Bendamustine: more ammunition in the battle against mantle cell lymphoma

Abstract

While mantle cell lymphoma (MCL) outcomes appear to have improved in the last decade, it remains an incurable disease in the majority of cases. Generally speaking, the more “ ammunition ” one has to combat an incurable disorder, the better it is for patients and their treating physicians. Bendamustine has been available for several decades in Europe following its development in 1963 in the German Democratic Republic, but only more recently has it been made available for investigation in the USA [1]. Th e effi cacy of bendamustine has been demonstrated in chronic lymphocytic leukemia [2] and indolent non-Hodgkin lymphoma (NHL) [3], with several studies including smaller subsets of MCL. Based on these reports, bendamustine is emerging as a new therapeutic option for MCL, in both the frontline and relapsed settings. Th e report by Warsch et al . provides an analysis of the multicenter experience with bendamustine for treatment of MCL [4]. Although the conclusions that can be drawn from these data are limited by the small sample size and retrospective nature of the analysis, the reported outcomes provide a better understanding of response rates and tolerability with this agent. Previous reports of bendamustine activity in MCL were derived from trials including multiple NHL histologies, with only small fractions represented by MCL. Th e overall response rate (ORR) of 83% and complete response (CR) rate of 50% observed in this study [4] are consistent with other data. Robinson et al . observed an ORR of 92% and CR or unconfi rmed CR rate of 59% among the subgroup of patients with relapsed MCL [5]. Data regarding progression-free survival (PFS) are somewhat more diffi cult to compare in this retrospective analysis. Here, Warsch et al . observed a timeto-treatment failure of 16.2 months in this predominantly relapsed population [4], while Robinson et al . reported a higher median PFS of 23 months, but with this endpoint reported for the entire cohort of indolent NHL and MCL [5]. Toxicity appears acceptable in this series, particularly considering that this is a relatively heavily pretreated population [4]. Rates of grade 3 – 4 infections were observed in 10% of treated patients, and neutropenic fever occurred in only 7% of patients. Th rombocytopenia is common with bendamustine, and 20% of patients experienced grade 3 – 4 thrombocytopenia, although notably without signifi cant bleeding complications observed. Th ese toxicity data are compatible with prior reports of bendamustine rituximab (BR) in indolent NHL and MCL. In the report by Robinson et al ., 66 patients with relapsed indolent NHL or MCL (18%) were treated with BR, with 36% of patients experiencing grade 3 – 4 neutropenia but only 10% of patients experiencing grade 3 – 4 infections. Th rombocytopenia was manageable, with only 9% of patients experiencing grade 3 – 4 thrombocytopenia [5]. Current therapy options for relapsed MCL are limited. Bortezomib is the solitary Food and Drug Administration (FDA)-approved regimen for relapsed MCL in the USA, with a primary dose-limiting toxicity being sensory neuropathy. Th e risk for sensory neuropathy with bortezomib is further exacerbated by frequent exposure to vincristine in many upfront MCL regimens. Th e PINNACLE trial observed an ORR of 33% with single-agent bortezomib in patients with relapsed MCL after no more than two prior therapies, with a median duration of response of 9.2 months and time-to-progression (TTP) of 6.2 months [6]. Other agents with reported activity in MCL have similarly demonstrated reasonable rates of objective response but with disappointing PFS. For example, in a phase II study with cladribine rituximab in 29 patients with previously untreated MCL, a CR rate of 52% was achieved but with a median TTP of 12.1 months [7]. Although bendamustine has not been compared with other standard regimens in a randomized trial in relapsed MCL, comparisons of available data suggest that bendamustine may provide improved outcomes in the setting of relapsed disease. Emerging data are also suggestive of high rates of durable response in newly diagnosed MCL. Th e StIL (Study Group Indolent Lymphomas) trial reported by Rummel et al . also observed a more favorable toxicity profi le with BR compared