Abstract
The optimal dose, schedule, and other aspects of bendamustine plus rituximab treatment remain unclear for patients with relapsed or refractory follicular lymphoma (FL). Herein, we analyzed the efficacy of bendamustine combined with rituximab (RB-120) treatment for Japanese patients with relapsed or refractory FL. This phase II clinical trial included patients with relapsed or refractory FL who received 375 mg/m2 rituximab on day 1 and 120 mg/m2 bendamustine on days 2 and 3 every 28 days for up to 6 cycles. The primary endpoint was the overall response rate (ORR), and the secondary endpoints included the complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. Thirty-seven patients were enrolled in the trial (median age 62 years, range 42–75 years). All patients were previously treated with rituximab-containing chemotherapy, and 83.8% were previously treated with the R-CHOP regimen. A median of 5 cycles (range 1–6) and 48.6% of patients completed 6 cycles. The ORR was 91.9% (95% confidence interval [CI] 78.1–98.3%), with a CR rate of 86.5% (95% CI 71.2–95.5%). The 3-year PFS and OS were 70.9% (95% CI 52.3–83.3%) and 88.9% (95% CI 73.1–95.7%), respectively, with the median 39.5 months follow-up duration. The most-frequently observed grade 3/4 adverse events were hematologic: lymphopenia (95%) and neutropenia (70%). No treatment-related deaths were observed. RB-120 showed a good efficacy with equivalent toxicities, compared with the bendamustine 120 mg/m2 monotherapy. However, the problem of high drop-out incidences cannot be ignored.
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References
Cheson BD, Rummel MJ (2009) Bendamustine: rebirth of an old drug. J Clin Oncol 27:1492–1501
Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, la Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD (2008) Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol 26:204–210
Kahl BS, Bartlett NL, Leonard JP et al (2010) Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer 116:106–114
Rummel MJ, Al-Batran SE, Kim SZ et al (2005) Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol 23:3383–3389
Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD (2008) Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 26:4473–4479
Cheson BD, Wendtner CM, Pieper A, Dreyling M, Friedberg J, Hoelzer D, Moreau P, Gribben J, Knop S, Montillo M, Rummel M (2010) Optimal use of bendamustine in chronic lymphocytic leukemia, non-Hodgkin lymphomas, and multiple myeloma: treatment recommendations from an international consensus panel. Clin Lymphoma Myeloma Leuk 10:21–27
Ogura M, Ando K, Taniwaki M, Watanabe T, Uchida T, Ohmachi K, Matsumoto Y, Tobinai K, for the Japanese Bendamustine Lymphoma Study Group (2011) Feasibility and pharmacokinetic study of bendamustine hydrochloride in combination with rituximab in relapsed or refractory aggressive B cell non-Hodgkin’s lymphoma. Cancer Sci 102:1687–1692
Cheson BD, Horning SJ, Coiffier B et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V, International Harmonization Project on Lymphoma (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25:579–586
Ohmachi K, Ando K, Ogura M, Uchida T, Itoh K, Kubota N, Ishizawa K, Yamamoto J, Watanabe T, Uike N, Choi I, Terui Y, Usuki K, Nagai H, Uoshima N, Tobinai K, The Japanese Bendamustine Lymphoma Study Group (2010) Multicenter phase II study of bendamustine for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Cancer Sci 101:2059–2064
Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48:452–458
Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J (2016) Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol 17:57–66
Trotman J, Luminari S, Boussetta S, Versari A, Dupuis J, Tychyj C, Marcheselli L, Berriolo-Riedinger A, Franceschetto A, Julian A, Ricard F, Guerra L, Haioun C, Biasoli I, Tilly H, Federico M, Salles G, Meignan M (2014) Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies. Lancet Haematol 1:e17–e27
Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M (2013) Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 31:2103–2109
Ogura M, Ishizawa K, Maruyama D et al (2017) Bendamustine plus rituximab for previously untreated patients with indolent B-cell non-Hodgkin lymphoma or mantle cell lymphoma: a multicenter phase II clinical trial in Japan. Int J Hematol 105:470–477
Acknowledgments
The authors would like to thank the patients and their families, the investigators, and staff who participated in this multicenter trial for their excellent cooperation. We also thank Atsuko Yoshizawa, Etsuo Miyaoka, and the staff of the Department of Mathematics, Faculty of Science, Tokyo University of Science, for their technical assistance with data management.
Funding
This study was funded by the Translational Research Network Program, Project of Translational and Clinical Research Core Centers (University of Tokyo), Japan Agency for Medical Research and Development, AMED.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments.
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Dr. Sakai has received research funding from Chugai, Kyowa Hakko Kirin, Ono, Yakult, Taiho, and Eisai and honoraria from Takeda, Bayer, Bristol-Meyer-Squibb, Sumitomo Dainippon, Celgene, Mundipharma, Eisai, and Kyowa Hakko Kirin. Dr. Ohmachi has received honoraria from Chugai, Kyowa Hakko Kirin, Eisai, Pfizer, Takeda, Celgene, and Meiji Seika. Dr. Sano has received research funding from Chugai and Kyowa Hakko Kirin and honoraria from Celgene, Janssen, Bristol-Meyer-Squibb, Eisai, Pfizer, Chugai, and Alexion. Dr. Takasaki has received honoraria from Kyowa Hakko Kirin, Eisai, and Janssen. Dr. Miyazaki has received research funding from Astellas. Dr. Yamamot has received honoraria from Celgene, Janssen, Kyowa Hakko Kirin, Bristol-Meyer-Squibb, MSD, Meiji Seika, Novartis, Shaire Japan, Alexion, and Chugai. Dr. Tomita has received research funding from Terumo Foundation for Life Sciences and Arts. Dr. Ando has received research funding from Kyowa Hakko Kirin, Eisai, Bristol-Meyer-Squibb, Novartis, and Takeda. All remaining authors have declared no conflicts of interest.
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Sakai, R., Ohmachi, K., Sano, F. et al. Bendamustine-120 plus rituximab therapy for relapsed or refractory follicular lymphoma: a multicenter phase II study. Ann Hematol 98, 2131–2138 (2019). https://doi.org/10.1007/s00277-019-03750-7
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DOI: https://doi.org/10.1007/s00277-019-03750-7