June 2013, Vol 4 No 4
The Developing Treatment Role of BendamustineUncategorized
Bendamustine has demonstrated activity as monotherapy and in combination for patients with lymphoid and hematologic as well as solid tumors. In the United States, bendamustine has been approved by the FDA for the treatment of patients with indolent B-cell non-Hodgkin lymphoma (NHL) who have progressed during or within 6 months of receiving rituximab or a rituximab-containing regimen and in patients with chronic lymphocytic leukemia (CLL). HowÂever, the efficacy of bendamustine in CLL relative to first-line therapies other than chlorambucil has not been established.
While bendamustine has already received FDA approval for its use in the CLL population, its role in the treatment of patients with CLL continues to evolve. Initial studies of bendamustine in CLL were generally single-agent trials in relapsed/refractory patients. Based on the activity of bendamustine and its favorable side effect profile, it is often tested in combination with other therapies to optimize outcomes. Phase 1 and 2 trials combining bendamustine with rituximab, alemtuzumab, or fludarabine and rituximab have reported response rates of 50% to 70% in previously treated patients.1-3 These trials conveyed toxicities such as myelosuppression, nausea, and fatigue. While the activity of bendamustine in the relapsed and refractory populations has been reported, the role of bendamustine in therapy-naive patients continues to be refined. The CLL10 trial, sponsored by the German CLL Study Group, is a phase 3 randomized study comparing fludarabine, cyclophosphamide, and rituximab (FCR) with bendamustine and rituximab in previously untreated patients with CLL. This trial has completed enrollment, and the forthcoming outcomes will provide much needed information regarding the use of bendamustine as frontline therapy.
Bendamustine is also an effective agent in the treatment of indolent NHL and mantle cell lymphoma (MCL). Studies report activity among patients refractory to rituximab.4 As with CLL, the role of bendamustine in frontline therapy continues to develop. The results of 2 phase 3 trials comparing bendamustine plus rituximab (BR) with rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were recently published. The German Study Group for Indolent Lymphoma trial included over 500 therapy-naive patients, including a subset of patients with MCL. Both regimens had response rates over 90%, with the BR group reporting complete responses (CRs) in 39.8% compared with 30% in the R-CHOP group (P=.021). Patients who achieved a CR were associated with a prolonged progression-free and overall survival.5 Investigators from the BRIGHT trial, another phase 3 trial, also reported their experience comparing BR and R-CHOP/rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) as frontline therapy in indolent NHL. They reported response rates similar to the aforementioned study (94% vs 84%). The CR rates for the regimens were similar; however, the subset of patients with MCL had a higher CR rate in the BR group compared with the R-CHOP/R-CVP arm. The BRIGHT trial also highlighted the difference between the toxicity profiles of the regimens. The R-CHOP/R-CVP group was more likely to have dose reductions, and fewer patients in the BR group reported neutropenia, suggesting that the BR combination is less myelosuppressive.6
Bendamustine is a versatile agent that has activity in a variety of malignancies such as Hodgkin lymphoma, multiple myeloma, and even solid tumors. In several European countries, bendamustine has an indication for the treatment of multiple myeloma. Several clinical trials have reported efficacy with bendamustine either as monotherapy or in combination with other agents for patients not eligible for an autoÂlogous transplant or for those with relapsed or refractory disease. For patients with Hodgkin lymphoma, bendamustine has demonstrated activity in case studies and in small trials in patients with relapsed disease after stem cell transplantation. Monotherapy with bendamustine was able to produce durable responses in order to bridge patients to allogeneic stem cell transplant.7 Finally, bendamustine has also been studied in a variety of patients with relapsed or refractory solid tumors, including small cell lung cancer, soft tissue sarcomas, germ cell tumors, and ovarian and breast cancer. While bendamustine has some activity in all of these tumor types, a considerable amount of data has been published on its use with metastatic breast cancer both as initial therapy and in the salvage setting.
Cancer treatments have made tremendous progress in the past 20 years. Patients are surviving the diagnosis of cancer and living longer with their disease. However, many patients still succumb to their disease. Clinicians remain actively engaged in improving existing therapies and providing more options to cancer patients. Bendamustine is an effective agent with a toxicity profile that provides clinicians with the ability to use it as monotherapy or in combination in a variety of malignancies in the battle against cancer.
1. 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.
2. Wierda WG, Balakrishnan K, Ferrajoli A, et al. Fludarabine, bendamustine, and rituximab (FBR) chemoimmunotherapy is a safe and active regimen for relapsed/refractory CLL with in vivo mechanism of action for combination chemotherapy. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 437.
3. Tedeschi A, Rossi D, Coscia M, et al. Final report of bendamustine and alemtuzumab (BEN CAM) combination in relapsed and refractory chronÂic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2898.
4. Rummel MJ, Gregory SA. Bendamustineâ€™s emerging role in the management of lymphoid malignancies. Semin Hematol. 2011;48(suppl 1):S24-S36.
5. Rummel MJ, Niederle N, Maschmeyer G, et al. Subanalysis of the StiL NHL 1-2003 study: achievement of complete response with bendamustine-rituximab (B-R) and CHOP-R in the first-line treatment of indolent and mantle cell lymphomas results in superior survival compared to partial response. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 2724.
6. Flinn IW, Van der Jagt RH, Kahl BS, et al. An open-label, randomized study of bendamustine and rituximab (BR) compared with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line treatment of patients with advanced indolent non-Hodgkinâ€™s lymphoma (NHL) or mantle cell lymphoma (MCL): the Bright study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 902.
7. Corazzelli G, Angrilli F, Dâ€™Arco A, et al. Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma. Br J Haematol. 2013;160:207-215.
Novel Approaches in the Treatment of Hematologic Malignancies Utilizing Bendamustine
This is the fourth article in a 4-part series on bendamustine. While the previous articles discussed the efficacy and safety of bendamustine for patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymÂphoma (NHL) in the registration studies cited in the US product labeling, this article discusses ongoing clinical investigations of [ Read More ]
Bendamustine: Progress in Clinical Investigations
At the 54th Annual Meeting of the American Society of Hematology, a number of abstracts were presented demonstrating the efficacy and toxicities of bendamustine either alone or in combination with other agents for the treatment of several lymphoid malignancies such as chronic lymphocytic leukemia (CLL) and indolent as well as [ Read More ]