AUTHOR=Ali Awol Mekonnen , Adam Haileyesus , Hailu Daniel , Engidawork Ephrem , Howe Rawleigh , Abula Teferra , Coenen Marieke J. H. 

TITLE=Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1159307

DOI=10.3389/fphar.2023.1159307

ISSN=1663-9812

ABSTRACT=<p><bold>Introduction:</bold> Genetic variation in the <italic>thiopurine S-methyltransferase</italic> (<italic>TPMT</italic>) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in <italic>TPMT</italic> still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously.</p><p><bold>Objective:</bold> The aim of this study was to evaluate the effect of genetic variants in <italic>ITPA</italic>, <italic>TPMT</italic>, <italic>NUDT15</italic>, <italic>XDH</italic>, and <italic>ABCB1</italic> on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia.</p><p><bold>Methods:</bold> Genotyping of <italic>ITPA</italic>, and <italic>XDH</italic> was performed using KASP genotyping assay, while that of <italic>TPMT</italic>, <italic>NUDT15,</italic> and <italic>ABCB1</italic> with TaqMan<sup>®</sup> SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment.</p><p><bold>Results:</bold> In this study, genetic variants in <italic>XDH</italic> and <italic>ITPA</italic> were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for <italic>XDH</italic> rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494–5.849, <italic>p</italic> = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype.</p><p><bold>Conclusion:</bold> In conclusion, in this cohort, <italic>XDH</italic> rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than <italic>TPMT</italic> involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.</p>