Expression of eukaryotic initiation factor 4E predicts clinical outcome in patients with mantle cell lymphoma treated with hyper-CVAD and rituximab, alternating with rituximab, high-dose methotrexate, and cytarabine.

Abstract

Oncogenic AKT/mammalian target of rapamycin (mTOR) signaling has recently been shown to contribute to tumor survival and proliferation in mantle cell lymphoma (MCL) through its downstream effector eukaryotic initiation factor 4E (eIF4E), which may control cyclin D1 protein levels. However, the clinical significance of eIF4E expression in MCL is unknown. The authors investigated the prognostic significance of eIF4E expression in 70 MCL patients uniformly treated with hyper-CVAD and rituximab, alternating with the rituximab, high-dose methotrexate, and cytarabine regimen (R-hyper-CVAD). eIF4E expression was assessed using tissue biopsy specimens obtained before treatment, immunohistochemical methods, and a highly specific monoclonal antibody. Failure-free (FFS) and overall (OS) survival were used as endpoints in univariate and multivariate survival analysis. High eIF4E expression was found in 28 (40%) MCL tumors. After a median follow-up of 51 months for survivors, the 5-year FFS was 20.6% for patients with high eIF4E expression, compared with 63.5% for patients with low or no eIF4E expression (P=.01, log-rank). Similarly, the 5-year OS was 40.1% for patients with high eIF4E expression, compared with 73.8% for patients with low or no eIF4E expression (P=.018, log-rank). In multivariate analysis, eIF4E expression was associated with poorer FFS and OS, along with age>60 years and high beta2-microglobulin in the final prognostic model. In summary, eIF4E, which seems to recapitulate most of the biologic effects of mTOR signaling in MCL, is an independent predictor of clinical outcome in MCL patients uniformly treated with the R-hyper-CVAD regimen.