Article date: April 2011
By: Tiphaine Adam de Beaumais, May Fakhoury, Yves Medard, Said Azougagh, Daolun Zhang, Karima Yakouben, Evelyne Jacqz‐Aigrain, in Volume 71, Issue 4, pages 575-584
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 × 108 RBC was associated with an increased risk of hepatotoxicity.
AIMS 6‐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 [6‐MMPN]) 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.
METHODS Sixty‐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.
RESULTS During maintenance, steady‐state RBC 6‐TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 108RBC) than in older children (600 pmol/8 × 108RBC). 6‐MMPN concentrations were low in patients with TPMT variant/wild‐type ITPA (1862 pmol/8 × 108RBC), intermediate in wild‐type patients and high (16468 pmol/8 × 108RBC) in patients wild‐type TPMT/variant ITPA. A 6‐MMPN threshold of 5000 pmol/8 × 108RBC was associated with an increased risk of hepatotoxicity.
CONCLUSION In 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.
DOI: 10.1111/j.1365-2125.2010.03867.x
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