Influence of xanthine oxidase and inosine monophosphate dehydrogenase polymorphisms on 6-mercaptopurine treatment response in pediatric acute lymphoblastic leukemia.

Over the past decades, survival outcomes for childhood acute lymphoblastic leukaemia (ALL) have significantly improved. However, adverse drug reactions (ADRs), particularly those related to 6-mercaptopurine (6-MP), remain a major concern. Myelosuppression associated with 6-MP administration can lead to infections or treatment interruptions. Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. This study investigates genetic variants influencing 6-MP response in children with ALL. Seventeen tagSNPs in key enzymes involved in 6-MP metabolism, GMPS, IMPDH1, XO, and ITPA, were analysed. Genetic data were correlated with clinical and pharmacological parameters in 280 ALL patients treated under DFCI ALL 05-001, 11-001, and 16-001 protocols at CHU Sainte-Justine. Outcomes included 6-MP dose intensity, 6-TGN and 6-MMP metabolite levels, and hematologic and hepatic toxicities during consolidation II and maintenance phases. Results revealed that the rs6710015 variant allele in the XO gene is linked to lower 6-TGN and higher 6-MMP levels, while rs1884725 variant allele in the same gene is correlated with reduced neutropenia and higher cumulative 6-MP doses. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.