Using Bendamustine/Rituximab in Frontline Setting for MCL, Non-Hodgkin Lymphoma Strengthened by Long-Term Findings

Ian W. Flinn, MD, PhD

Ian W. Flinn, MD, PhD

Long-term follow-up findings from the BRIGHT study support the use of bendamustine plus rituximab (BR) as a first-line treatment option for patients with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL).

Five-year results from the study (NCT00877006) demonstrated BR was noninferior to the standard treatment of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) in treatment-naïve patients. The findings give patients a much wider range of treatment options than was the case 10 years ago. Choice of treatment in the frontline setting of iNHL may be driven more by patient preferences regarding the differences in toxicity profile, according to the investigators, led by Ian W. Flinn, MD, PhD, in a report recently published in theJournal of Clinical Oncology.¹

In the study, patients with iNHL or MCL (n = 447) were preassigned to receive standard treatment on the basis of their performance status, comorbidities, and general health. Patients were then randomly assigned to receive the standard or BR. In total, 224 patients were assigned BR and 223 patients assigned to receive R-CHOP (n = 104) or R-CVP (n = 119).

There were 371 patients with iNHL, 74 patients with MCL, and 2 patients whose disease was unassigned. Patients were scheduled to receive 6 cycles of treatment, and up to 2 additional cycles could be given at the investigator’s discretion. After completion of treatment, patients were observed for a minimum of 5 years.

The median time to progression was not reached for patients in either the BR or R-CHOP/R-CVP regimens. Progression-free survival (PFS) rates were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with hazard ratio (HR) of 0.61 (95% CI, 0.45-0.85;P= .0025).

The investigators reported that overall survival (OS) rates were similar between the groups (HR, 1.15; 95% CI, 0.72-1.84;P= .5461). When OS was compared in patients who received (HR, 1.71; 95% CI, 0.62 to 4.72;P= .2973)or did not receive (HR, 0.80; 95% CI, 0.44 to 1.45;P= .4550) rituximab, the investigators reported no significant difference between the treatment arms.

Adverse events (AEs) were not monitored or collected during the follow-up period, according to the investigators, but 1 new serious AE of hepatitis B was spontaneously reported in the BR group. This patient developed hepatitis B reactivation 3 years after the last dose of the study drug and subsequently died of acute hepatic failure. The patient had received maintenance rituximab for approximately 5 months after the end of study treatment, and the patient was not receiving prophylactic hepatitis treatment.

A significantly higher incidence of secondary malignancy was observed in the BR treatment group relative to the R-CHOP/R-CVP treatment group, most notably in the incidence of squamous and basal cell carcinomas of the skin, noted the investigators.

Five patients (2.2%) in the BR group and 7 patients (3.2%) in the R-CHOP/R-CVP group had transformed disease or diffuse large B-cell lymphoma during follow-up. For 4 patients in the BR treatment group and 9 patients in the R-CHOP/R-CVP treatment group, the new cancer diagnosis occurred after the start of second-line therapy.

The incidence of new cancer diagnosis in patients with and without maintenance rituximab was 16.5% and 20.5%, respectively, for the BR treatment group and 10.0% and 11.4%, respectively, for the R-CHOP/R-CVP treatment group. The difference in the incidence in new cancer diagnoses was smallest for patients treated in the United States (11.5% for BR vs 9.3% for R-CHOP/R-CVP), with lower incidence reported in patients who were Hispanic or Latino (3.6%) than in non-Hispanic and non-Latino patients (16.9%). The median time to secondary malignancies was 29.2 months in the BR group and 30.2 months in the R-CHOP/R-CVP group (HR, 0.83; 95% CI, 0.49-1.39;P= .4757).

In both treatment groups, patients who received maintenance rituximab had longer PFS and OS than those who did not. This improvement is difficult to assess because the maintenance treatment was not assigned on a randomized basis but was rather at the discretion of the investigator.

The greater sensitivity of patients with MCL to bendamustine observed in this study is consistent with previous experience. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected, according to the investigators. There was no indication of a significant difference in early non—disease-related mortality between treatment groups.

Flinn et al reported that major limitations to this study affecting the PFS comparison include the open-label design, the lack of prespecified imaging follow-up at prescribed intervals, and the lack of review by an independent committee.

Reference:

Flinn IW, van der Jagt R, Kahl B, et al. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study.J Clin Oncol. 2019:JCO1800605. doi: 10.1200/JCO.18.00605.