L ymphomas Lisa G Roth MD Division of HematologyOncology Weill Cornell Medical College New York NY Overview How to define double hit lymphoma FISH IHC Prognostic relevance of MYC and BLC2 aberrations ID: 287066
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Slide1
MYC-associated and Double Hit Lymphomas
Lisa G Roth, MDDivision of Hematology/OncologyWeill Cornell Medical CollegeNew York, NY Slide2
Overview
How to define double hit lymphomaFISHIHCPrognostic relevance of MYC and BLC2 aberrations Management challengesSlide3
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”Slide4
Burkitt Lymphoma (BL) clinical variants
Endemic BLEBV pos children sub-Saharan Africa MYC/IG breakpoints (somatic hypermutation)
Sporadic BL
EBV +/- adults MYC/IgH locus
8q24
MYC rearrangement
14q32 (80%)
2p11 (15%)22q11 (5%)Immunodeficiency-related BLEBV pos Cooperation with HIV?Slide5
MYC translocation is not specific for Burkitt Lymphoma
Diffuse large B-cell lymphomaB-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (BCL, U) Follicular lymphoma Slide6
Frequency of MYC-rearrangements
in DLBCLReferenceN
Treatment
MYC rearranged
Outcome
UK
245
R-CHOP35/245 (14%)2-yr OS 35%BCCA135R-CHOP12/135 (9%)5-yr OS 33%Japan252CHOP28/252 (11%)5-yr OS 44%France161
R-CHOP, R-CVP, R-FCM
28/161 (17%)
NR
Barrans JCO 28:3360-3365; Savage
Blood. 2009;114: 3533-3537;
Niitsu Ca Sci 2009; Cuccioni Blood 2010Slide7
Outcome for MYC pos
DLBCL
66%
31%
PFS
OS
72%
33%
Savage Blood 2009Slide8
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 Slide9
MYC rearrangement alone may not explain poor prognosisSlide10
Frequency of MYC and
BCL2-rearrangements in DLBCL
Ref.
N
MYC
rearr
.
MYC and BCL2 rearr.CommentsBarrans24535 (14%)19 (7.7%)MYC as sole abnl was rare (2%)BCCA13512 (9%)3 (2%)Japan
394
24 (6%)
19 (4.8%)
Only looked at
pts
with cytogenetic
abnl
MYC
BCL2
proliferation
Anti-apoptosis
+
=
“DOUBLE HIT LYMPHOMA”
Barrans
JCO 2010;
Savage Blood
2009;
Niitsu
Slide11
Double hit lymphoma
: BCL2 expression associated with inferior prognosis Johnson Blood 2009
Johnson Blood 2009
Overall SurvivalSlide12
Immunophenotype
of Double hit LymphomaDLBCL and BCL, U histology
CD10
+, GCB
phenotype
BCL2
+ in 95% of
casesHigh proliferative index median 90% Ki67+
Aukema
et al, Blood 2011Slide13
Clinical Characteristics of
Double hit LymphomaHigher IPIWorse PS
Higher LDH
Increased advanced stage disease
Increased
extranodal
sites
Increased CNS disease
Petrich
, Cancer 2014Slide14
How to detect MYC aberrations
Routine karyotypingFISH break-apart
Rearrangement
Increased copy number
Images courtesy
of Dr.
Gordana
Raca
, The University of ChicagoSlide15
NEW: Immunohistochemistry for MYC
Images courtesy of Dr. Girish Venkataraman, The University of Chicago HematopathologySlide16
Relative frequency of MYC via IHC
Ref.NSubtype
MYC
rearr
MYC
IHC
BCL2
rearrBCL2 IHCBCL2 and MYC IHCHorn 2013442DLBCL (RICOVER)8.8%32%(>40%)13.5%80%
(>0%)
Johnson 2012
167
DLBCL
(training)
11%
29%
(>40%)
18%
44%
18% overall (vs. 5% with DHL)
Johnson 2012
140
DLBCL
(validation)
13%
37%
(>40%)
30%
62%
Hu 2013
466
DLBCL (training)
NR
64%
(>40%)
NR
50%
(>70%)
34% (vs. 3% with DHL)
Johnson JCO 2012; Horn Blood 2013; Hu Blood 2013Slide17
IHC expression of BCL2 and MYC is associated with poor prognosis
Overall survival
EFS
Perry BJH
2014Slide18
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%Slide19
Clinicopathologic features lymphoma expressing MYC and Bcl2
Hu Blood 2013
Age, PS, B
sx
, stage
CR, COO, Ki67
IPISlide20
Prognostic relevance of COO and MYC/Bcl2 protein expression
Co-expression of BCL2 and MYC is 2-fold higher in ABC DLBCL
Co-expression of BCL2 and MYC drives the negative outcomes in ABC DLBCL
Hu, et al., Blood
. 2013;121(20):4021-4031 Slide21
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 retrospectiveAll data to date is on DHL defined by FISH/cytogenetics
not IHCSlide22
Are more intensive regimens better? MDACC experience
Oki BJH 2014Slide23
MDACC: SCT in patients achieving CR
Oki BJH 2014Slide24
Are more intensive regimens better?
Petrich et al, Blood 124 (15), 2014Slide25
What is the role of SCT in patients who achieve a CR?
Petrich et al, Blood 124 (15), 2014Slide26
Treatment of double hit lymphoma in 2014:
Many questions, no answersWhat 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? Slide27
Ongoing trials and new agents
Phase II trial of DA-EPOCH-R (NCI)Phase I/II trial of lenalidomide plus DA-EPOCH-RNew agents: Bromodomain inhibitors Direct inhibitors of BCL2
Dasatinib
Slide28
Thank you!