Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy

Authors


Professor Evelyne Jacqz-Aigrain MD PhD, Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, 48 Boulevard Sérurier, 75019 Paris, France. Tel.: + 33 1 4003 2150 Fax: + 33 1 4003 4759 E-mail: evelyne.jacqz-aigrain@rdb.aphp.fr

Abstract

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.

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