1. No category

MYC-associated and Double Hit
Lymphomas
Lisa G Roth, MD
Division of Hematology/Oncology
Weill Cornell Medical College
New York, NY
Overview
• How to define double hit lymphoma
– FISH
– IHC
• Prognostic relevance of MYC and BLC2
aberrations
• Management challenges
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”
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?
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
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
R-CHOP
12/135 (9%)
Japan
252
CHOP
28/252 (11%) 5-yr OS 44%
France
161
R-CHOP, RCVP, R-FCM
28/161 (17%) NR
Barrans JCO 28:3360-3365; Savage Blood. 2009;114:
3533-3537; Niitsu Ca Sci 2009; Cuccioni Blood 2010
5-yr OS 33%
Outcome for MYC pos DLBCL
66%
PFS
31%
72%
OS
33%
Savage Blood 2009
Outcome for MYC+ DLBCL
• N=303 de novo DLBCL
• All treated with R-CHOP
• Med f/u 4 years
Barrans J Clin Oncol 28:3360-3365, 2010
MYC rearrangement alone may not
explain poor prognosis
Frequency of MYC and BCL2-rearrangements
in DLBCL
Ref.
N
MYC
rearr.
MYC and
BCL2 rearr.
Barrans
245 35 (14%) 19 (7.7%)
BCCA
135 12 (9%)
3 (2%)
Japan
394 24 (6%)
19 (4.8%)
MYC
proliferation
+
BCL2
Antiapoptosis
Barrans JCO 2010; Savage Blood 2009; Niitsu
=
Comments
MYC as sole abnl
was rare (2%)
Only looked at pts
with cytogenetic
abnl
“DOUBLE HIT
LYMPHOMA”
Overall Survival
Double hit lymphoma: BCL2 expression
associated with inferior prognosis
Johnson Blood 2009
Johnson Blood 2009
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
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
How to detect MYC aberrations
Routine
karyotyping
FISH breakapart
Rearrangement
Images courtesy of Dr. Gordana Raca, The University of Chicago
Increased copy
number
NEW: Immunohistochemistry for MYC
Images courtesy of Dr. Girish Venkataraman, The University of Chicago
Hematopathology
Relative frequency of MYC via IHC
Ref.
N
Subtype
MYC
rearr
Horn
2013
442
DLBCL
(RICOVER)
8.8%
Johnson
2012
167
DLBCL
(training)
11%
Johnson
2012
140
DLBCL
(validation)
13%
Hu 2013
466
DLBCL
(training)
NR
MYC
IHC
32%
BCL2
rearr
13.5%
(>40%)
29%
BCL2
IHC
80%
(>0%)
18%
44%
30%
62%
NR
50%
(>40%)
37%
(>40%)
64%
(>40%)
Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013
BCL2 and
MYC IHC
(>70%)
18%
overall (vs.
5% with
DHL)
34% (vs.
3% with
DHL)
IHC expression of BCL2 and MYC is
associated with poor prognosis
Overall survival
Perry BJH 2014
EFS
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
Hu Blood 2013
75%
30%
73%
27%
Clinicopathologic features lymphoma
expressing MYC and Bcl2
Age, PS, B
sx, stage
IPI
CR, COO,
Ki67
Hu Blood 2013
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):40214031
Co-expression of BCL2 and MYC drives
the negative outcomes in ABC DLBCL
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
Are more intensive regimens better?
MDACC experience
Oki BJH 2014
MDACC: SCT in patients achieving CR
Oki BJH 2014
Are more intensive regimens better?
Petrich et al, Blood 124 (15), 2014
What is the role of SCT in patients
who achieve a CR?
Petrich et al, Blood 124 (15), 2014
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?
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
Thank you!