Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study

Abstract

Background: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment.

Methods: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR.

Results: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities.

Conclusion: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients.

Clinical trial registration: ClinicalTrials.gov, No. NCT01596621; https://ichgcp.net/clinical-trials-registry/NCT01596621.

Conflict of interest statement

Teva employees were involved in the study design, data collection and analysis, and in the writing of this manuscript. All authors had full access to all the study data and had final responsibility for the decision to submit for publication. Leonard James and Edward Hellriegel are former employees of Teva Pharmaceuticals.

Copyright © 2021 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.

Figures

Figure 1

Patient disposition (N = 102). ∗Includes patients who withdrew during cycles 7 and 8. +Includes leukopenia, lymphocytopenia, and neutropenia.

Figure 2

Kaplan-Meier curves for (A) DoR and (B) PFS by IRC in patients with relapsed, indolent B-cell NHL who had received at least one dose of bendamustine hydrochloride 120 mg/m2; for patients with a CR or PR. CR: Complete response; DoR: Duration of response; IRC: Independent review committee; NHL: Non-Hodgkin lymphoma; PFS: Progression-free survival; PR: Partial response.

Figure 3

Mean (standard deviation) plasma concentration-vs.-time profiles of bendamustine and the metabolites, M3 and M4, in patients with relapsed, indolent B-cell NHL following bendamustine 120 mg/m2 on day 1 of cycle 1 (n = 15). NHL: Non-Hodgkin lymphoma.