Significance of TPMT and NUDT15 variants in 6-mercaptopurine metabolism in acute lymphoblastic leukaemia/lymphoma patients

Abstract

Introduction. Among main curative substances in acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is 6-mercaptopurine (6-MP). However, the severity of adverse reactions (ADRs) to this drug varies considerably among patients, which is sometimes conditioned by individual single nucleotide polymorphisms in key 6-MP metabolism enzyme genes.Aim — a literature review on the role of TPMT and NUDT15 gene variants in 6-MP metabolism in ALL/LBL.Main findings. The TPMT and NUDT15 genes encode enzymes mediating key steps of the 6-MP metabolism. The metabolites determine the 6-MP therapeutic and toxic properties, with ADRs emerging when their concentrations alter. A number of TPMT and NUDT15 single nucleotide polymorphisms are associated with varied activities of the encoded enzymes, and their allelic combinations condition functional and non-functional phenotypes. Non-functional variant carriers more likely develop toxicity on 6-MP treatment compared to functional phenotypes. Non-functional TPMT/NUDT15 carriers should have the 6-MP dosage reduced to minimise emerging ADRs.