A team from the USA and Italy assessed the thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA). They also evaluated their clinical management.
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.
|Frequency of TPMT deficiency or heterozygosity:|
Thiopurine-intolerant patients: 65%
|Journal of Clinical Oncology|
Of 23 patients evaluated, 6 had TPMT deficiency (homozygous mutant), 9 had intermediate TPMT activity (heterozygotes), and 8 had high TPMT activity (homozygous wildtype).
The frequency of TPMT-deficient and heterozygous individuals among the toxic patients was 65%. This was significantly greater than the expected 10% frequency in the general population.
TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients. However, 5 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 26%. Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype.
After adjustment of thiopurine dosages, the researchers found that TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.
Researcher William E. Evans, of the St Jude Children's Research Hospital, Memphis, Tennessee, concluded on behalf of the group, "There is a significant (greater than 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."