WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacogenetic polymorphisms of both TPMT and ITPA are associated with individual variability in 6-mercaptopurine (6-MP) intracellular metabolism.• The balance between red blood cell (RBC) 6-thioguanine nucleotide (6TGN) and 6-methylated metabolite (6-MMPN) concentrations has an important impact on efficacy in children treated for acute lymphoblastic leukemia.• Hepatotoxicity is a frequent complication of the association 6-MP and methotrexate during maintenance therapy. WHAT THIS STUDY ADDS• RBC 6-TGN concentrations are dependant on TPMT genotype and age, while RBC 6-MMPN concentrations depend on TPMT and ITPA polymorphisms. • Children aged 6 years or less had lower RBC 6-TGN concentrations during maintenance therapy, demonstrating an age effect on 6-MP intracellular metabolism.• Hepatotoxicity is a frequent complication of the association of 6-MP and methotrexate. A 6-MMPN threshold of 5000 pmol/8 ¥ 10 8 RBC was associated with an increased risk of hepatotoxicity. AIMS6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides ) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response. METHODSSixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2 + 21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis. RESULTSDuring maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger ( CONCLUSIONIn this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies, in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland and Spain. At least one genetic alteration leading to targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these were considered "ready for routine use". Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies, 56% of them within early clinical trials, mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, those of patients with "ready for routine use" alterations was 38%. In patients with extra-cerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell free DNA (cfDNA).

This review presents the pharmacogenetic aspects of 6-MP metabolism in great detail. We have focused on published data on ALL treatment supporting the great potential of 6-MP pharmacogenetics to improve efficacy, tolerance, and event-free survival rates in children with ALL.