MYC Gene Single Hit Diffuse Large B Cell Lymphoma Behaves Similarly To MYC/BCL2 Double Hit Lymphoma and Needs Similar Aggressive Treatment

Double hit diffuse large B cell lymphoma (DHL) is a heterogeneous group of high grade B-cell lymphoma with concurrent MYC and BCL2 (or other) gene rearrangements. It is well known that DHL has an aggressive clinical course, is resistant to standard R-CHOP chemotherapy, and confers a poor prognosis. Little is known about MYC single hit diffuse large B cell lymphoma (SHL) and how they behave and respond to therapy compared to MYC/BCL2 DHL.

The aim of the study was to delineate the characteristics of MYC SHL and compare it to MYC/BCL2 DHL with regards to its clinicopathologic features, especially response to treatment and prognosis.

One hundred and fifteen patients diagnosed with large B cell lymphoma between September 2009 and June 2013 at our institution were included in this study. MYC and BCL2 gene rearrangement were confirmed by fluorescence in situ hybridization (FISH) using MYC breakapart probe and BCL2 and IgH dual color dual fusion probes, respectively. BCL6 gene rearrangement was revealed in a subset of cases either by FISH using breakapart probe or karyotype. MYC/BCL2 DHL cases were identified if they had rearrangements of MYC and BCL2. SHL cases were identified if they only had MYC rearrangement. Tumor cells were defined positive for MYC and BCL2 protein expression by immunostain if >40% and 50% of cells showed positive expression, respectively. Patient survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. Fisher's exact test was used to compare the two groups.

Of the 115 patients, 15 were MYC SHL and 24 were MYC/BCL2 DHL. Four DHL also had BCL6 rearrangement. All cases with karyotype available showed complex karyotype, both in SHL and DHL (Table 1). Of the 15 SHL patients, 9 were male and 6 were female with a median age of 63 years (range 36-78) at diagnosis. Eleven of 14 patients had elevated serum LDH. 10 patients (67%) had bone marrow involvement and 12 (80%) had more than one extranodal sites involved. Thirteen patients (87%) had advanced stage disease (stages III and IV). Most patients (93%) had high intermediate or high risk based on the International Prognostic Index (IPI). By immunostain, MYC was expressed in 12/13 (92%) cases, BCL2 in 9/15 (60%) cases, and MYC and BCL2 were coexpressed in 7/13 (54%) cases. All the above clinicopathologic features were similar between SHL and DHL patients (Table 1, p> 0.05), with the only exception of more prevalent BCL2 expression in DHL patients (p=0.01).

All 15 SHL patients received chemotherapy: 2 (13%) received R-CHOP, 2 (13%) received R-Hyper CVAD/Ara-C/MTX, 7 (47%) received R-EPOCH and 4 (27%) received other aggressive regimens. One patient also received stem cell transplant (SCT). Twenty one of the 24 DHL patients had treatment information available and there was no statistically significant difference between the two groups (p=0.25). At a median follow up of 16 months, the median overall survival was 10.4 months for SHL, which was not significantly different from that of DHL (19.9 months; p=0.10; Figure 1).

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Our data suggests that clinicopathologic features of MYC SHL is similar to DHL, including the MYC/BCL2 protein coexpression by immunohistochemistry. Despite similar treatment approach in both groups, the response to treatment and prognosis of patients with MYC SHL is similar to those with DHL. Therefore, both MYC SHL and MYC/BCL2 DHL need to be approached similarly while implementing therapeutic decisions. Novel inhibitors in combination with multi-agent chemotherapy to improve prognosis are urgently needed in this subgroup of lymphoma.

No relevant conflicts of interest to declare.