Influence of rituximab plus bendamustine chemotherapy on the immune system in patients with refractory or relapsed follicular lymphoma and mantle cell lymphoma

Abstract

Bendamustine is an agent that contains a nitrogen mustard group and a purine-like benzimidazole ring, thus combining alkylating and antimetabolic properties. It is highly active against relapsed or refractory low-grade B-cell lymphoma and m ande cell lymphoma, especially when used in combi nation with rituximab (hereafter referred to as RB therapy) [1,2]. Although bendamustine has a favorable safety pro file, myelosuppression including lymphocytopenia occurs relatively frequendy [1][2][3][4][5], which may cause severe and prolonged immunodeficiency. Given the adverse effect of rituximab on immune function [6], it is a major concern that the combined use of rituximab and bendamustine may enhance immunosuppression. However, to date little is known about whether and to what extent RB therapy affects the immune system. With the aim of providing insights into this issue, we conducted a retrospective analysis of serial blood lymphocyte subset counts and serum immuno globulin (Ig) levels in patients with relapsed or refractory low-grade B-cell lymphoma or mantle cell lymphoma who received RB therapy at our hospital. The study was approved by the Institutional Review Board of the Fujita Health Uni versity School of Medicine.Between January 2011 and January 2013, RB therapy was administered to 21 patients with relapsed or refractory lowgrade B-celi lymphoma or mantle cell lymphoma. Of these 21 patients, 13 with serial measurement of blood lymphocyte subset counts and serum Ig levels were included in the study. The characteristics of the 13 patients are summarized in Table I and Supplementary Table I available online at http:// inform ahealthcare.com/doi/abs/10.3109/10428194.2014. 921298. RB therapy consisted of intravenous infusion of rituximab at a dose of 375 m g/m 2 on day 1, followed by intravenous infusion of bendamustine at a dose of 60, 90 or 120 m g/m 2 on days 2 and 3 for the first cycle and on days 1 and 2 for the second and subsequent cycles. RB therapy was repeated at intervals of 3-4 weeks for a total of 3-8 cycles.During RB therapy, all patients received sulfamethoxazole (400 mg/day)-trimethoprim (80 mg/day) and acyclovir (200 mg/day) prophylactically. To assess immune function, blood counts of lymphocyte subsets (CD4-positive [CD4+], CD8+, and CD20 + cells) were measured using a Cytomics FC500 (Beckman Coulter, Inc., CA), and serum IgG, IgA and IgM levels using a JCA-BM6010 (JEOL Ltd., Tokyo, Japan). Data were obtained before and after RB therapy, and at approximately 3, 6, 9 and 12 months after completion of treatment. For the follow-up samples, only those collected within 1 month of each defined time point were used in the analyses. Descriptive statistics were reported as median and range for continuous variables, and as frequencies and pro portions for categorical variables. The Wilcoxon signed-rank test was used to assess the changes in lymphocyte subset counts and serum Ig levels before and after RB therapy. Figure 1(A) shows the kinetics of the CD4 + cell counts for each individual patient. The median...

Kinetics of T‐cell subset reconstitution following treatment with bendamustine and rituximab for low‐grade lymphoproliferative disease: a population‐based analysis

“…Significantly less CD4+ lymphopenia was seen in the CHOP and CVP arms (Hiddemann et al , ). Limited data on lymphocyte subsets following bendamustine therapy is also available from small retrospective analyses ( n = 13 and n = 23) with limited observation times (Ito et al , ; Yutaka et al , ), suggesting that BR induces profound CD4+ lymphopenia.…”

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL

“…7,8,16–19 Specifically, a significant decrease in CD4+ and CD8+ T-lymphocyte counts was observed for up to six months after the end of BR therapy although the impact of lymphopenia on the rate of infections has been controversial. Some studies found no increase of atypical infections, 7,8,17,18 whereas others noted conflicting data, 16,19 particularly with regard to cytomegalovirus infections. 19 …”

Bendamustine‐associated infections—systematic review and meta‐analysis of randomized controlled trials

“…The rate of grade 3 to 4 lymphopenia was higher in the bendamustine arm compared with alkylating regimens. This is not surprising because bendamustine alone has been shown to cause lymphopenia, most frequently involving T cells, while the BR may cause combined T‐cell lymphopenia and B‐cell lymphopenia, sometimes with more profound T‐cell depletion . The grade 3 to 4 lymphopenia rates in the 2 trials , that compared BR with R‐CHOP were 74% and 62%, respectively, and in the trial by Knauf et al that compared bendamustine alone to chlorambucil, it was 6.2%.…”