<i>ABCC4</i>, <i>ITPA</i>, <i>NUDT15</i>, <i>TPMT</i> and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia

Abstract

Inter-individual variance in 6-mercaptopurine (6-MP) dose intensity is common in patients with acute lymphoblastic leukemia (ALL). We aimed to evaluate the association of common variants of <i>ABCC4</i>, <i>ITPA</i>, <i>NUDT15</i>, and <i>TPMT</i> with 6-MP dose intensity and toxicity in pediatric ALL patients. In this cohort, 13.8% of patients were intolerant to 6-MP with actual dosage less than 50% of scheduled dose. Twenty percent of patients were found to be heterozygous or homozygous mutated with <i>NUDT15</i>. <i>NUDT15</i> c.415C > T and the genotype-predicted NUDT15 activity were significantly associated with 6-MP intolerance. <i>TPMT</i>*3C variants were not common in this cohort (2.8%). <i>NUDT15</i> polymorphisms and genotype predicted NUDT15 activity were significantly associated with 6-MP dose intensity and leukopenia episodes. Combination of <i>ABCC4</i> and <i>ITPA</i> variants (<i>ABCC4</i> c.912G > T and <i>ITPA</i> c.94C > A) also showed significant positive association with 6-MP intolerance in Chinese children with ALL. Further study on pharmacogenetic screening for ALL patients to avoid 6-MP induced toxicity is recommended.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1973628.