

16. IHC score DH DLBCL and treatment with R-CHOP
EFS OS
One point for findings above median IHC+
BCL2+ > 70%
MYC+ > 40%
Green et al, JCO 2012

17. R-CHOP and MYC+/BCL2+ (IHC)
EFS OS
Johnson et al, JCO 2012

18. 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

19. C-MYC and DH/TH DLBCL and outcomes
Generally retrospective analyses
Non-comparative studies
Less favorable outcome than other DLBCL with R-CHOP
Risk seems to be beyond age, IPI
Also less favorable at progression
Rearrangements noted
BCL2 31%
BCL6 18%
C-MYC 13%
C-MYC worse PFS and OS

20. 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

21. 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

22. DA-R-EPOCH and MYC+ DLBCL
Similar
risk by IPI
High RR/PFS in BL
How many had
DH?
EFS OS
Dunleavy et al, Lugano 2011

23. c-MYC+ plasmablastic lymphoma
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
NCT