Optimal Cycles of Bendamustine-Plus Rituximab Therapy for Indolent B Cell Lymphoma
Authors: Toyama Kazuhiro , Takezaki Toshiaki , Honda Akira , Kogure Yasunori , Chiba Akira , Nakamura Fumihiko , Nakazaki Kumi , Kurokawa Mineo 
Published: November 2019

Backgrounds
Although bendamustine-plus rituximab therapy (BR) is considered as one of the standard therapy for several indolent B cell lymphomas, the optimal cycles of BR is not still uncovered. To elucidate the optimal cycles of BR, we performed a single center retrospective study of patients with indolent lymphoma treated with BR.
Methods
All patients with follicular lymphoma (n=40), lymphoplasmacytic lymphoma (n=11) and mucosa associated lymphoid tissue lymphoma (n=6) who underwent BR in our institute in the period between April 2011 and September 2017 were included in this study.
The clinical information including the number of repeated cycles, overall survival (OS), progression free survival (PFS), laboratory findings, backgrounds, and the response to BR were analyzed retrospectively.
Rituximab was administered at day 1 and bendamustine was administered at day 1 and 2, or 2 and 3, in each 28 days cycle. In the study cohort, the number of repeated cycles was allowed up to 6. The cessation of BR was allowed after 4 cycles in the patients with response to BR, according to the discretion of attending physicians. The dosage of bendamustine was reduced to 67% and 50% in 70 to 79 years and not less than 80 years, respectively.
All patients in this study were prescribed trimethoprim-sulfamethoxazole combination or pentamidine for the prevention of pneumocystis pneumonia, and acyclovir for the prevention of herpes zoster.
Results
In total 57 patients, the median age was 65 years (range, 37 to 83). Thirty four were male, and 23 were female. Three patients were newly diagnosed and 54 were relapsed or refractory patients. The median observation period was 51.7 months (5.1 to 83.6). The overall response rate was 86.0% (CR 54.4% and PR 31.6%). The median number of repeated cycles of BR was 4 (1 to 6). There was no significant correlation between patient characteristics and the number of repeated cycles of BR.
All patients were stratified by their number of repeated cycles of BR. The early cessation group (n=17) was identified that the number was from 1 to 3, and the late cessation group (n=40) was identified that the number was from 4 to 6. The 5-year OS rates in early and late cessation groups were 56.1% and 87.0%, respectively. The 5-year PFS rates in early and late cessation groups were 31.4% and 50.6%, respectively. Both 5-year OS and PFS rates in late cessation group were significantly longer than that in early cessation group (p=0.011 and p<0.01, respectively).
In late cessation group, the number of the patient who underwent 4 cycles of BR (4 cycles group) was 21, and the number of the patient who underwent 5 or 6 cycles of BR (over 4 cycles group) was 19. The 5-year OS rates in 4 cycles group and over 4 cycles group was 85.7% and 85.2%, respectively. There was no significant difference between these groups in the 5-year OS rates (p=0.58). The 5-year PFS rates in 4 cycles group and over 4 cycles group was 71.8% and 31.0%, respectively. The 5-year PFS rates in 4 cycles group were significantly longer than that in over 4 cycles group (p<0.01).
The most common reason of the cessation of BR was adverse event (n=15). BR were stopped in 9 patients who achieved response after 4 or 5 cycles, and in 8 patients who became relapsed or refractory.
Conclusions
Our study indicated that the outcome of the patients with indolent lymphoma who stopped BR after 4 cycles was not inferior to that of the patients who stopped BR after 5 or 6 cycles. The results suggest that the cessation of BR after 4 cycles may be permissible in the patients with response to BR.

Disclosures
Toyama: Celgene K.K.: Speakers Bureau; Chugai Pharmaceutical Company: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau. Nakamura:Astellas Pharma Inc.: Speakers Bureau. Kurokawa:Shionogi & Co., Ltd: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Consultancy, Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Speakers Bureau; Sumitomo Dainippon Pharma Co.,Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Yakult Honsha Company: Speakers Bureau; Pfizer Japan Inc.: Research Funding; Teijin Limited: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Shire Japan K.K.: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; Daiichi Sankyo Conpany: Speakers Bureau; Celgene K.K.: Consultancy, Speakers Bureau; MSD K.K.: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Bioverativ Japan ltd.: Consultancy.