Dual Translocation Is An Independent Poor Prognostic Factor in Diffuse Large B-Cell Lymphoma,

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of diseases, that are associated with variable survival outcomes depending on the presence of certain genetic and molecular features. Of particular interest is a subset known as the “double-hit” (DH) lymphoma. DH lymphoma (dual translocation) is defined by the presence of a chromosomal breakpoint affecting the MYC/8q24 locus with a second oncogene translocation, most commonly a BCL2 rearrangement, and less commonly involving BCL6 or CCND1 rearrangements. However, the incidence of DH lymphoma remains to be determined. These patients typically have poor prognostic factors, with a dismal outcome when treated with rituximab-CHOP (RCHOP) chemotherapy. The aim of this study was to identify any clinical defining characteristics in patients with DH lymphoma, and to compare their outcomes with that of DLBCL patients without dual translocation.

202 newly diagnosed DLBCL patients, of whom 90% received rituximab based chemotherapy, were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH), using breakapart FISH probes targeting BCL2, BCL6, MYC, CCND1 and IgH genes. The clinical characteristics and survival outcomes of patients who were identified with DH lymphoma were compared to those without the dual translocation.

Out of the 202 patients with DLBCL, we identified 10 cases (5%) with two or more concurrent translocations involving MYC and BCL2, or MYC and BCL6. Among the 10 patients with DH lymphoma, there were 6 patients with concurrent BCL2 and MYC translocations, 1 patient with BCL6 and MYC translocations and 3 patients with all 3 abnormalities. 7 of the 10 patients were male, with a median age of 68 years (42 – 84). Patients with DH lymphoma also presented with a significantly higher incidence of high-risk clinical features, including advanced stage disease, bulky disease, extranodal disease, bone marrow involvement and a high IPI score. Interestingly, the majority of patients with DH lymphoma expressed a germinal center (GC) phenotype (8 out of 9 patients) based on the Han's criteria. These patients also demonstrated a significantly poorer overall survival (OS) when compared to patients without dual translocation (2 yr OS 33% vs 84%, p = < 0.001). On multivariate analysis, the presence of a dual translocation was found to be an independent poor prognostic factor for OS (hazard ratio 8.84, 95% CI 3.54 to 22.08). Other factors predictive of an inferior OS included age, stage, bone marrow involvement and patients treated without rituximab.

Our findings showed that the presence of dual translocation is an independent poor prognostic factor in DLBCL. It was present in 5% of our cohort and was associated with more advanced disease. Patients with dual translocation also had a significantly poorer survival following treatment with standard chemotherapy such as RCHOP, even though most patients exhibited the GC phenotype. Therefore, the use of novel agents in combination with chemotherapy is an area that deserves further exploration in this type of lymphoma.

No relevant conflicts of interest to declare.