Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed on refractory leukemia (CCG-0955): A report from the children's cancer group Journal Article

Authors: Steinherz, P. G.; Seibel, N. L.; Ames, M. M.; Avramis, V. I.; Krailo, M. D.; Liu-Mares, W.; Reid, J. M.; Safgren, S. L.; Reaman, G. H.
Article Title: Phase I study of gemcitabine (difluorodeoxycytidine) in children with relapsed on refractory leukemia (CCG-0955): A report from the children's cancer group
Abstract: To determine the maximum tolerated dose (MTD) and assess the toxicity profile and pharmacokinetics of weekly gemcitabine infusions in pediatric patients with refractory hematologic malignancies. Fourteen patients under 21 years old were given infusions of gemcitabine for escalating durations at 10 mg/m 2/min weekly for three consecutive weeks. Two males and two females were studied at each dose level. Pharmacokinetics of the drug's metabolism were measured by high pressure-liquid chromatography (HPLC) for 24h after the first dose. Intracellular difluorodeoxycytidine triphosphate formation in leukemic blasts was measured in selected patients. The MTD of gemcitabine in these patients was 3600 mg/m 2/week for three consecutive weeks (10mg/m 2/min for 360 min). Hepatotoxicity was the dose limiting toxicity. Thirty to fifty percent of patients exhibited fever, rash, or myalgia. Rare instances of hypotension and pulmonary toxicity were observed. Two of six patients [one acute lymphoblastic leukemia (ALL) and one acute myelogenous leukemia (AML)] treated at the MTD had at least M 2 marrows, although peripheral blood counts did not recover sufficiently for the patients to be considered in complete response. Pharmacokinetics of gemcitabine fit a two-compartment open model with terminal half-life and plasma clearance value of 62 min and 2.21/min/m 2, respectively. No gender differences were observed. In conclusion, the MTD of gemcitabine was 10mg/m 2/min for 360 min every week for 3 weeks. This is the recommended phase II dose schedule for children with leukemia. The activity of the drug at this schedule in heavily pretreated, refractory patients warrants a phase II trial in hematologic malignancies.
Keywords: adolescent; child; clinical article; controlled study; preschool child; child, preschool; leukemia; acute granulocytic leukemia; clinical trial; drug activity; cancer recurrence; salvage therapy; dose response; gemcitabine; methodology; controlled clinical trial; liver toxicity; lung toxicity; phase 2 clinical trial; myalgia; cyclophosphamide; hematuria; acute lymphoblastic leukemia; fever; rash; hypotension; infant; chemically induced disorder; drug response; drug derivative; drug clearance; nausea and vomiting; liver disease; liver diseases; metabolic clearance rate; sex difference; hyperbilirubinemia; drug metabolism; blood cell count; high performance liquid chromatography; maximum tolerated dose; phase 1 clinical trial; chromatography, high pressure liquid; drug half life; half life time; childhood leukemia; deoxycytidine; cell level; half-life; bronchospasm; biotransformation; compartment model; blast cell; gemcitabine triphosphate; humans; human; male; female; priority journal; article; children's cancer group; hpcl; relapsed or refractory leukemia
Journal Title: Leukemia and Lymphoma
Volume: 43
Issue: 10
ISSN: 1042-8194
Publisher: Taylor & Francis Group  
Date Published: 2002-10-01
Start Page: 1945
End Page: 1950
Language: English
DOI: 10.1080/1042819021000015880
PUBMED: 12481889
PROVIDER: scopus
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Peter G Steinherz
    219 Steinherz