Combination of Rituximab, Bortezomib and Hyper-Fractionated Cyclophosphamide (RBC) in “True” Elderly Patients with Advanced Mantle Cell Lympoma.
Authors: Guariglia Roberto , Pietrantuono Giuseppe , Villani Oreste , Martorelli Maria Carmen , D’Auria Fiorella , Zupa Angela , Bianchino Gabriella , Grieco Vitina , Digiovannantonio Luigina , Benvenuto Alessandra , Feudale Elisa , Pinto Antonello , Ferrara Felicetto , Musto Pellegrino 
Published: October 2019

Abstract
Mantle-cell lymphoma (MCL) is recognized as a distinct clinico-pathologic entity, accounting for 3–10% of all non-Hodgkin’s lymphomas, with median overall survival not exceeding 3–4 years. Patients with MCL are typically older adults with a male predominance and usually present with stage IV disease. The neoplastic cells are characterized as CD20+ CD5+ CD23−, with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochemistry. The current, most diffused regimens for the treatment of MCL include either R-CHOP or R-HyperCVAD, followed by autologous stem cell transplantation or observation, depending on the patient’s eligibility. However, considering that MCL is frequently diagnosed in elderly subjects with relevant co-morbidities, high dose chemotherapy or the use of drugs with potential cardiotoxicity, such as anthracyclines, may result not feasible in a significant proportion of patients. In this setting, recent data suggest that the proteasome inhibitor bortezomib is well tolerated and has significant single-agent activity in patients with MCL. Thus, we evaluated safety and efficacy of the RBC regimen, a 21-day cycle, anthracycline-free combination of rituximab (375 mg/m(2) on day 1), bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11) and hyper-fractionated cyclophosphamide (600 mg/m(2)/d given as a double, three-hour infusion on days 1–3) in “true” (≥ 75 year-old) elderly patients with advanced MCL. Diagnosis was made according to standard histological, phenotypic and molecular criteria. The results of an early analysis on feasibility in the first six patients enrolled (3 male, 3 female) are reported here. Mean age was 79.8 years (range 75–84). All patients had stage IV disease, evidencing extranodal localizations (n. 2) or marrow/leukemic involvement (n. 4). IPI score was 2 in three patients, 3 in two patients and 4 in one patient. Three patients received RBC as first line therapy, the others were treated at relapse after (R)-CHOP- like regimens. Hematological toxicities consisted in grade 1 (n. 2) and grade 2 (n. 1) thrombocytopenia, while one patient experienced grade 3 neutropenia, requiring G-CSF support. No extra-hematological toxicities higher than grade 1 were observed. Full doses of RBC were constantly administered. One patient, who presented with a WBC count > 200.000/μl, died during the first cycle due to progressive disease; another patient showed an initial response in extranodal sites and then progressed before the fourth planned cycle. The remaining four patients received six cycles: one patient achieved a partial response and three obtained a complete response, one of whom showing a molecular remission using PCR for t(11;14) bcl-1/IgH determination. All responders (66.6%) maintain their remission phase 7–10 months after the start of RBC treatment. Although very preliminary, these results indicate that RBC regimen is feasible, well tolerated and may be effective (including the possibility to obtain molecular response) in very elderly patients with advanced MCL. Larger and more mature data will be presented at the Meeting.