Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine

Purpose: to assess thiopurine 5-methyltransferase (TPMT) phenotype and geno type 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 assesse d in all patients referred between 1994 and 1999 for evaluation of excessiv e toxicity while receiving MP or AZA. TPMT activity was measured by radioch emical analysis, TPMT genotype was determined by mutation-specific polymera se chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *38, and *3C alleles, and thiopurine metabolites were measure d 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 a ctivity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT act ivity(> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TP MT-deficient and heterozygous individuals among these toxic patients is sig nificantly greater than the expected 10% frequency in the general populatio n (P <.001, <chi>(2)). TPMT phenotype and genotype were concordant in all T PMT-deficient and all homozygous-wildtype patients, whereas five patients w ith heterozygous phenotypes did not have a TPMT mutation detected. Before t hiopurine dosage adjustments, TPMT-deficient patients experienced more freq uent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, w hereas hepatotoxicity occurred in six patients (26%). Both patients who pre sented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygou s patients tolerated therapy without acute toxicity. Conclusion: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hemato poietic toxicity from therapy containing thiopurines. However, with appropr iate dosage adjustments, TPMT-deficient and heterozygous patients can be tr eated with thiopurines, without acute dose-limiting toxicity. (C) 2001 by A merican Society of Clinical Oncology.