The t(14;18)(q32;q21) characterizes a subset of patients with diffuse large-B cell lymphoma of germinal center origin with poor outcome: report from the International DLBCL Rituximab-CHOP Consortium Program Study

Abstract

INTRODUCTION: Diffuse large B cell lymphoma (DLBCL) has a highly variable outcome, and individual risk assessment is largely based on clinical features. Gene expression profiling (GEP) stratifies patients into those with germinal center B-cell (GCB) and activated B-cell subtype (ABC) subtype with different prognoses. These groups have been shown to predict prognosis in patients treated with CHOP or R-CHOP. Conversely, the role of other recognized prognostic markers, such as BCL2 gene abnormalities or Bcl2 expression has been questioned in the new therapeutic era. MATERIALS AND METHODS: In 438 patients treated with R-CHOP for de novo DLBCL, we analyzed the tumors by immunohistochemistry for Bcl2 protein expression and by interphase fluorescence in situ hybridization (FISH) for BCL2 translocation and other abnormalities. All cases were successfully studied by GEP. The cutoff for Bcl2 protein expression, 60%, used as prognostic factor was determined using receiver operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: The t(14;18)(q32;q21) was detected in 82 cases (18.7%) and BCL2 gains occurred in 63 cases (14.3%). Both t(14;18) and BCL2 gains strongly correlated with higher levels of Bcl2 protein expression (p<0.0001 for both). Presence of t(14;18) was associated with the GCB subtype (p<0.0001), whereas BCL2 gains were associated with the ABC subtype (p=0.004). BCL2 gains were not predictive of PFS in any patients' subgroups. Conversely, within the GCB subtype, patients with the t(14;18) displayed a significantly worse outcome compared to GCB patients without t(14;18) with a 5-year PFS of 45% vs 68%, respectively (p<0.0001). Outcome of patients with DLBCL associated with t(14;18) was similar to patients with the ABC subtype (45% vs 48%, p=0.30, Figure 1). No impact of the t(14;18) and BCL2 gains was observed on patients with ABC-DLBCL. Using immunohistochemistry, patients with Bcl2 positive (>60%) tumors had significantly inferior PFS in the GCB subgroup (p=0.03), but not in the ABC subgroup (p=0.54). Multivariate analysis revealed that the presence of the t(14;18), but not Bcl2 protein expression, was independent of the International Prognostic Index in predicting outcome of our patients. CONCLUSIONS: Patients with the GCB subtype and t(14;18) exhibit a significantly worse prognosis than patients without t(14;18) when treated with R-CHOP. The assessment of t(14;18) by FISH approach not only functions as a valuable prognosticator for individual risk estimation in GCB-DLBCL patients in addition to the established parameters, but also provides valuable result for therapeutic intervention.