TY - JOUR
T1 - Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy
AU - Adam de Beaumais, Tiphaine
AU - Fakhoury, May
AU - Medard, Yves
AU - Azougagh, Said
AU - Zhang, Daolun
AU - Yakouben, Karima
AU - Jacqz-Aigrain, Evelyne
PY - 2011/4/1
Y1 - 2011/4/1
N2 - 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 (493pmol/8 × 10 8RBC) than in older children (600pmol/8 × 10 8RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862pmol/8 × 10 8RBC), intermediate in wild-type patients and high (16468pmol/8 × 10 8RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000pmol/8 × 10 8RBC 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.
AB - 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 (493pmol/8 × 10 8RBC) than in older children (600pmol/8 × 10 8RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862pmol/8 × 10 8RBC), intermediate in wild-type patients and high (16468pmol/8 × 10 8RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000pmol/8 × 10 8RBC 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.
KW - Hepatotoxicity
KW - Leukaemia
KW - Mercaptopurine
KW - Metabolism
KW - Paediatrics
KW - Pharmacogenetics
UR - http://www.scopus.com/inward/record.url?scp=79952604351&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2125.2010.03867.x
DO - 10.1111/j.1365-2125.2010.03867.x
M3 - Article
C2 - 21395650
AN - SCOPUS:79952604351
SN - 0306-5251
VL - 71
SP - 575
EP - 584
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
IS - 4
ER -