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A Commentary on the Efficacy of Bendamustine in Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

Faculty Perspectives March 2013 Vol 4 No 2
Susanne Liewer, PharmD, BCOP
Clinical Pharmacy Coordinator
Stem Cell Transplant, Nebraska Medicine
Department of Pharmacy, Omaha
Clinical Associate Professor
University of Nebraska Medical Center
College of Pharmacy, Omaha, NE

Bendamustine is an active chemotherapy agent that has been studied for many years in a variety of malignancies; however, it has only been approved for use in the United States since 2008.1 Structurally, bendamustine shares similarities with both purine analogs and alkylating agents. The addition of the benzimidazole ring contributes to its unique structure and extended spectrum of activity. Ben­damustine is currently FDA approved for the treatment of both chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (NHL) that has progressed during or within 6 months of receiving rituximab or rituximab-containing regimens.1

CLL is the most common leukemia diagnosed in Western countries. This disease tends to affect older populations, with a median age at diagnosis of 72 years.2 Therapy for patients with CLL must be individualized based on multiple factors such as age, overall health, comorbid conditions, and specific cytogenetic abnormalities. Bendamustine is a very active agent in the treatment of CLL and has demonstrated efficacy when used as monotherapy as well as in combination with other agents. The FDA approved its use based on a phase 3 randomized, open-label trial that compared bendamustine with chlorambucil as initial therapy in patients with advanced CLL. The overall response rate (ORR) and median progression-free survival (PFS) achieved were 59% and 18 months in the bendamustine group versus 26% and 6 months in the chlorambucil group, respectively (P<.0001).1 In addition to the efficacy of bendamustine when used as a single agent, it has been successfully combined with rituximab in the treatment of CLL. The German CLL Study Group (GCLLSG) reported the results of a phase 2 trial of bendamustine combined with rituximab in the treatment of previously treated patients with CLL. The ORR was reported as 59%, with 9% of the patients experiencing a complete response (CR).3 Based on these results, the GCLLSG is currently conducting a phase 3 trial comparing bendamustine and rituximab with the active regimen fludarabine, cyclophosphamide, and ri­tuximab. The results from this study may help to further define the use of bendamustine in this patient population.

Bendamustine has also demonstrated significant activity in the treatment of indolent NHL, which is a very heterogeneous disease and the most common hematologic malignancy in the United States. The histology and stage of the disease guide treatment for patients with indolent NHL. In the past decade the use of the anti-CD20 monoclonal antibody rituximab has had a significant impact on response rates and overall survival. Though rituximab is traditionally incorporated into front-line therapies, new and innovative regimens have been developed for patients who relapse after receiving rituximab-containing regimens. Bendamustine was approved by the FDA for the treatment of patients with indolent NHL in 2008. This approval was based on the results in 100 patients with indolent NHL who had been previously treated with rituximab or rituximab-containing regimens. All patients received bendamustine as monotherapy for up to 8 cycles. The ORR reported was 74%, with a median duration of response of 9.2 months.4 Bendamustine has also been studied in combination with rituximab. A randomized phase 3 trial compared rituximab plus bendamustine with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line therapy in patients with advanced follicular lymphoma and indolent and mantle cell lymphomas (n=513). The ORR was similar in both groups. However, the CR, median PFS, and event-free survival were all significantly higher in the bendamustine plus rituximab arm compared with the R-CHOP arm. In addition, patients who received bendamustine experienced fewer serious adverse events associated with treatment.5 Encouraging results in patients with relapsed and refractory follicular lymphoma have also been reported with novel combinations such as bendamustine, rituximab, and bortezomib.6

Bendamustine has demonstrated significant activity as monotherapy or in combination when used as frontline therapy or for relapsed/refractory disease. With a tolerable toxicity profile, bendamustine provides a versatile and favorable treatment option for patients with CLL or indolent NHL.

References
1. Treanda [package insert]. Frazer, PA: Cephalon, Inc; 2010.
2. National Cancer Institute. SEER Stat Fact Sheets: Chronic Lymphocytic Leukemia. http://seer.cancer.gov/statfacts/html/clyl.html. Accessed February 2013.
3. Fischer K, Cramer P, Busch R, et al. Bendamustine combined with ri­tuximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29:3559-3566.
4. Hallek M, Pflug N. State of the art treatment of chronic lymphocytic leukaemia. Blood Rev. 2011;25:1-9.
5. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood (ASH Annual Meeting Abstracts). 2009;114. Abstract 405.
6. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011;29:3389-3395.

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Last modified: May 21, 2015