ArticleOncology and therapy2026
Association of Variants in Candidate Pharmacogenes with Response to Mercaptopurine and Methotrexate in Pediatric Acute Lymphoblastic Leukemia: A Single-Center Experience from Croatia.
Article in Oncology and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionInterindividual variability in the efficacy and toxicity of 6-mercaptopurine (6-MP) and methotrexate (MTX) drugs remains a major challenge in the treatment of pediatric acute lymphoblastic leukemia (ALL). Germline variation in pharmacogenes involved in drug metabolism, transport, and folate pathways may contribute to this variability.
methodsIn this retrospective cohort study, 43 pediatric patients with ALL treated at a tertiary referral center in Croatia according to ALL IC-BFM 2002 or 2009 protocols were genotyped for eleven variants in TPMT, ITPA, NUDT15, PACSIN2, MTHFR, TYMS, SLC19A1, and SLCO1B1 genes. Associations with average 6-MP dose during maintenance therapy, MTX pharmacokinetics during consolidation and MTX-related toxicity were analyzed. A polygenic risk score (PRS) was constructed to assess cumulative genetic risk of developing toxicity when administering these two drugs.
resultsCarriers of the ITPA rs1127354 variant required significantly lower average 6-MP doses compared with wild-type carriers. The NUDT15 rs61973267 variant was associated with higher tolerated 6-MP doses after exclusion of outliers. No significant associations were observed between individual variants and MTX clearance. A trend toward reduced risk of oral mucositis was observed in carriers of the SLCO1B1 rs4149056 variant. PRS analyses that included carriers of the TPMT rs1142345 and ITPA rs1127354 variants showed a borderline association with the requirement for 6-MP dose reduction.
conclusionsOur findings support a role for ITPA and NUDT15 variants in modulating 6-MP dose requirements, while single-variant associations with MTX pharmacokinetics and toxicity were limited and not supported. These results underscore the complexity of antimetabolite pharmacogenetics and suggest that integrative polygenic approaches may better capture clinically relevant pharmacogenetic risk.
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