Rituximab-Bendamustine Cytarabine (R-BAC) As Frontline Therapy in Mantle Cell Lymphoma: A Single-Center Experience
Authors: Branca Antonio , Gianesello Ilaria , Brugnaro Luca , Berno Tamara , Imbergamo Silvia , Lessi Federica , Sammartin Kety , Vianello Fabrizio , Adami Fausto , Binotto Gianni , Gurrieri Carmela , Trentin Livio , Visco Carlo , Zambello Renato , Piazza Francesco , Semenzato Gianpietro 
Published: October 2019

Abstract
Background and objectives. Bendamustine in combination with rituximab has demonstrated a relevant clinical activity and a good toxicity profile in patients with mantle cell lymphoma (MCL). Cytosine arabinoside (Ara-C) is a key drug in induction chemotherapy regimens of young patients with MCL. In vitro studies have shown that bendamustine increases the cytotoxic effect of Ara‐C in leukemic blasts and lymphoma cells, and the two drugs display high synergistic activity when used in consecutive combinations. Clinically, it has recently been demonstrated that rituximab + bendamustine + Ara‐C (R-BAC) combination has a remarkable activity and is well tolerated both in untreated and in relapsed/refractory patients with MCL (Visco C et al. J Clin Oncol 2013 31:1442-1449). In the present study, we report data from an Italian single-center experience evaluating the efficacy and tolerability of R-BAC association in previously untreated MCL patients both eligible and ineligible for transplantation.
Design and methods. From January 2009 to November 2014, 25 newly diagnosed patients with MCL (median 67 years; range 57-83 years) were treated with immunochemotherapy according to R-BAC schedule (Rituximab 375 mg/mq day 1; Bendamustine 70 mg/mq days 2, 3; Ara-C 500 mg/mq days 2-4) x 4 or 6 28-day cycles. All patients received G-CSF prophylaxis. Ninety-six percent of patients had stage III/IV disease; MIPI score was high in 24%, intermediate in 60% and low in 12%; in one patient it was not evaluable.
Results. Twenty-two patients (88%) completed the scheduled treatment (4 or 6 cycles). The ORR was 88%: CR 84% (21 patients); PR 4% (1 patient); 1 patient was in SD, but he received only 1 cycle due to toxicity and died still in SD about three years later. Seven patients (28%) underwent autologous stem cell transplantation (ASCT); seven patients (28%) received rituximab maintenance for two years. Two patients (8%) experienced disease progression during first line therapy, both had intermediate MIPI score. After a median follow up of 33 months (range 4-65 months), the OS was 80% (one patient died for unrelated causes) and the PFS was 80%. At this time point, 19 (76%) and 1 (4%) patient were in CR and in PD, respectively. The latter patient is currently undergoing salvage chemotherapy. Patients who received either maintenance immunotherapy with rituximab or consolidation with ASCT after R-BAC (overall 56%) seemed to experience longer PFS and OS. In the ASCT group the OS was 100% at a median follow up of 23 months; in the rituximab maintenance group the OS was 71% at a median follow up of 41 months. In the group of patients that received R-BAC induction therapy only, the OS was 61% at a median follow up of 26 months (p=0.14, likely due to the low number). The most common adverse events (AEs) during R-BAC were hematological: grade 3-4 neutropenia (88%), grade 3-4 thrombocytopenia (64%) and grade 3-4 anemia (36%). The numbers of common grade 3/4 non hematological AEs in the study included: febrile neutropenia (28%), acute coronary syndrome (4%), lung infection (4%) and hyperglycemia (4%). No treatment-related mortality was observed, one patient died of secondary acute myeloid leukemia four years later from induction therapy.
Conclusions. The present retrospective study confirms that R-BAC as frontline regimen in MCL is well tolerated and highly effective in ASCT ineligible patients and that it can be administered also in ASCT eligible patients as induction therapy. Moreover, our data suggest that a consolidation therapy (ASCT or maintenance immunotherapy) after R-BAC induction could improve the outcome.

Disclosures
No relevant conflicts of interest to declare.