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

Awol Mekonnen Ali; Haileyesus Adam; Daniel Hailu; Ephrem Engidawork; Rawleigh Howe; Teferra Abula; Marieke J H Coenen

doi:10.3389/fphar.2023.1159307

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

Front Pharmacol. 2023 May 9:14:1159307. doi: 10.3389/fphar.2023.1159307. eCollection 2023.

Authors

Awol Mekonnen Ali¹, Haileyesus Adam², Daniel Hailu², Ephrem Engidawork¹, Rawleigh Howe³, Teferra Abula¹, Marieke J H Coenen⁴

Affiliations

¹ Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
² Department of Pediatrics and Child Health, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
³ Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
⁴ Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Abstract

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT 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. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan^® 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. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH 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 TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Keywords: 6-mercactopurine; acute lymphoblastic leukemia; neutropenia; pharmacogenetics; xanthine dehydrogenase.

Grants and funding

This work is funded by the Office of the Graduate Program of Addis Ababa University with grant PV-470931 (www.aau.edu.et). The Armauer Hansen Research Institute (PV-470931, https://ahri.gov.et) and Center for Innovative Drug Development and Therapeutic Trials for Africa (https://www.cdt-africa.org/) also granted a research visit.