By William B. Ershler, MD, Editor
SYNOPSIS: In an international, randomized, non-inferiority trial, bendamustine-rituximab proved comparable in overall response rate when compared with R-CHOP or R-CVP in the management of indolent NHL and mantle cell lymphoma. Progression-free and overall survival comparisons remain to be determined. Notably, toxicity profiles were significantly different, with higher rates of reported nausea and vomiting with BR and neuropathy and alopecia with R-CHOP/R-CVP.
SOURCE: Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: The BRIGHT study. Blood 2014;123:2944-2952.
Standard approaches to the treatment of indolent non-Hodgkin's lymphoma (NHL) have evolved over the past few decades with the incorporation of targeting agents coupled with selected chemotherapeutics. This, with advances in supportive care, has resulted in improved outcomes, including survival. Bendamustine is one agent that has gained recent attention because of its demonstrated activity in relapsed NHL, CLL, and in rituximab-resistant NHL.1-4
In light of these and other findings, the German Study Group, Indolent Lymphoma (STiL), conducted a phase 3 non-inferiority trial to determine whether 6 cycles of bendamustine and rituximab (BR) were equivalent to 6 cycles of R-CHOP for initial treatment of indolent NHL. Entry criteria included untreated advanced stage disease requiring therapy (rapid progression, disease-related symptoms, bulk, or threatened organ function). The study enrolled 514 subjects and at a median follow-up of 45 months, the median progression-free survival was significantly longer in the BR arm (69.5 vs. 31.2 months; p < .0001).5 Treatment with BR was associated with a higher complete response rate, and overall response rates were similar between the two groups. Fewer serious adverse events were reported in the BR arm compared with R-CHOP (19% vs. 29%). Neutropenia, leukopenia, and serious infections were also less common following bendamustine.
With this as background, Flinn and colleagues currently present data from an industry-sponsored validation trial. Its design was a randomized, non-inferiority (NI), international, phase 3 study to determine the efficacy and safety of BR vs. a standard rituximab-chemotherapy regimen, either R-CHOP or R-CVP, in the initial treatment of patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators pre-assigned the standard treatment regimen (i.e., R-CHOP or R-CVP) they considered most appropriate for each patient. Thereafter, patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles. The data indicated that BR was non-inferior to R-CHOP/R-CVP, as assessed by the primary endpoint of complete response rate (31% vs. 25%, respectively; p = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (p = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (p < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard therapy regimens (p < .05).
The data support the conclusion that BR is non-inferior to standard therapy with regard to clinical response with an acceptable safety profile. Whether the combination is actually superior will not be evident without longer follow-up and a comparison of progression-free survival, overall survival, and the incidence of long-term toxicities. Oncologists are very familiar with the nuances of R-CHOP (and R-CVP) management, and it is notable that toxicity profiles were sufficiently different with BR. For example, BR-treated patients had a higher rate of significant lymphopenia, whereas R-CHOP/R-CVP was associated with increased neutropenia. BR was also associated with a slightly increased risk of opportunistic infections and nausea but decreased neuropathy and alopecia compared with R-CHOP/R-CVP. Although follow-up data are anticipated and may prove superiority of one approach over the other, clinical oncologists can be reassured that BR may be a suitable alternative to R-CHOP or R-CVP and treatment decisions may be based on factors including scheduling, ease of administration, and comorbidities.