Phase 1 study of bendamustine in combination with clofarabine, etoposide, and dexamethasone in pediatric patients with relapsed or refractory hematologic malignancies

Abstract

BACKGROUND:A phase 1 study was conducted to determine the maximum tolerated dose of bendamustine when given in combination with clofarabine, etoposide, and dexamethasone daily for 5 days in children and adolescents with relapsed or refractory hematologic malignancies. METHODS: Patients younger than 22 years with second or greater relapsed or refractory acute leukemia or lymphoma after 2 or more prior regimens were eligible. With the rolling 6 design, participants received escalating doses of bendamustine (30, 40, or 60 mg/m 2 /d) in combination with clofarabine (40 mg/m 2 ), etoposide (100 mg/m 2 ), and dexamethasone (8 mg/m 2 ) daily for 5 days. Optional pharmacokinetic studies were performed in cycle 1 on day 1 and day 5. RESULTS: Sixteen patients were enrolled. Six patients were treated at the dose level of 30 mg/m 2 /d, 6 were treated at the dose level of 40 mg/m 2 /d, and 4 were treated at the dose level of 60 mg/m 2 /d. The dose-limiting toxicity was prolonged myelosuppression. The combination was otherwise well tolerated. The recommended dose of bendamustine in this combination was 30 mg/m 2 /d for 5 days. Ten responses were observed after 1 cycle: 6 complete remissions, 1 durable minimal residual disease-negative complete remission without platelet recovery in a patient with early T-cell precursor leukemia, and 3 partial remissions. Six patients proceeded to transplantation. The event-free survival rate was 40.6% (95% confidence interval [CI], 17.5%-63.7%) at 1 year and 33.9% (95% CI, 11.9%-55.9%) at 3 years. CONCLUSIONS: Bendamustine is well tolerated in combination with clofarabine, etoposide, and dexamethasone. The combination administered over 5 days is effective for multiple relapsed and refractory hematologic malignancies. This trial is registered with ClinicalTrials.gov (NCT01900509).