Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival

Abstract

BCL2 and MYC are oncogenes commonly deregulated in lymphomas. Concurrent BCL2 and MYC translocations (BCL2(+)/MYC(+)) were identified in 54 samples by karyotype and/or fluorescence in situ hybridization with the aim of correlating clinical and cytogenetic characteristics to overall survival. BCL2(+)/MYC(+) lymphomas were diagnosed as B-cell lymphoma unclassifiable (BCLU; n = 36) with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL); DLBCL (n = 17), or follicular lymphoma (n = 1). Despite the presence of a t(14;18), 5 cases were BCL2 protein-negative. Nonimmunoglobulin gene/MYC (non-IG/MYC) translocations occurred in 24 of 54 cases (44%) and were highly associated with DLBCL morphology (P < .001). Over a median follow-up of 5.3 years, 6 patients remained in remission and 32 died within 6 months of the MYC(+) rearrangement, irrespective of whether MYC(+) occurred at diagnosis (31 of 54) or transformation (23 of 54; P = .53). A non-IG/MYC translocation partner, absent BCL2 protein expression and treatment with rituximab-based chemotherapy, were associated with a more favorable outcome, but a low International Prognostic Index score and DLBCL morphology were independent predictors of overall survival. A comprehensive cytogenetic analysis of BCL2 and MYC status on all aggressive lymphomas may identify a group of high-risk patients who may benefit from chemotherapeutic regimens that include rituximab and/or BCL2-targeted therapy.

Figure 1

Correlation between the presence of mutations in the BCL2 gene and BCL2 protein expression by immunohistochemistry using clones 124 and E17. (A) BCL2 protein expression by immunohistochemistry and corresponding amino acid sequence derived from sequencing the BCL2 gene in 3 BCL2⁺/MYC⁺ lymphoma samples. The affected amino acid changes are highlighted in red. (B) DLBCL sample (sample 2) stained with the BCL2 antibody clone 124 (Dako North America; original magnification ×200). (C) The same DLBCL sample (sample 2) stained with the BCL2 antibody E17 (Epitomics; original magnification, ×200). Ref indicates reference genome hg 19, May 2009; IHC, immunohistochemistry; P, positive; and N, negative.

Figure 2

Survival curves of patients with BCL2⁺/MYC⁺ lymphomas according to the timing of MYC⁺ rearrangement and treatment regimen. (A) Timing of MYC⁺ rearrangement: at diagnosis or at relapse. x-axis represents cumulative survival; y-axis, time (years). (B) Treatment regimen. ● represent long-term survivors; x-axis, cumulative survival; y-axis, time (years); Dx, diagnosis; R, rituximab; HD, high-dose chemotherapy with or without stem cell transplantation; and P, palliative.

Figure 3

Survival curves of patients with BCL2⁺/MYC⁺ lymphomas according to morphology, bone marrow involvement, MYC translocation partner, and BCL2 protein expression. Median overall survivals are shown in parentheses. (A) Morphology. (B) Bone marrow involvement. (C) MYC translocation partner. (D) BCL2 protein expression (clone 124). In all graphs, x-axis represents cumulative survival; and y-axis, time (years). BCLU indicates B-cell lymphoma unclassifiable; DLBCL, diffuse large B-cell lymphoma; BM^neg, no bone marrow involvement with MYC⁺ lymphoma; BM^pos, bone marrow involvement with MYC⁺ lymphoma; BCL2^neg, no BCL2 protein expression by clone 124; BCL2^pos, BCL2 protein expression by clone 124; and IG/MYC, MYC translocation involving one of the immunoglobulin genes.