Introduction:Genetic variation in thethiopurine S-methyltransferase(TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants inTPMTstill 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 inITPA,TPMT,NUDT15,XDH, andABCB1on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia.Methods:Genotyping ofITPA, andXDHwas performed using KASP genotyping assay, while that ofTPMT,NUDT15,andABCB1with 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 inXDHandITPAwere associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) forXDHrs2281547 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,XDHrs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other thanTPMTinvolved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.