myc-associated and double hit lymphomas lisa g roth, md division of hematology/oncology weill...
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MYC-associated and Double Hit Lymphomas
Lisa G Roth, MDDivision of Hematology/Oncology
Weill Cornell Medical CollegeNew 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
EBV pos children sub-Saharan Africa MYC/IG breakpoints (somatic hypermutation)
Sporadic BL
EBV +/- adults MYC/IgH locus
8q24MYC rearrangement
• 14q32 (80%)• 2p11 (15%)• 22q11 (5%)
Immunodeficiency-related BLEBV 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%) 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 28:3360-3365; Savage Blood. 2009;114: 3533-3537; Niitsu Ca Sci 2009; Cuccioni Blood 2010
Outcome for MYC pos DLBCL
66%
31%PFS
OS72%
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.
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
MYC BCL2
proliferation Anti-apoptosis
+ = “DOUBLE HIT LYMPHOMA”
Barrans JCO 2010; Savage Blood 2009; Niitsu
Double hit lymphoma: BCL2 expression associated with inferior prognosis
Johnson Blood 2009
Johnson Blood 2009
Ove
rall
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viva
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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 break-apart
Rearrangement Increased copy number
Images courtesy of Dr. Gordana Raca, The University of Chicago
NEW: Immunohistochemistry for MYC
Images courtesy of Dr. Girish Venkataraman, The University of Chicago Hematopathology
Relative frequency of MYC via IHCRef. N Subtype MYC
rearrMYC 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%(>40%)
18% 44% 18% overall (vs. 5% with DHL)Johnson
2012140 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 2013
IHC expression of BCL2 and MYC is associated with poor prognosis
Overall survival EFS
Perry BJH 2014
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
Hu Blood 2013
Age, PS, B sx, stage
CR, COO, Ki67
IPI
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
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!