title: Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia.
abstract: The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: G
authors.initials: G
authors.lastname: Stocco
authors.forename: M H
authors.initials: MH
authors.lastname: Cheok
authors.forename: K R
authors.initials: KR
authors.lastname: Crews
authors.forename: T
authors.initials: T
authors.lastname: Dervieux
authors.forename: D
authors.initials: D
authors.lastname: French
authors.forename: D
authors.initials: D
authors.lastname: Pei
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: C
authors.initials: C
authors.lastname: Cheng
authors.forename: C-H
authors.initials: CH
authors.lastname: Pui
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000378:metabolism*; D009503:Neutropenia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics* / Q000378:metabolism; D000097630:Inosine Triphosphatase
chemical_list: D015122:Mercaptopurine; D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase