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Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study

From the Departments of Hematology-Oncology and Pharmaceutical Sciences, St Jude Children’s Research Hospital, and Department of Pediatrics, University of Tennessee, College of Medicine, Memphis, TN; Children’s Oncology Group Research Data Center, Gainesville, FL; Department of Pediatric Hematology/Oncology, University of California San Diego Medical Center, San Diego, CA; Department of Pediatric Hematology/Oncology, Washington University Medical Center, St Louis, MO; Department of Pediatric Oncology, Baylor College of Medicine, Houston, TX; Department of Pediatric Hematology/Oncology, University of Arkansas, Little Rock, AK; and Department of Hematology/Oncology, Saint Justine Hospital, Montreal, Quebec, and Department of Pediatric Hematology/Oncology, Hospital for Sick Children, Toronto, Ontario, Canada.

Address reprint requests to Wayne L. Furman, MD, Children’s Oncology Group, PO Box 60012, Arcadia, CA 91066-6012; email: wayne.furman{at}stjude.org

PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia.

PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m²/d for 5 days and 2.4 mg/m²/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days).

RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m²/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m² (range, 9.4 to 45.9 L/h/m²) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days.

CONCLUSION: The MTD was 2.4 mg/m²/d for 9 days. Further testing is warranted of TPT’s schedule dependence in children with leukemia.

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