Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma Ken Ohmachi, Nozomi Niitsu, Toshiki Uchida, Seok Jin Kim, Kiyoshi Ando, Naoki Takahashi, Naoto Takahashi, Naokuni Uike, Hyeon Seok Eom, Yee Soo Chae, Takashi Terauchi, Ukihide Tateishi, Mitsuaki Tatsumi, Won Seog Kim, Kensei Tobinai, Cheolwon Suh, and Michinori Ogura Ken Ohmachi and Kiyoshi Ando, Tokai University; Ukihide Tateishi, Yokohama City University Hospital, Kanagawa; Nozomi Niitsu and Naoki Takahashi, Saitama Medi- cal University International Medical Center, Saitama; Toshiki Uchida and Michinori Ogura, Nagoya Daini Red Cross Hospital, Aichi; Naoto Takahashi, Akita University Hospital, Akita; Naokuni Uike, National Kyushu Cancer Center, Fukuoka; Takashi Terauchi, National Cancer Center; Kensei Tobinai, National Cancer Center Hospital, Tokyo; Mitsuaki Tatsumi, Osaka University Hospital, Osaka, Japan; Seok Jin Kim and Won Seog Kim, Samsung Medical Center; Cheolwon Suh, Asan Medical Center, Seoul; Hyeon Seok Eom, National Cancer Center, Gyeonggi-do; and Yee Soo Chae, Kyungpook National University Hospital, Daegu, Korea. Published online ahead of print at www.jco.org on May 6, 2013. Written on behalf of the Japanese and Korean Bendamustine Lymphoma Study Group. Research support was provided by SymBio Pharmaceuticals. Assistance with the writ- ing of this article was provided by Satosih Sakima, MD, and was funded by SymBio Pharmaceuticals and Eisai. Presented at the 48th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Clinical trial information: NCT01118845 Corresponding author: Kiyoshi Ando, MD, PhD, Department of Hematology and Oncology, Tokai University, School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan; e-mail: andok@keyaki.cc.u-tokai.ac.jp. © 2013 by American Society of Clinical Oncology 0732-183X/13/3117w-2103w/$20.00 DOI: 10.1200/JCO.2012.46.5203 A B S T R A C T Purpose Effective and less aggressive therapies are required for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who are not eligible for or have undergone autologous stem-cell transplantation (ASCT). The present phase II study assessed the efficacy and safety of benda- mustine plus rituximab (BR) in this population. Patients and Methods Patients with relapsed or refractory DLBCL treated with one to three prior chemotherapy regimens received rituximab 375 mg/m 2 intravenous (IV) infusion on day 1 and bendamustine 120 mg/m 2 by IV infusion on days 2 and 3 of each 21-day cycle for up to six cycles. The primary end point was overall response rate (ORR), and the secondary end points were complete response (CR) rate, progression-free survival (PFS), and safety. Results Sixty-three patients were enrolled, and 59 received BR. The median age was 67 years (range, 36 to 75 years), and 62.7% of patients were 65 years of age or older. Fifty-seven patients (96.6%) were previously treated with rituximab-containing chemotherapy. The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a CR rate of 37.3% (95% CI, 25.0% to 50.9%). The ORRs were comparable between patients  65 years of age and less than 65 years (62.2% and 63.6%, respectively). The median PFS was 6.7 months (95% CI, 3.6 to 13.7 months). The most frequently observed grade 3 or 4 adverse events were hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 lymphopenia (66.1%), and thrombocytopenia (22.0%). Conclusion BR is a promising salvage regimen for patients with relapsed or refractory DLBCL after rituximab-containing chemotherapy, warranting further investigation. J Clin Oncol 31:2103-2109. © 2013 by American Society of Clinical Oncology INTRODUCTION Diffuse large B-cell lymphoma (DLBCL) belongs to the category of mature B-cell neoplasms among non-Hodgkin lymphomas (NHLs) and is the most common lymphoid malignancy in the world. 1-4 Significant improvements in the overall clinical outcomes of DLBCL have been achieved by the in- troduction of rituximab in combination with cyclo- phosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). 5,6 Despite the proven effi- cacy of this first-line regimen for DLBCL, approxi- mately one third of patients develop relapsed or refractory disease, which remains a major cause of morbidity and mortality. 7 In a study of patients with relapsed DLBCL who were treated with rituximab- containing salvage chemotherapy followed by high- dose chemotherapy with autologous stem-cell transplantation (ASCT), 3-year overall survival was estimated to be less than 50%. 8 Therefore, effective and well-tolerated salvage therapies are required for elderly and/or frail patients, who are less likely to be candidates for intensive chemotherapies with ASCT. Bendamustine was originally and rationally de- signed to have both alkylating and antimetabolic actions, and the former is currently considered pre- dominant 9,10 ; combined with rituximab in vitro, bendamustine showed synergistic antitumor effects in various leukemia and lymphoma cell lines. 11,12 Bendamustine alone 13-15 or in combination with rituximab (BR) 16,17 demonstrated efficacy and JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 17  JUNE 10 2013 © 2013 by American Society of Clinical Oncology 2103 Downloaded from ascopubs.org by 3.231.217.96 on June 10, 2022 from 003.231.217.096 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.