The Prognostic Impact Of Gene Rearrangements and Protein Expression Of MYC, BCL2 and BCL6 In Young High-Risk Patients With DLBCL

A number of retrospective analyses have looked into the prognostic implication of MYC, BCL2 and BCL6 rearrangements and protein expression for MYC, BCL2 and BCL6 in patients with diffuse large B-cell lymphoma (DLBCL). Many of these studies suffer from small patient cohorts and differing or unknown treatment strategies (with or without Rituximab) administered to patients under study. Furthermore, the median age of these patients was relatively high. We for the first time report on the prognostic consequences of MYC, BCL2 and BCL6 alterations in younger (18-60 years) high-risk patients (aaIPI 2 or 3) with DLBCL.

The MegaCHOEP study (Schmitz et al. Lancet Oncology 2012: 13, 1250) randomized patients to 8xCHOEP-14 or sequential high-dose therapy supported by repeated infusions of autologous stem cells. Both treatment arms included 6 infusions of R (375 mg/ sqm). The median patient age was 48 years, and 27% of patients scored an aaIPI of 3. Paraffin-embedded tumor samples from 112 de novo DLBCL were investigated using immunohistochemistry for MYC, BCL2, and BCL6, and fluorescence in-situ hybridisation (FISH) to detect breaks of MYC, BCL2 and BCL6.

Rearrangements of MYC, BCL2 and BCL6 were detected in 13.6%, 20.7% and 30.9% of DLBCL, respectively. A double or triple hit constellation occurred in 10.8%. Presence of BCL2 breaks (RR=4.7, 95% CI: 1.8-12.2) and MYC breaks (RR=2.4, 95% CI: 0.8-7.5), but not of BCL6 breaks were associated with inferior overall survival in univariate and multivariate analyses adjusted for aaIPI and treatment arm. Protein overexpression of MYC ≥30% (RR=2.4, 95% CI: 0.9-6.5), but not BCL2 (≥60%) or BCL6 (≥30%) indicated inferior overall survival. BCL2 overexpression was associated with inferior EFS (RR=2.2, 95% CI: 0.9-5.5) and PFS (RR=2.8, 95% CI: 1.0-8.2). If the same cutpoint for BCL2 used for a similar analysis in elderly patients treated on the RICOVER-60 trial (Horn et al. Blood 2013) was applied, no differences in EFS or PFS were observed.

Rearrangements of MYC and BCL2 seem to be relevant prognostic factors also in young high-risk patients. The frequencies of MYC and BCL2 rearrangements are not substantially higher than reported for other, mostly elderly patient groups carrying IPI scores from 0 - 5; it seems unlikely, therefore, that the rearrangements described here (completely) explain the poor prognosis of young, high-risk patients. The prognostic role of BCL2, BCL6, and MYC as well as other biological risk factors must be validated in independent data sets.

No relevant conflicts of interest to declare.