Protracted intermittent schedule of topotecan in children with refractory acute leukemia: A pediatric oncology group study

• Published in: Journal of clinical oncology Vol. 20; no. 6; pp. 1617 - 1624
• Main Authors: FURMAN, Wayne L, STEWART, Clinton F, PRATT, Charles, KIRSTEIN, Mark, KEPNER, James L, BERNSTEIN, Mark L, KUNG, Faith, VIETTI, Teresa J, STEUBER, C. Philip, BECTON, David Lee, BARUCHEL, Sylvain
• Format: Journal Article
• Language: English
• Published: Baltimore, MD Lippincott Williams & Wilkins 15-03-2002
• Subjects: Adolescent; Adult; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Biological and medical sciences; Chemotherapy; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Infant; Infusions, Intravenous; Leukemia, Myeloid, Acute - drug therapy; Male; Medical sciences; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Topotecan - administration & dosage; Topotecan - adverse effects; Topotecan - pharmacokinetics; Topotecan - pharmacology; Treatment Outcome; Human; Antineoplastic agent; Treatment resistance; Intravenous administration; Enzyme; Maximal dose; Acute; DNA topoisomerase; Enzyme inhibitor; Administration schedule; Topotecan; Malignant hemopathy; Nonlymphocytic leukemia; Chemotherapy; Isomerases; Limit dose; Treatment; Lymphoproliferative syndrome; Phase I trial; Acute lymphocytic leukemia; Child; Prolonged
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2002.20.6.1617

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.
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/m(2)/d for 5 days and 2.4 mg/m(2)/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).
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/m(2)/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/m(2) (range, 9.4 to 45.9 L/h/m(2)) 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.
The MTD was 2.4 mg/m(2)/d for 9 days. Further testing is warranted of TPT's schedule dependence in children with leukemia.