Bendamustine is a unique cytotoxic compound. Its chemical structure contains a 2-chloroethyl (nitrogen mustard) group that confers alkylating (DNA-damaging) properties and a benzimidazole ring. The precise contribution of the benzimidazole ring to the activity of the drug has not been defined, but it may affect the types of cross-links formed and the susceptibility to DNA repair.9,10
Two previous German studies have demonstrated substantial single-agent activity in recurrent, indolent lymphoma. Heider and Niederle conducted a study of single-agent bendamustine at a dose of 120 mg/m2
on Days 1 and 2 repeated every 21 days.11
Despite a high frequency of alkylator-resistant disease, the ORR in that study was 73%, and the median DOR was 16 months. Bremer evaluated single-agent bendamustine in a similar patient population but at a dose and schedule of 60 mg/m2
daily for 5 days every 4 to 6 weeks and observed an ORR of 82%.12
A recently published, multicenter North American study confirmed the efficacy of single-agent bendamustine in recurrent NHL.17
Seventy-six patients with rituximab-refractory indolent and transformed B-cell lymphoma were treated using a dose and schedule of 120 mg/m2
on Days 1 and 2 every 21 days. An ORR of 77% was observed, and the median DOR was 6.7 months. The median DOR was only 2.3 months in the transformed population, but limiting the analysis to the patients who had indolent histology resulted in a median DOR of 9 months. Toxicities were mainly hematologic and reversible.
The current trial confirms and expands upon the results observed in the previous North American study.17
Our trial used the same dose and schedule of bendamustine in a very similar patient population and produced an ORR of 75% and a median DOR of 9.2 months. When evaluating these results, it is important to consider the patient population under study. This trial included 100 patients who had received a median of 2 prior chemotherapy regimens (range, 0-6 regimens), and almost all of them (97 of 100 patients) were refractory to rituximab. Most patients (91 of 100) had received prior alkylating-agent therapy, 44 patients had received prior purine analogue therapy, and 24 patients had received prior radioimmunotherapy. Thirty-six patients were deemed chemotherapy-refractory (30 patients were alkylator-refractory) based on the lack of an objective response to their most recent chemotherapy treatment. Despite the heavily pretreated nature of this population, single-agent bendamustine demonstrated encouraging efficacy, including an ORR of 64% and a PFS of 7.5 months in the chemotherapy-refractory population. These clinical data support the in vitro findings of bendamustine's activity in cell lines that are resistant to other alkylating agents.9,10
The efficacy appears to be comparable in the different indolent histologic subtypes. For example, the ORR was 74% among the 62 patients who had follicular lymphoma and 71% among the 21 patients who had small lymphocytic lymphoma.
All of the patients in this study were refractory to rituximab, and most developed rituximab resistance after they received rituximab-chemotherapy combinations rather than single-agent rituximab. Preclinical data suggest that the biologic basis of rituximab resistance may vary as a function of the prior therapies received.21,22
Thus, it is important to establish benchmarks of activity in this unique and growing patient population for which there are no published trials evaluating other agents or regimens. The closest comparison that can be made is to radioimmunotherapy studies in a rituximab-refractory population, which was defined as no response or a time to progression of <6 months after single-agent rituximab. Witzig et al6
reported an ORR of 74% and a median DOR of 6.8 months using yttrium-90 ibritumomab tiuxetan, and Horning et al7
reported an ORR of 65% and a median DOR of 10.4 months using iodine-131 tositumomab in such patients.6,7
The major toxicities associated with bendamustine were reversible myelosuppression, gastrointestinal toxicity, and infection. Some of the infections observed suggested a degree of immunosuppression beyond what would be anticipated from transient neutropenia, including 12 episodes of herpes zoster and 5 episodes of CMV infection. The CMV reactivation was unexpected, because this infection has not been reported in other bendamustine trials. No clear risk profile for CMV reactivation emerged from the data (of the 5 patients with CMV, 2 had received prior purine nucleoside analogues, 2 had CLL/small lymphocytic lymphoma, and 3 had follicular lymphoma). Given the absence of CMV in other bendamustine trials, we do not advocate monitoring CMV viral load in asymptomatic individuals who are receiving bendamustine, but we do recommend a low threshold for testing in individuals who develop signs or symptoms compatible with CMV reactivation. It is important for clinicians to be aware of the potential risk for CMV infection, because complications of CMV infection largely can be prevented with early recognition and appropriate therapy.23
The 6 deaths that occurred during the current study were considered at least possibly related to treatment. Although this rate is higher than expected, a previous study of single-agent bendamustine that used the same dose and schedule in a virtually identical patient population reported no treatment-related deaths among 76 patients.17
It is unclear why this difference was observed between the 2 trials; however, when estimating the risk of serious complications from single-agent bendamustine, it is worthwhile to consider the entire body of literature.
A legitimate concern associated with DNA-damaging agents is the risk of secondary myelodysplasia (MDS)/acute myelogenous leukemia (AML). It is estimated that the cumulative risk in this patient population approaches 5% after chemotherapy or radioimmunotherapy.24-27
Only 1 episode of MDS was noted during the reporting period for the current study; however, given the natural history of treatment-related MDS/AML, longer follow-up of this patient cohort will be needed before the risk can be fully assessed.
Some of the myelosuppression and associated infectious complications noted in the current trial may have been a function of the dose and schedule selected for study. There are now 3 reports of bendamustine treatment in indolent lymphoma and mantle cell lymphoma using a dose of 90 mg/m2
on Days 1 and 2 every 28 days in combination with rituximab. A multicenter trial that was conducted in Germany noted that 16% of patients had grade 3/4 neutropenia, 3% had grade 3/4 thrombocytopenia, and there were no treatment-related deaths.13
A recently completed North American trial that involved 66 patients reported that 36% had grade 3/4 neutropenia, 9% had grade 3/4 thrombocytopenia, and there was 1 death because of toxic epidermal necrolysis (which was considered possibly related to therapy).28
A second interim analysis of an ongoing randomized clinical trial comparing bendamustine-rituximab (BR) with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (CHOP-R) as initial therapy for indolent lymphoma and mantle cell lymphoma recently was reported.29
Response rates and PFS were comparable in the 2 arms. Toxicity appeared to be less with BR compared with CHOP-R for alopecia (0% vs 89%), grade 3/4 leukocytopenia (19% vs 36%), and infectious complications (25% vs 37%). These encouraging results support further study to determine the optimal bendamustine dose and schedule.
The current results confirmed the promising clinical activity of bendamustine with acceptable toxicity in patients with rituximab-refractory, indolent B-cell lymphoma and provided the basis for approval by the United States Food and Drug Administration in October 2008. These data, combined with the emerging worldwide experience for bendamustine, strongly suggest that bendamustine is a valuable addition to the treatment armamentarium for this patient population, which has limited treatment options.