Thiopurine Methyltransferase TPMT Deficiency and Immunosuppressive Antileukemic Drugs

TPMT deficiency is ascribed to a series of SNPs that result in low TPMT activity. TPMT deficiency is associated with serious acute and delayed intolerance to immunosuppressive and antileukemic drugs (6-mercaptopurine, 6-thioguanine, azathiopurine). At least eight alleles that confer low levels of TPMT have been reported, but only two of these appear to account for the majority of subjects with low TPMT activity.26,47 TPMT deficient persons administered these agents are predisposed to several forms of toxicity. They may suffer bone marrow toxicity that is potentially fatal. TPMT-deficient or heterozygous patients treated with mercaptopurine while receiving cranial radiotherapy for CNS leukemia are at risk of developing secondary brain tumors. However, in the latter group, patients received more intensive systemic antimetabolite therapy before and during radiotherapy. Studies have also suggested that the TPMT genotype may influence the risk of secondary malignancies such as acute myelogenous leukemia.26 Clinically significant interactions may also occur when agents that are potent TPMT inhibitors (e.g., olsalazine) are coadministered with standard doses of thiopurine drugs to produce phenocopies of subjects with genetically low TPMT activity.48 It is also known that thiopurine efficacy is low in persons with high TPMT activity,49 which may require higher thiopurine doses. However, a dose increase of thiopurines for such patients may cause adverse effects. For instance, a patient with high TPMT who receives 6-mercaptopurine generates methylmercaptopurine, a cytotoxic byproduct that can cause serious side effects such as hepatotoxicity.50

It has been shown that an average of 78% of adverse drug reactions from thiopurine drugs is not associated with TPMT polymorphisms.51 Nevertheless, a strong argument can be made for pharmacogenetic testing prior to thiopurine treatment and is being practiced clinically.52

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