1. MYC-associated and Double Hit Lymphomas
Lisa G Roth, MD
Division of Hematology/Oncology
Weill Cornell Medical College
New York, NY

2. Overview How to define double hit lymphoma
FISH
IHC
Prognostic relevance of MYC and BLC2 aberrations
Management challenges

3. What is a “double hit” lymphoma?
Recurrent oncogene rearrangements, one being MYC
MYC and BCL2 rearrangements most common
BCL6, CCND1 and BCL3 may also occur
Can also have “triple hit”

4. Burkitt Lymphoma (BL) clinical variants
Endemic BL
Sporadic BL
EBV pos children sub-Saharan Africa MYC/IG breakpoints (somatic hypermutation)
EBV +/- adults MYC/IgH locus
8q24
MYC rearrangement
14q32 (80%)
2p11 (15%)
22q11 (5%)
Immunodeficiency-related BL
EBV pos Cooperation with HIV?

5. MYC translocation is not specific for Burkitt Lymphoma
Diffuse large B-cell lymphoma
B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCL, U)
Follicular lymphoma

6. Frequency of MYC-rearrangements in DLBCL
Reference N
Treatment
MYC rearranged
Outcome UK
245
R-CHOP
35/245 (14%)
2-yr OS 35%
BCCA
135
12/135 (9%)
5-yr OS 33%
Japan
252
CHOP
28/252 (11%)
5-yr OS 44%
France
161
R-CHOP, R-CVP, R-FCM
28/161 (17%) NR
Barrans JCO 28: ; Savage Blood. 2009;114: ; Niitsu Ca Sci 2009; Cuccioni Blood 2010

7. Outcome for MYC pos DLBCL
66%
31%
PFS OS
72%
33%
Savage Blood 2009

8. Outcome for MYC+ DLBCL N=303 de novo DLBCL All treated with R-CHOP
Med f/u 4 years
Barrans J Clin Oncol 28: , 2010

9. MYC rearrangement alone may not explain poor prognosis

10. Frequency of MYC and BCL2-rearrangements in DLBCL
Ref. N
MYC rearr.
MYC and BCL2 rearr.
Comments
Barrans
245
35 (14%)
19 (7.7%)
MYC as sole abnl was rare (2%)
BCCA
135
12 (9%)
3 (2%)
Japan
394
24 (6%)
19 (4.8%)
Only looked at pts with cytogenetic abnl + =
“DOUBLE HIT LYMPHOMA”
MYC
BCL2
Anti-apoptosis
proliferation
Barrans JCO 2010; Savage Blood 2009; Niitsu

11. Double hit lymphoma: BCL2 expression associated with inferior prognosis
Overall Survival
Johnson Blood 2009
Johnson Blood 2009

12. Immunophenotype of Double hit Lymphoma
DLBCL and BCL, U histology
CD10+, GCB phenotype
BCL2 + in 95% of cases
High proliferative index
median 90% Ki67+
Aukema et al, Blood 2011

13. Clinical Characteristics of Double hit Lymphoma
Higher IPI
Worse PS
Higher LDH
Increased advanced stage disease
Increased extranodal sites
Increased CNS disease
Petrich, Cancer 2014

14. How to detect MYC aberrations
Routine karyotyping
FISH break-apart
Rearrangement
Increased copy number
Images courtesy of Dr. Gordana Raca, The University of Chicago

15. NEW: Immunohistochemistry for MYC
Images courtesy of Dr. Girish Venkataraman, The University of Chicago Hematopathology

16. Relative frequency of MYC via IHC
Ref. N
Subtype
MYC rearr
MYC IHC
BCL2
rearr
BCL2 IHC
BCL2 and MYC IHC
Horn 2013
442
DLBCL (RICOVER)
8.8%
32%
(>40%)
13.5%
80%
(>0%)
Johnson 2012
167
DLBCL
(training)
11%
29%
18%
44%
18% overall (vs. 5% with DHL)
140
(validation)
13%
37%
30%
62%
Hu 2013
466
DLBCL (training) NR
64%
50%
(>70%)
34% (vs. 3% with DHL)
Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013

17. IHC expression of BCL2 and MYC is associated with poor prognosis
Overall survival
EFS
Perry BJH 2014

18. Prognosis of classic double hit lymphoma vs
Prognosis of classic double hit lymphoma vs. MYC/BCL2 expressing lymphomas
OS and PFS for classic DHL (MYC/BCL2 rearranged)
OS and PFS for MYC/BCL2 expression
75%
73%
30%
27%
Hu Blood 2013

19. Clinicopathologic features lymphoma expressing MYC and Bcl2
Age, PS, B sx, stage
IPI
CR, COO, Ki67
Hu Blood 2013

20. Prognostic relevance of COO and MYC/Bcl2 protein expression
Co-expression of BCL2 and MYC is 2-fold higher in ABC DLBCL
Hu, et al., Blood. 2013;121(20):
Co-expression of BCL2 and MYC drives the negative outcomes in ABC DLBCL

21. How should we treat double hit lymphoma?
Questions:
R-CHOP vs. intensified treatment?
If intensified treatment – which regimen?
Upfront SCT?
Considerations:
All data to date is retrospective
All data to date is on DHL defined by FISH/cytogenetics not IHC

22. Are more intensive regimens better? MDACC experience
Oki BJH 2014

23. MDACC: SCT in patients achieving CR
Oki BJH 2014

24. Are more intensive regimens better?
Petrich et al, Blood 124 (15), 2014

25. What is the role of SCT in patients who achieve a CR?
Petrich et al, Blood 124 (15), 2014

26. Treatment of double hit lymphoma in 2014: Many questions, no answers
What is the best initial treatment?
Should patients with DHL and IHC-DHL be approached similarly?
Should autologous stem cell transplant be offered as consolidation?
How should relapsed disease be treated?

27. Ongoing trials and new agents
Phase II trial of DA-EPOCH-R (NCI)
Phase I/II trial of lenalidomide plus DA-EPOCH-R
New agents:
Bromodomain inhibitors
Direct inhibitors of BCL2
Dasatinib

28. Thank you!