Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia

Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopuri nes, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits g enetic polymorphism, with about 1/300 inheriting TPMT deficiency as an auto somal recessive trait. If treated with standard doses of thiopurines, TPMT- deficient patients accumulate excessive thioguanine nucleotides in hematopo ietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being cl arified as an important determinate of event-free survival in childhood leu kemia. In addition, there are emerging data that TPMT genotype may influenc e the risk of secondary malignancies, including brain tumors and acute myel ogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on t hiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together , these advances hold the promise of improving the safety and efficacy of t hiopurine therapy.