Bendamustine Is Not Associated With An Increase In Infections – Systematic Review and Meta-Analysis Of Randomized Controlled Trials
Authors: Gafter-Gvili Anat , Gurion Ronit , Raanani Pia , Shpilberg Ofer , Vidal Liat 
Published: October 2019

Abstract

Background
Bendamustine is a chemotherapeutic drug with structural similarities to both alkylating agents (nitrogen mustard derivative) and purine analogues (benzimidazole ring). Theoretically, due to its nucleoside-like properties it might be associated with more infections. Data in the literature is lacking regarding the infection-related adverse events of bendamustine-containing regimens. Thus, we aimed to assess this risk.

Methods
Systematic review and meta-analysis of all randomized controlled trials comparing bendamustine containing regimens (alone or combined with other chemotherapeutic agents and/or rituximab) to any other regimens. Trials evaluating bendamustine for any indication (hematological as well as solid malignancies) were included. A comprehensive search of The Cochrane Library, MEDLINE, conference proceedings and references was conducted until July 2013. Two reviewers appraised the quality of trials and extracted data. Outcomes assessed were: any infections, grade 3-4 infections, fatal infections, grade 3-4 neutropenia and grade 3-4 lymphopenia. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. We used fixed effect model to pool data, unless there was significant heterogeneity, in which case we used the random effects model.

Results
Ten trials conducted between the years 1998 and 2013 and randomizing 2360 patients were included. We included 4 trials of patients with non-Hodgkin lymphoma (Rummel 2013, Rummel 2010, Herold 2006 and the Bright study 2013), 3 trials of CLL (Knauf 2009, Niederle 2013, LeBlond 2013), 1 trial of patients with multiple myeloma (Ponish 2006) and 2 trials of breast carcinoma patients. The bendamustine arm included: bendamustine alone (2 trials), bendamustine-rituximab (BR) (4 trials), bendamustine, vincristine, prednisone (BOP) (1 trial), bendamustine, MTX. 5FU (BMF) (2 trials) and bendamustine, prednisone (BP) (1 trial). The comparator arms in 8 of the trials included other alkylating agents: chlorambucil, R -CHOP, cyclophosphamide, MTX, 5-FU (CMF) and melphalan-prednisone (MP) – each regimen used in 2 trials and COP used in 1 trial. In 2 trials the comparator arm included fludarabine based regimens (alone or with rituximab).
There was no statistically significant effect for bendamustine on the rate of any type of infection (RR 1.06 [95% CI 0.83, 1.34], 6 trials, figure). This analysis included only trials of hematological malignancies. There was no increase in the rate of grade 3-4 infections (RR 1.45 [95% CI 0.86, 2.45], 7 trials) or fatal infection (RR 0.69 [95% CI 0.30, 1.58], 3 trials). Data were too scarce to analyze by specific types of infections separately. There was no increase in the rate of grade 3-4 neutropenia in the bendamustine arm (RR 0.9 [95% CI 0.58, 1.42], 6 trials). This was true both when the comparator was alkylating agent containing regimens (RR 0.87 [95% CI 0.52, 1.48], 4 trials) or fludarabine containing regimens (RR 1.02 [95% CI 0.54, 1.91], 2 trials). There was a significant increase in grade 3-4 lymphopenia in the bendamustine arm compared to alkylating agent containing regimens (RR 1.95[95% CI 1.54, 2.47).

Conclusions
Our systematic review demonstrates no effect of bendamustine on the rate of infections when compared to either alkylating agents or fludarabine, in hematological as well as in solid malignancies, despite an increase in lymphopenia. Thus, bendamustine remains a safe therapeutic option. The main drawback of this meta-analysis is the heterogeneity between malignancies and treatments.

Disclosures:
No relevant conflicts of interest to declare.