Efficacy of Rituximab Maintenance for Diffuse Large B Cell Lymphoma with Transformation
Authors: Uryu Hideki , Mishima Yuko , Yokoyama Masahiro , Nishimura Noriko , Kusano Yoshiharu , Inoue Norihito , Nishihara Anna , Fukuta Takanori , Shirouchi Yuko , Tsuyama Naoko , Takeuchi Kengo , Terui Yasuhito 
Published: October 2019

Abstract
<Introduction>
The transformation of indolent lymphoma is biologic event leading to aggressive lymphoma status. As same de-novo diffuse large B cell lymphoma (DLBCL), the outcome of DLBCL with transformation has improved by the use of rituximab contained therapy. However, the effects of rituximab maintenance for DLBCL with transformation remain unknown. We performed a retrospective analysis to evaluate the efficacy of rituximab maintenance for DLBCL with transformation.
<Patients and Methods>
We studied patients newly diagnosed as transformed DLBCL from March 2005 to November 2017 in our institution. The pathological diagnosis was performed based on morphological and immunohistochemical analyses. Transformed DLBCL was defined in our study as a coexistence with components of follicular lymphoma (FL) or MALT lymphoma and DLBCL in a biopsied tissue at the diagnosis. Almost all patients were treated with R-CHOP chemotherapy (2 were treated by radiation with or without rituximab therapy, one was R-ICE chemotherapy). 15 patients received rituximab maintenance therapy for two years after achieving good PR or more by first therapy. PET-CT was used to evaluate the stage at the diagnosis and the response after therapy. The statistical analyses of characteristics of patients were performed by Fisher's exact test. The survivals were calculated by the Kaplan Meier method, and statistical analysis were performed by log rank test. Factors affecting OS and PFS were evaluated using Cox proportional hazard model.
<Results>
We analyzed 52 transformed patients. Median age was 64 years old (range 43-87), 35 patients were male (67%) and 17 were female (33%), 44 (84%) were transformed from FL and 8 (16%) were from MALT lymphoma. Germinal center B cell (GCB) type were 35 (67%) and activated B cell (ABC) were 16 (30%). An ECOG performance status (PS) ≧2 was only 1 patient (1.9%). 3 (5.7%) had B symptoms, 16 (30%) had LDH ≧ULN, 28 (53%) had stage of Ⅲ or Ⅳ, 5 (9.6%) had bone marrow invasion, 13 (25%) had IPI score ≧3, and 26 (50%) had one or more extranodal diseases. There were no significant differences in characteristics between rituximab maintenance group and no maintenance group. After induction therapy, CR was achieved in 48 (92%) and PR was 4 (8%). With a median follow up of 66 months (range 7-143), 5-year OS and 5-year PFS were 95.6% (range 83.3-98.9) and 71.7% (range 55.4-83.0) respectively. There were not statistically significant in OS and PFS between the rituximab maintenance group and the observation group (5-year OS: 100% vs 93.6%, p=0.0895, 5-year PFS: 100% vs 65.7%, p=0.0792). However, subgroup analyses showed that rituximab maintenance group was significantly superior to no maintenance group in PFS in the cases of stage III or more (5-year PFS 100% vs 30.7%, p=0.0137), males (100% vs 56.7%, p=0.0436), and GCB type (100% vs 60.0%, p=0.029). The rituximab maintenance (P=0.0356: HR 0.20; 95% CI 0.046-0.899) was indicated as the clinical parameters related to PFS by multivariate analysis.
<Discussion and Conclusion>
Generally, DLBCL with transformation have poor prognosis. There are several previous reports about rituximab maintenance for patients with aggressive B-cell lymphoma, which concluded that rituximab maintenance in first remission didn't provide an advantage to OS and PFS. NHL 13 trial demonstrated statistical benefit of rituximab maintenance for males and low IPI group. Regard to transformed lymphoma, the study for maintenance of rituximab was really few. Hany R et al reported the outcome of patients with transformation that rituximab maintenance post R-CHOP and the number of maintenance rituximab cycles were associated with better PFS. Our data provided that rituximab maintenance was effective in transformed DLBCL with regard to prolonged PFS in subgroups of progressive stage, men, and GCB. In conclusion, from our study it was suggested that rituximab maintenance therapy have possible to improve outcomes for DLBCL with transformation.

Disclosures
Mishima: Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Nishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Takeda pharmaceutical: Honoraria; Janssen Pharmaceutical KK: Honoraria; Celgene: Honoraria; Bristol myers Squib: Honoraria; Novartis pharma: Honoraria.