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Toxicity of Bendamustine Therapy

Faculty Perspectives May 2013 Vol 4 No 3 TON - Drug Updates
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 approved by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) and for specific populations of patients with non-Hodgkin lymphoma (NHL). While bendamustine has been reported to be very effective in treating these malignancies, its tolerable toxicity profile has made it a useful agent in a variety of patient populations.

Bendamustine, like many other cytotoxic therapies, is associated with hematologic adverse events including neutropenia, anemia, and thrombocytopenia. Myelosuppression associated with bendamustine therapy is generally reversible. The median time to neutrophil and platelet nadir is approximately 21 days, with recovery occurring in 8 and 14 days, respectively.1 Man­agement strategies for patients experiencing bone marrow suppression include blood product transfusions, colony-stimulating growth factors, and dose reductions for future bendamustine cycles. Further cycles of bendamustine should be delayed until the absolute neutrophil count is ≥1000 cells/mL and the platelet count is ≥75,000 cells/mL.

Since myelosuppression has been reported in trials in which bendamustine was used as either monotherapy or in combination therapy, patients are at an increased risk for infectious complications. Prophylactic antimicrobials were not routinely administered to patients enrolled in bendamustine trials. Commonly reported infections when bendamustine was given as monotherapy include pneumonia, herpes zoster, and Candida infections. When bendamustine was given in combination with rituximab, viral infections such as cytomegalovirus, herpes simplex, and herpes zoster were reported, as well as fungal infections, pneumonia, and bacterial sepsis.2 All patients experiencing myelosuppression during bendamustine therapy should be counseled to immediately report all symptoms of infection.

Nonhematologic toxicities have also been reported with bendamustine therapy. Gastrointestinal effects such as nausea and vomiting can affect up to 40% of patients.1 Most studies report that the majority of patients experience grade 1/2 toxicities that do not require dose adjustment of bendamustine. Bendamustine is considered a moderately emetogenic agent by the National Comprehensive Cancer Network in the 2013 guidelines for antiemesis.3 It is recommended that each patient receives a serotonin antagonist prior to each dose. Patients should also be given prescriptions for antiemetic agents to be used as needed after chemotherapy. Follow-up prior to each cycle of chemotherapy is suggested to determine if the antiemetic therapy needs adjustment.

Monitoring patients during and after bendamustine infusions is very important. Tumor lysis syndrome has been reported, so tumor burden, electrolytes, and renal function should be evaluated prior to the first cycle. For high-risk patients, agents such as allopurinol or rasburicase with further laboratory monitoring may be necessary. Infusion-related reactions have also occurred during bendamustine therapy. These reactions generally occur during or shortly after the completion of the infusion. Fever, chills, pruritus, shortness of breath, hypotension, and rash have been reported and are more commonly associated with the second or subsequent cycles of therapy. Rarely, anaphylactic reactions have occurred with bendamustine administration. Patients experiencing severe reactions may need to discontinue therapy. However, for less severe reactions, patients may be rechallenged if premedicated with antihistamines and corticosteroids.4 Finally, long-term follow-up of bendamustine patients is essential. Premalignant and secondary malignancies have been reported in patients who have received bendamustine therapy. Most of these cases occurred soon after the completion of bendamustine therapy.5 While concerning, a direct association with bendamustine therapy cannot be made at this time.

Bendamustine has demonstrated it is an active agent in patients with CLL and specific populations of NHL. Even though this agent is generally well tolerated, a discussion of potential and serious side effects should occur with both patient and caregivers prior to the initiation of therapy. Patients and caregivers should be given an opportunity to ask questions. Also, written information regarding side effects and provider contact information can be a helpful resource for patients. As the clinical experience with bendamustine matures, it will be important to document the long-term safety profile of this agent. Long-term follow-up of patients and submission of adverse events to the manufacturer will help define the role and toxicity profile of bendamustine in these patient populations.

References
1. Elefante A, Czuczman MS. Bendamustine for the treatment of indolent non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J Health Syst Pharm. 2010;67:713-723.
2. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26:
4473-4479.
3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Antiemesis. Version 1.2013. www.nccn.org/professionals/physician_gls/f_guidelines.asp#antiemesis. Accessed April 1, 2013.
4. Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008;26:204-210.
5. Cheson BD. Etiology and management of tumor lysis syndrome in patients with chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2009;
7:263-271.

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Last modified: May 21, 2015