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Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or Azathioprine

From the St Jude Children’s Research Hospital and University of Tennessee, Memphis; Vanderbilt University Medical Center, Nashville; East Tennessee State University, Johnson City, TN; Baylor College of Medicine, Houston; Cook Children’s Medical Center, Fort Worth; University of Texas Southwestern Medical Center at Dallas, Dallas, TX; Stanford University, Stanford; Children’s Hospital of Los Angeles, Los Angeles; Children’s Hospital of San Diego, San Diego, CA; University of New Mexico, Albuquerque, NM; West Virginia University, Morgantown, WV; Miami Children’s Hospital, Miami, FL; Children’s Hospital of Michigan, Detroit, MI; and Ospedale Pediatrics Meyer, Florence, Italy.

Address reprint requests to William E. Evans, PharmD, St Jude Children’s Research Hospital, 332 N Lauderdale, PO Box 318, Memphis, TN 38101-0318; email: william.evans{at}stjude.org

PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.

PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.

RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P < .001, ²). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.

CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

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