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

Sur

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!