Role of BCL2 and MYC Alterations in Patients with Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) represents more than 80% of high grade lymphomas and is considered a heterogeneous entity regarding clinical presentation, morphology, molecular and cytogenetic features. The Revised International Prognostic Index (R-IPI) is a clinically useful prognostic index that may help guide treatment. In this context, BCL2 and MYC gene rearrangements, that have been associated to specific variants of lymphoma, seem to have a prognostic implication. Consideration of these genetic markers together with classical parameters could contribute to a better stratification of patients.

To analyze the incidence and possible clinical relevance of BCL2 and MYC gene alterations in the outcome of patients with DLBCL.

This retrospective analysis included 20 patients with DLBCL (January 2008-April 2011), 74% (20/27) males with a median age of 70 years (range 17–82). Median follow-up was 300 days (range 17–1134). Fluorescence in situ hybridization (FISH) was performed on paraffin-embedded (n=12) or fresh (“touch-down” preparation) samples (n=8) from different tissues (7 lymphadenopathies, 3 central nervous system, 3 biologic fluids and 7 others). Each sample was hybridized with break-apart probes for BCL2 (18q21) and MYC (8q24) genes (Vysis Inc). 200 nuclei were scored per slide to reach 7% sensitivity.

Seventy percent (14/20) of patients analyzed showed BCL2 and/or MYC alterations at diagnosis (rearrangement and/or extra signals). BCL2 was present as unique alteration in 30% (6/20) of the samples, MYC was present as unique alteration in 30% (6/20) and 10% (2/20) showed both BCL2 and MYC rearrangement (Table 1).

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Two out of six patients with BCL2 as unique alteration showed rearragement, were treated with standard chemotherapy (R-CHOP or high dose of Citarabine/Methotrexate in central nervous system) and both patients relapsed. The other 4 patients presented extra signals as BCL2 alteration and also received standard chemotherapy. Fifty percent of these patients relapsed (Table 1).

On the other hand, 3 out of 6 patients with MYC as unique alteration presented gene rearrangement, they were treated with standard chemotherapy, and all 3 relapsed. The other 3 patients with MYC alterations presented extra signals, received standard chemotherapy and 33.3% (1/3) relapsed.

Finally, the 2 patients with simultaneous BCL2 and MYC rearrangement were treated with intensive chemotherapy and they reached and maintained complete remission.

According to the results obtained from this study, FISH analysis on paraffin-embedded or fresh samples from lymphoma tissues is a feasible and useful technique at diagnosis in DLBCL patients. Although genetic markers are not included in the R-IPI score, the identification of BCL2 and/or MYC alterations at diagnosis, associated to other biological markers, could help to identify a subgroup of high risk patients who could benefit from more aggressive therapies. Further studies of larger series and genes are needed to confirm this observation.

No relevant conflicts of interest to declare.