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Bendamustine: Can you teach an old dog new tricks?
Since being used for chemical warfare in the First World War, alkylating agents have become the workhorses of therapy for a wide variety of malignancies. Although this class of agents includes many drugs with differing chemical structures, they generally have a similar mechanism of action, which is to bind directly to DNA, leading to cross-linking and breaking DNA strands, preventing cell division and ultimately leading to cell death. Resistance to alkylating agents occurs through several well-described mechanisms, including enhanced DNA repair mechanisms, decreased activation by cytochrome P450 enzymes, increased deactivation through enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol levels, and an altered cellular apoptotic response to DNA repair.
Bendamustine (Treanda, Cephalon) was approved by the FDA in March 2008 for the treatment of patients with chronic lymphocytic leukemia, but was originally designed in the 1960s with the goal of developing a bifunctional cytotoxic agent with both alklyating and antimetabolite properties. Although bendamustine’s exact mechanism of action is not completely understood, it forms covalent linkages with DNA that lead to cell death through several apoptotic-dependent and apoptotic-independent pathways. Leoni et al published a study suggesting that bendamustine has multiple cytotoxic mechanisms of action that differentiate it from conventional alkylating agents.
Although bendamustine has been commercially available in Germany since the 1970s, it was not until recently that clinical trials were undertaken to further describe its efficacy in several hematologic and solid tumor malignancies in the United States. It has demonstrated clinical activity in CLL, lymphoma, multiple myeloma, breast cancer, small-cell lung cancer and other solid tumors. Also, preclinical and clinical studies with bendamustine appear to indicate a lack of complete cross-resistance with conventional alkylating agents. Development of bendamustine is most advanced in patients with hematologic malignancies.
Clinical activity
The pivotal trial that led to the FDA approval of bendamustine was a phase-3 randomized controlled trial comparing bendamustine (100 mg/m2 IV on days 1 and 2 every 28 days) to oral chlorambucil (0.8 mg/kg on days 1 and 15 every 28 days) in 305 treatment-naive B-cell CLL patients with Binet stage B and C disease. At a median follow-up of 18.5 months, the results demonstrated a significantly higher overall remission rate (68% vs. 39%; P<.0001) and median PFS (21.7 months vs. 9.3 months; P<.0001) wRith bendamustine compared to chlorambucil. No difference in overall survival was seen between the two groups. Grade-3/4 infections occurred in 6% of patients on bendamustine and in 3.5% of those on chlorambucil. Although these are exciting results, data comparing bendamustine to fludarabine-containing regimens as front-line therapy for CLL are not yet available. To date, the combination regimen of fludarabine, cyclophosphamide and rituximab is associated with the highest overall response rates, complete remission rates and disease-free survival in B-cell CLL.
In patients with relapsed/refractory B-cell CLL, a phase-2 trial exploring the activity of single-agent bendamustine was completed (n=81). Bendamustine was given at a dose of 70 mg/m2 IV on days 1 and 2 combined with rituximab 375 mg/m2 for the first cycle and 500 mg/m2 for all subsequent cycles. Treatment was administered every 28 days for up to six cycles. In a preliminary report presented at the American Society of Hematology Meeting in December 2007, 23 patients were evaluable for response with an OR rate of 65% (15 patients), a CR rate of 13% (3 patients), and a partial response rate of 52% (12 patients). Of note, no patients with the cytogenetic abnormality 17p deletion responded and no molecular remissions were observed. Notable toxicity included grade 3/4 myelosuppression (anemia, 6%; neutropenia/leukopenia, 11%, thrombocytopenia, 12% of all courses) and infections (six episodes, three deaths). These results warrant further evaluation to better determine which patients benefit from bendamustine in this treatment-refractory setting.
Bendamustine was first used in Germany for multiple myeloma and continues to be studied as monotherapy and in combination with rituximab and other cytotoxic agents for the treatment of Hodgkin’s and non-Hodgkin’s lymphoma. Clinical trials appear to also indicate some activity of bendamustine in breast cancer, small-cell lung cancer, and leiomyosarcomas.
Dosing, administration and toxicity
Several different dosing strategies have been attempted with bendamustine over the years. Weekly therapy was initially thought to be better tolerated in terms of leukopenia and thrombocytopenia in clinical trials with solid tumor patients, but lymphocytopenia became dose limiting and was associated with more opportunistic infections with weekly therapy compared with less frequent dosing strategies. In clinical trials with hematologic malignancies, bendamustine was typically given on days one and two administered every 28 days. However, dosages that extend out as far as five days have been investigated (daily 3 five days every 28 days). The FDA-approved dose for CLL is 100 mg/m2 administered on days one and two of a 28-day cycle.
Premedications for bendamustine should include antiemetics prior to each dose as this appears to be a moderately emetogenic agent. In the pivotal trial with bendamustine in CLL, the rates of nausea and vomiting were rather low (20% and 16%, respectively), but in older studies the rates are as high as 50%. Rare cases of hypersensitivity, including anaphylaxis, have been reported with the second and subsequent cycles of bendamustine and patients should be monitored closely. Premedications with antihistamines, antipyretics and/or corticosteroids should be considered in subsequent cycles in patients who have previously experienced grade-1/2 infusion reactions. The exact mechanism of this reaction is not clear, but may warrant drug discontinuation for a small fraction of patients (2%).
Serious adverse events associated with bendamustine include myelosuppression and infections, infusion reactions, anaphylaxis/allergic reactions, tumor lysis syndrome and severe skin reactions. Infections have been associated with hospitalization, sepsis, and death. The most common adverse events (occurring in >15% of patients) include myelosuppression (neutropenia 28%, thrombocytopenia 23%, anemia 15%, leukopenia 18%), pyrexia (24%), nausea (20%) and vomiting (16%). When bendamustine is administered as a single agent, febrile neutropenia occurs in only 3% of patients and does not warrant primary myeloid growth factor support. White blood cell nadirs associated with bendamustine appear to occur during the third week of therapy (typically between days 14-20) and generally require a 28-day cycle length when dosed as a daily times 2 regimen. Dose reductions are often warranted depending on the degree of myelosuppression experienced by the patient. In patients at high risk of tumor lysis syndrome, allopurinol prophylaxis should be considered and patients should be closely monitored for vigorous response to treatment. The most frequent adverse reactions leading to study withdrawal in the comparative CLL trial were hypersensitivity (2%) and pyrexia (1%).
Bendamustine is metabolized via cytochrome P450 (CYP) 1A2 to active metabolites and eliminated predominately through the renal route (45% as unchanged drug). Therefore, drugs that inhibit CYP 1A2 may increase concentrations of bendamustine and decrease concentrations of the active metabolites. Concurrent administration of CYP 1A2 inducers with bendamustine may decrease concentrations of the parent drug and increase concentrations of the active metabolites. The clinical consequences of these pharmacokinetic changes are currently unknown. However, caution should be used, or alternatives considered, if concurrent use of bendamustine with strong CYP 1A2 inhibitors or inducers is needed.
Bendamustine is an exciting new alkylating agent with interesting clinical activity in both hematologic and solid malignancies. It is FDA-approved for CLL, but ongoing clinical trials will also determine its place in therapy for lymphomas, myelomas, and breast cancers, among other malignancies. Further studies will be required to elucidate the optimal dose and method of administration when combining bendamustine with other active anticancer agents in all of these different malignancies.
Laura Boehnke Michaud, PharmD, BCOP, is Manager of Clinical Pharmacy Services at The University of Texas M.D. Anderson Cancer Center.
Hillary Prescott, PharmD, BCOP, is a Clinical Pharmacy Specialist at The University of Texas M.D. Anderson Cancer Center.
For more information:
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