title: High-dose mercaptopurine followed by intermediate-dose cytarabine in relapsed acute leukemia.
abstract: OBJECTIVE
  This phase I/II study was designed to explore the feasibility, toxicity, and potential efficacy of administering high-dose continuous intravenous mercaptopurine (6MP) followed by intermediate-dose continuous intravenous cytarabine (Ara-C) to children with relapsed or unresponsive acute leukemia.
  
  
  METHODS
  Twenty-three children with relapsed or unresponsive acute leukemia (13 myeloid, 10 lymphoid) were entered onto the study. After initial hydration and alkalinization, 1,000 or 1,250 mg/m2 of 6MP was administered by continuous intravenous infusion over 24 hours. Following another period of hydration, 500 mg/m2 of Ara-C was administered by continuous intravenous infusion daily for 4 days. In 17 children, plasma concentrations of 6MP were measured at hours 4, 24, and 27 of the 6MP infusions. Plasma concentrations of Ara-C were measured at hours 8, 24, 48, 72, and 96 of the Ara-C infusions. Intracellular Ara-C triphosphate (Ara-CTP) concentrations were measured in peripheral-blood leukemia cells of the five patients with sufficient cells for measurement. Children who developed remission received repeated courses of this regimen every 3 to 4 weeks until relapse or completion of 12 courses.
  
  
  RESULTS
  Of 13 children with acute myeloid leukemia (AML), six developed complete remissions (CRs) lasting 7 months to nearly 4 years. Two children remain in CR with normal growth, development, and health 3 years after cessation of treatment. Of 10 children with acute lymphoid leukemia (ALL), one had a CR of 2 months' duration. Dose-limiting toxicity consisted of severe hematosuppression with fever, neutropenia, and serious infection. There were two toxic deaths. The mean steady-state plasma concentrations of 6MP were approximately 4 mumol/L and of Ara-C approximately 3 mumol/L. The median Ara-CTP concentration in peripheral-blood leukemia cells was 308 mumol/L at hour 8 of the Ara-C infusion.
  
  
  CONCLUSIONS
  High-dose continuous intravenous 6MP followed by intermediate-dose intravenous Ara-C produced CRs of longer than 6 months in approximately half of children with relapsed or unresponsive AML. Further study of this drug regimen is justified.
authors.affiliation: Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: S
authors.initials: S
authors.lastname: Lockhart
authors.forename: W
authors.initials: W
authors.lastname: Plunkett
authors.forename: S
authors.initials: S
authors.lastname: Jeha
authors.forename: I
authors.initials: I
authors.lastname: Ramirez
authors.forename: T
authors.initials: T
authors.lastname: Zipf
authors.forename: A
authors.initials: A
authors.lastname: Cork
authors.forename: D
authors.initials: D
authors.lastname: Pinkel
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D015122:Mercaptopurine