© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 23, 2001-2008,
December 1, 1999
© 1999 Oxford University Press
Mercaptopurine Therapy Intolerance and Heterozygosity at the Thiopurine S-Methyltransferase Gene Locus
Affiliations of authors: M. V. Relling, E. Y. Krynetski, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, and College of Pharmacy, University of Tennessee, Memphis; M. L. Hancock, Department of Biostatistics and Epidemiology, St. Jude Children's Research Hospital, and Department of Preventive Medicine, University of Tennessee; G. K. Rivera, J. T. Sandlund, R. C. Ribeiro, C.-H. Pui, Department of Hematology/Oncology, St. Jude Children's Research Hospital, and College of Medicine, University of Tennessee; W. E. Evans, Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, and Colleges of Medicine and Pharmacy, University of Tennessee.
Correspondence to: Mary V. Relling, Pharm.D., St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105 (e-mail: mary.relling{at}stjude.org).
BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m2) and daily oral 6-mercaptopurine (75 mg/m2) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 108 erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (± standard deviations) of 417 (±179), 963 (±752), and 3565 (±1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P = .24), TPMT enzyme activity (P = .22), or average weekly prescribed dose of 6-mercaptopurine (P= .49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (± standard deviation) final weekly 6-mercaptopurine doses of 72 (±60), 449 (±160), and 528 (±90) mg/m2, respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait.
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