Bendamustine for Patients with Indolent Lymphoma an Updated Meta-Analysis of Randomized Controlled Trials (RCT)
Authors: Vidal Liat , Shargian Liat , Shpilberg Ofer , Ram Ron , Raanani Pia , Gurion Ronit , Gafter Anat 
Published: October 2019

Abstract
Background
In 2011 we performed a systematic review and meta-analysis evaluating the efficacy of bendamustine for patients with indolent lymphoproliferative malignancies. We included 5 trials. Since then several new trials of bendamustine for indolent lymphoproliferative malignancies were conducted, and some are still ongoing. Individual trials supported a progression free survival (PFS) benefit but none was powered to demonstrate an effect on overall survival (OS).
In order to evaluate the effect of bendamustine on the OS of patients with indolent lymphoproliferative malignancies we performed a systematic review and meta-nalysis of RCTs.
Methods
We included RCTs that compared bendamustine to other chemotherapy regimens for patients with indolent lymphoproliferative malignancies including chronic lymphocytic leukemia (CLL). We included patients in both first line and the relapsed setting. In July 2015 we searched The CochraneLibrary, MEDLINE, conference proceedings, and databases of ongoing trials. Two reviewers appraised the quality of trials and extracted data.The primary outcome wasall cause mortality. Secondary outcomes included: PFS, complete response (CR), and adverse events. Relative risk (RR) with 95% confidence intervals (CIs) were estimated and pooled for dichotomous data and hazard ratio (HR) for time to event data.
Results
We identified 8 trials, conducted between the years 1994 and 2012 (one trial is ongoing) randomizing 2484 adult patients with a mean/median age of 58 - 74 years. The rate of patients with follicular lymphoma ranged between 40% to 70%, and mantle cell lymphoma 16% to 22% in the 3 trials that included patients with those types of lymphoma. Four trials included only patients with CLL. The comparisons were between bendamustine, vincristine, prednisone to cyclophosphamide, vincristine, prednisone (CVP); bendamustine-rituximab (BR) to cyclophosphamide, adriamycin, vincristine, prednisone, rituximab (RCHOP), RCVP; BR to fludarabine-rituximab and to fludarabine, cyclophosphamide, rituximab (FCR); and bendamustine to chlorambucil (+-rituximab).
Bendamustine significantly reduced mortality risk of patients with indolent lymphoproliferative malignancies compared to control, RR for death 0.84; 95% CI 0.73 - 0.96, I2 = 0 (Figure). Including only CLL patients the RR is 0.84; 95% CI 0.69 - 1.03.
PFS was improved with bendamustine in each of the trials and when trials were pooled, HR 0.55, 95% CI 0.41 - 0.74, I2 of heterogeneity 78%. The rate of CR improved with bendamustine compared to control for patients with indolent lymphoma, RR 1.40; 95% CI 1.09 - 1.81, random effects model, I2 = 46%. We did not pool results of CR of patients with CLL due to a high statistical heterogeneity. The rates of grade 3/4 infection or any grade 3/4 adverse events were not different between the arms.
Discussion
This meta-analysis shows that bendamustine decreases the risk of mortality of patients with indolent lymphoma and CLL compared to other chemotherapy. In addition, PFS is improved. Further analysis of results with longer follow up is expected.

Disclosures
Shpilberg: Gilead: Consultancy; Millennium Takeda: Consultancy. Raanani:Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board; BMS: Other: Advisory Board; Pfizer: Other: Advisory Board.