a Phase I Trial of Bendamustine in Combination with Clofarabine and Etoposide in Pediatric Patients with Relapsed or Refractory Hematologic Malignancies

Introduction: Bendamustine is an alkylator with anti-metabolite properties that shows incomplete cross resistance with other alkylators such as cyclophosphamide. The combination of cyclophosphamide, clofarabine and etoposide is often used in the treatment of children with relapsed leukemia, most of whom have significant prior exposure to cyclophosphamide. We evaluated the maximum tolerated dose (MTD) and safety profile of bendamustine when used in combination with clofarabine and etoposide in pediatric patients with relapsed or refractory hematologic malignancies.

Methods: Patients are eligible if they are younger than 22 years-old, have relapsed or refractory hematologic malignancies following 2 or more prior regimens, and have adequate organ function. Using the rolling 6 design, participants received bendamustine at one of 3 dose levels (escalating doses of 30, 40, or 60mg/m²/day) on Days 1-5 in combination with clofarabine (40 mg/m²/day), etoposide (100 mg/m²/day), and dexamethasone (8 mg/m²/day) daily on Days 1-5. We obtained pharmacokinetic (PK) studies to assess for potential time-dependent changes in bendamustine clearance over the 5 day course in this combination regimen since most PK studies of bendamustine have been conducted in adult patients with dose schedules of 90-120 mg/m²/day for 2 days.

Results: Sixteen patients (12 males and 4 females) with median age 11 years (range 4 to 17 years) were enrolled: 10 B-cell acute lymphoblastic leukemia (B-ALL), 1 early T-cell precursor (ETP) leukemia, 1 gamma delta T-cell ALL, 2 Hodgkin lymphoma, and 2 T-cell non-Hodgkin lymphoma. Six patients were treated on dose level 1, six on dose level 2, and four on dose level 3. One patient with hyperleukocytosis died from severe systemic inflammatory response syndrome (SIRS). Dose limiting toxicity was failure to recover peripheral blood counts on Day 42. The recommended dose of bendamustine in this combination is 30mg/m² daily over 5 days. Ten responses were observed: 6 complete remissions (CR), 1 durable minimal residual disease (MRD)-negative CR without platelet recovery in the patient with ETP-ALL, and 3 partial remissions. Eight patients proceeded to transplant. Nine patients died (5 from progressive disease, 2 from transplant complications, 1 from SIRS and 1 from complications of subsequent salvage chemotherapy). Six patients are alive at a median follow up of 12 months (range 2 to 29 months).

Conclusions: Bendamustine is well tolerated in combination with clofarabine and etoposide and shows efficacy in multiple relapsed and refractory hematologic malignancies. Dose reductions on the first day of therapy are warranted in patients at risk of tumor lysis syndrome to avoid severe systemic inflammatory response.