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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Inamdar
Kedar V
KV
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Romaguera
Jorge E
JE
Drakos
Elias
E
Knoblock
Ronald J
RJ
Garcia
Mar
M
Leventaki
Vasiliki
V
Medeiros
L Jeffrey
LJ
Rassidakis
George Z
GZ
D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D011379:Prognosis; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D014408:Biomarkers, Tumor; D039561:Eukaryotic Initiation Factor-4E; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008727:Methotrexate