Positive Safety Profile of Bendamustine for Pediatric Patients with Relapsed or Refractory AML

SAN DIEGO, CA—The alkylating agent bendamustine has some activity in heavily pretreated pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) but not in those with relapsed or refractory acute myeloid leukemia (AML), according to preliminary data presented at the 53rd Annual Meeting and Exposition of the American Society of Hematology.

In children with ALL or AML, bendamustine was found to have an acceptable safety profile, Christopher Fraser, MD, of the Royal Children's Hospital, Brisbane, Australia, and colleagues reported. They conducted an international single-arm, Phase 1/2, dose-escalating trial between August 2010 and August 2011 at 45 centers. The goal of the study was to determine the recommended Phase 2 dose (RP2D), pharmacokinetics, safety profile and efficacy of bendamustine in pediatric patients with relapsed or refractory AML and acute lymphoblastic leukemia (ALL).

The study included children 1–20 years of age with histologically proven relapsed or refractory ALL or AML and without the opportunity for curative therapy. Investigators confirmed that acute toxic effects from previous therapy, which ended ≥2 weeks before the first bendamustine dose, had resolved to Grade ≤2.

Bendamustine was given intravenously over 60 minutes on Days 1 and 2 of each 21-day cycle, with a possible two-week delay for neutrophil and platelet recovery. Bendamustine was initiated at 90mg/m2 per dose with a planned escalation to 120mg/m2 and 150mg/m2 in subsequent cohorts of three. Patients were given the 150mg/m2 dose only if the 120mg/m2 dose was tolerated but produced subtherapeutic plasma levels when compared with data from adults. After the initial phase, patients were then enrolled with the determined RP2D.

Patients were followed for a maximum of 12 cycles or until disease progression, loss to follow-up, or withdrawal due to safety concerns. Following the last dose administered, patients were then evaluated every three months for 12 months, or until progression, death, or initiation of new cancer treatment. All drug recipients were assessed for overall response rate (ORR), defined as complete response (CR) or CR without platelet recovery (CRp). Patients who achieved CR or CRp were also assessed for response duration. Other data recorded were biologic activity (≥ partial response [PR]) and safety assessments, such as adverse events, concomitant medications, and other lab values.

In the dose escalation portion of the study (Phase 1), 11 patients were treated: five received bendamustine 90mg/m2 per dose and six received 120mg/m2 per dose. A total of 32 patients were treated in Phase 2 at the determined RP2D of 120mg/m2. Overall, prior anticancer therapy included radiotherapy in 14 patients, prior hematopoietic cell transplant in 21, and 26 patients had received >3 chemotherapy regimens.

There were 27 patients with ALL and 16 with AML. At the 90mg/m2 dose, two of five patients (40%) achieved CR, both with ALL. At the 120mg/m2 dose, two of 38 patients (5%) had a partial response, and seven (18%) had stable disease; of these nine patients, seven had ALL (two PR and five SD) and two had AML (both SD). Duration of response ranged from 1–8 months, with one patient still in remission after an unrelated stem cell transplant. Bendamustine was associated with an acceptable toxicity profile. A total of 42 patients had at least one patient/investigator-reported non-hematologic adverse event (AE, any cause) with hypokalemia as the most common Grade 3/4 AE (See Table). One patient who received 120mg/m2 withdrew due to an AE related to progressive AML.

Among the five patients receiving the bendamustine 90mg/m2 dose, three had one cycle of treatment, one had two cycles, and one had eight cycles. Median total dose was 182mg/m2 (range 177–1436) Among the 38 patients receiving the 120mg/m2 dose, 31 had one cycle of treatment and seven had two cycles; median total dose received was 241.5 mg/m2 (range 233–498). In this group, three patients had a dose delay and the dose was also adjusted for one of these patients.

Dr. Fraser concluded that bendamustine exerted minimal activity in heavily pretreated patients with relapsed or refractory ALL, but not in AML, and states that, “further studies will be required to evaluate the role of this agent in combination with regimens that are the backbone of current leukemia therapy in children.”