title: Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children.
abstract: BACKGROUND
  Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse.
  
  
  METHODS
  To investigate whether lower systemic exposure to mercaptopurine may increase the risk of relapse in acute lymphocytic leukemia, we prospectively studied 23 children receiving maintenance therapy. On the basis of disease features, 11 were classified as being at low risk of relapse, and 12 at standard risk. Those who relapsed (n = 10) did not differ from those who did not in their mean age, hemoglobin level, mean daily dose of mercaptopurine and weekly dose of methotrexate, or the total number of days during which mercaptopurine and methotrexate therapy was interrupted.
  
  
  RESULTS
  There was a significant difference in the mean (+/- SEM) area under the mercaptopurine concentration-time curve achieved by a dose of 1 mg of mercaptopurine per square meter of body-surface area: 1636 +/- 197 nmol per liter x minutes in those who relapsed, as compared with 2424 +/- 177 nmol per liter x minutes in those who did not (P less than 0.005). This caused a significantly lower total daily systemic exposure to mercaptopurine in those who relapsed (104,043 +/- 12,812 nmol per liter x minutes) than in those who did not (168,862 +/- 18,830 nmol per liter x minutes) (P less than 0.005). An identical tendency prevailed when patients at low risk and patients at standard risk were analyzed separately. Kaplan-Meier analysis revealed that children in whom an area under the curve of less than 1971 nmol per liter x minutes was achieved by a dose of 1 mg of mercaptopurine per square meter had a significantly poorer prognosis than those with larger areas under the curve (P less than 0.01). Similarly, those with a total daily systemic exposure of more than 137,970 nmol per liter x minutes had a significantly better prognosis than those with a lower exposure (P less than 0.005).
  
  
  CONCLUSIONS
  Low systemic exposure to oral mercaptopurine during maintenance therapy for acute lymphocytic leukemia in childhood adversely affects prognosis. Children should be studied at the beginning of maintenance therapy to establish the pharmacokinetics of mercaptopurine, and the dose should be tailored to achieve an appropriate systemic exposure.
authors.affiliation: Division of Clinical Pharmacology, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Koren
authors.forename: G
authors.initials: G
authors.lastname: Ferrazini
authors.forename: H
authors.initials: H
authors.lastname: Sulh
authors.forename: A M
authors.initials: AM
authors.lastname: Langevin
authors.forename: J
authors.initials: J
authors.lastname: Kapelushnik
authors.forename: J
authors.initials: J
authors.lastname: Klein
authors.forename: E
authors.initials: E
authors.lastname: Giesbrecht
authors.forename: S
authors.initials: S
authors.lastname: Soldin
authors.forename: M
authors.initials: M
authors.lastname: Greenberg
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001682:Biological Availability; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000401:mortality*; D011379:Prognosis; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D016019:Survival Analysis; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D015122:Mercaptopurine; D014969:Xanthine Oxidase; D008727:Methotrexate