title: Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia.
abstract: Genotyping of TPMT prior to 6-mercaptopurine (6-MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6-MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6-MP toxicity-related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6-MP dose reduction, therapy interruption and event-free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49-20·80; P = 2·7 × 10(-4) ). As leucopenia results in 6-MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m(2) for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event-free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6-MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity-related locus in Asians to date. Considerations for clinical application may be warranted.
authors.affiliation: Department of Clinical Pharmacy, Centre for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Paediatrics, The University of Tokyo, Tokyo, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.affiliation: Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.|Centre for Clinical Epidemiology, St. Luke's Life Science Institute, Tokyo, Japan.
authors.forename: Kevin Y
authors.initials: KY
authors.lastname: Urayama
authors.affiliation: Department of General Paediatrics & Interdisciplinary Medicine, National Centre for Child Health and Development, Tokyo, Japan.
authors.forename: Hisaya
authors.initials: H
authors.lastname: Nakadate
authors.affiliation: Department of Paediatrics, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kondoh
authors.affiliation: Department of Paediatrics, Teikyo University Hospital, Tokyo, Japan.
authors.forename: Kozue
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Haematology/Oncology, Saitama Children's Medical Centre, Saitama, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Koh
authors.affiliation: Department of Clinical Pharmacy, Centre for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Komiyama
authors.affiliation: Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
mesh_terms: D000293:Adolescent; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D044466:Asian People; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007564:Japan; D007970:Leukopenia / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D011755:Pyrophosphatases / Q000235:genetics*; D000096964:Nudix Hydrolases
chemical_list: D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D011755:Pyrophosphatases; C543721:NUDT15 protein, human; D000096964:Nudix Hydrolases
keywords: 6-MP; Japanese; NUDT15; childhood acute lymphoblastic leukaemia; toxicities