Pharmacology Update
Bendamustine Hydrochloride Injection (Treanda®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.
Bendamustine has received FDA approval, after priority review, for the treatment of chronic lymphocytic leukemia. It is a mechlorethamine derivative that acts as an alkylating agent. It is manufactured by Pharmachemie B.V. in the Netherlands and marketed by Cephalon, Inc as Treanda.
Indications
Bendamustine is indicated for the treatment of chron- ic lymphocytic leukemia (CLL).1
Dosage
The recommended dose is 100 mg/m2 given intravenously over 30 minutes on Day 1 and 2 of a 28-day cycle, up to 6 cycles. The dose should be delayed if Grade 4 hematologic toxicity or clinically significant Grade 2 or higher nonhematologic toxicities occurs. If the toxicities sufficiently improve bendamustine administration may be reinstated. The dose should be reduced to 50 mg/m2 if Grade 3 or greater hematologic toxicity occurs. If these recur, the dose should be reduced to 25 mg/m2. For nonhematologic Grade 3 or greater toxicity, the dose should be reduced to 50 mg/m2. Concomitant allopurinol should be considered for patients at risk for tumor lysis syndrome for the first few weeks of therapy.1
Bendamustine is available as 100 mg single-use vials.
Potential Advantages
Bendamustine's mechanism of action is believed to differ from other alkylating agents.2 When used as monotherapy, it was reported to be more efficacious than chlorambucil (monotherapy) in terms of overall response and progressive-free survival.1
Potential Disadvantages
Myelosuppression is the most common hemato- logic toxicity. The incidence of Grade 3 or 4 was as follows: neutropenia (24%), thrombocytopenia (13%), leucopenia (15%), and anemia (3%). Most common nonhematologic adverse events include nausea (20%), vomiting (16%), and pyrexia (24%). Toxic skin reactions have also been reported. Bendamustine has not been compared to other commonly used therapies such fludarabine or combination therapy with fludarabine, cladribine, chlorambucil, rituximab. CYP1A2 inducers and inhibitors may affect the levels of bendamustine.1
Comments
Bendamustine is the newest alkylating agent to be approved. Its mechanism of action is reported to differ from typical DNA-alkylating agents. Proposed mechanisms include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe.2 Bendamustine was compared to chlorambucil in an open-label, randomized, controlled trial in 301 subjects previously untreated with Binet Stage B or C CLL (n = 301). Bendamustine was reported to be more efficacious than chlorambucil in terms of over- all response rate (59% vs 26%, p < 0.001) and progressive-free survival (median of 18 months vs 6 months, HR (95% CI); 0.27 (0.17,0.43, p < 0.001).1 Response was based on improvement of clinical and laboratory criteria (eg, lymphocyte, neutrophil, and platelet counts, hemoglobin level without transfusion, hepatosplenomegaly, lymphadenopathy). The trial was terminated too early to assess survival. Myelosuppression is the most common hematologic adverse event and nausea and vomiting are the most common nonhematologic adverse events.
Clinical Implications
CLL is a rare slowly progressive blood and bone marrow disease. Survival varies between 2 years and longer than 10 years depending on the disease stage.3 Therapeutic options include steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant. Treatment varies based on disease stage/risk group, presence or absence of symptoms, and age.4,5 Bendamustine pro-vides a new option for treating CLL. Its ultimate role will depend on how it compares to agents such as flu- darabine as well as various combination regimens. Fludarabine has also been shown to provide a higher response rate and a longer duration of remission and progressive-free survival than chlorambucil.6 Bendamustine is currently being studied for rituximab-refractory indolent and transformed non-Hodgkin's lymphoma and multiple myeloma.7,8
References
1. Treanda Product Information. Cephalon. March 2008.
2. Leoni LM, et al. Clin Cancer Res. 2008;14(1):309-317.
3. Hallek M, et al. Hematology Am Soc Hematol Edu Program. 2005;285-291.
4. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/HealthProfessional. Accessed 4/11/08.
5. http://www.cancer.org/docroot/CRI/CRI. Accessed 4/11/08.
6. Rai KR, et al. N Engl J Med. 2000;343:1750-1757.
7. Friedberg JW, et al. J Clin Oncol. 2008;26:204-210.
8. Ponisch W, et al. J Cancer Res Clin Oncol. 2006;132:205-212.
Bendamustine has received FDA approval, after priority review, for the treatment of chronic lymphocytic leukemia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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