Combination of Rituximab, Bendamustine, and Cytarabine for Patients With Mantle-Cell Non-Hodgkin Lymphoma Ineligible for Intensive Regimens or Autologous Transplantation Carlo Visco, Silvia Finotto, Renato Zambello, Rossella Paolini, Andrea Menin, Roberta Zanotti, Francesco Zaja, Gianpietro Semenzato, Giovanni Pizzolo, Emanuele S.G. D’Amore, and Francesco Rodeghiero Carlo Visco, Silvia Finotto, Andrea Menin, Emanuele S.G. D’Amore, and Francesco Rodeghiero, San Bortolo Hospital, Vicenza; Renato Zambello and Gianpietro Semen- zato, Padua University School of Medicine, Padova; Rossella Paolini, Santa Maria della Misericordia Hospital, Rovigo; Roberta Zanotti and Giovanni Pizzolo, University of Verona, Verona; and Francesco Zaja, Azienda Ospedaliera Universitaria Santa Maria Misericordia, Udine, Italy. Published online ahead of print at www.jco.org on February 11, 2013. Supported in part by grants from the Asso- ciazione Vicentina per le Leucemie, i Linfomi e il Mieloma/Associazione Italiana Leucemie (Vicenza, Italy) and Hematology Project Foundation (HPF; Fondazione Progetto Ematologia, Vicenza, Italy); by Mundipharma Pharmaceuticals, which provided bendamustine and a grant to HPF to partially cover management costs of this study; by Mundipharma International, which supported the editorial production of this article; and by Zaicom Medical Market- ing Communications, which provided edito- rial support. Presented in part at the 11th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 15-18, 2011 and 53rd Annual Meeting of the American Soci- ety of Hematology, San Diego, CA, December 10-13, 2011. Neither Mundipharma Pharmaceuticals nor Munidpharma International had input in the content or interpretation of the study or saw the final results before submission. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT00992134. Corresponding author: Francesco Rodeghiero, MD, Department of Hematol- ogy, San Bortolo Hospital, Via Rodolfi 37, 36100 Vicenza, Italy; e-mail: rodeghiero@ hemato.ven.it. © 2013 by American Society of Clinical Oncology 0732-183X/13/3111-1442/$20.00 DOI: 10.1200/JCO.2012.45.9842 A B S T R A C T Purpose The combination of bendamustine (B) and rituximab (R) is efficacious, with favorable toxicity in mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age  65 years who were previously untreated or relapsed or refractory (R/R) after one prior immunochemotherapy treatment. Patients and Methods In stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stage two, patients received R (375 mg/m 2 intravenously [IV] on day 1), B (70 mg/m 2 IV on days 2 and 3), and cytarabine (MTD IV on days 2 to 4) every 28 days for four to six cycles. The primary end point (overall response rate [ORR]) was evaluated by positron emission tomography. Secondary end points included safety, progression-free survival (PFS), response duration, and overall survival. Results Forty patients (median age, 70 years; 20 previously untreated patients) were enrolled; 93% had Ann Arbor stage III/IV disease; 49% had high Mantle Cell International Prognostic Index scores, with 15% blastoid histology. All R/R patients (35% refractory) had previously received R-containing regimens. The cytarabine MTD used in stage two was 800 mg/m 2 , and R-BAC was well tolerated, with an 85% treatment completion rate. The major toxicity was transient grades 3 to 4 thrombocytopenia (87% of patients); febrile neutropenia occurred in 12%. The ORR was 100% (95% complete response [CR]) for previously untreated and 80% (70% CR) for R/R patients. The 2-year PFS rate ( standard deviation) was 95%  5% for untreated and 70%  10% for R/R patients. Conclusion R-BAC is well tolerated and active against MCL. J Clin Oncol 31:1442-1449. © 2013 by American Society of Clinical Oncology INTRODUCTION Mantle-cell lymphoma (MCL) is one of the more aggressive forms of non-Hodgkin lymphoma, with a median survival of 3 to 5 years. 1 Intensive regimens adopted for younger patients with MCL (age  65 years) have provided encouraging short-term results, 2-4 with the incorporation of high-dose cytar- abine being widely recognized as highly beneficial. 2-7 However, two thirds of patients diagnosed with MCL are older than age 60 years, and effective and well-tolerated low-toxic first-line therapeutic op- tions are urgently needed for this large group of elderly or unfit patients. 5 Combination chemoimmunotherapy regimens, such as R-CHOP (rituximab plus cyclophospha- mide, doxorubicin, vincristine, and prednisone), are accepted by many groups as standard treatment for elderly patients, and their effectiveness has been recently shown to be improved by rituximab maintenance. 5-8 Bendamustine is also an active monotherapy that is well tolerated by older or frail patients. 9,10 Improved efficacy was demonstrated when bendamustine was combined with rituximab in comparison with R-CHOP in a randomized trial including patients with MCL. 11 Rituximab, bendamustine, and cytarabine have demonstrated distinct and synergistic mecha- nisms of action in preclinical studies. Our group recently reported that bendamustine significantly increased cytarabine cytotoxicity in MCL cell lines, especially when administered sequentially. 12,13 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 11  APRIL 10 2013 1442 © 2013 by American Society of Clinical Oncology 208.61.250.70 Information downloaded from jco.ascopubs.org and provided by at Information Resource Center on March 24, 2016 from Copyright © 2013 American Society of Clinical Oncology. All rights reserved.