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- Title
Susceptibility to 6- MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia.
- Authors
Tanaka, Yoichi; Kato, Motohiro; Hasegawa, Daisuke; Urayama, Kevin Y.; Nakadate, Hisaya; Kondoh, Kensuke; Nakamura, Kozue; Koh, Katsuyoshi; Komiyama, Takako; Manabe, Atsushi
- 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/m2 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.
- Subjects
JAPAN; LYMPHOBLASTIC leukemia in children; PUBLIC health; DISEASE susceptibility; IMMUNOSUPPRESSIVE agents; DRUG toxicity; GENETICS
- Publication
British Journal of Haematology, 2015, Vol 171, Issue 1, p109
- ISSN
0007-1048
- Publication type
Article
- DOI
10.1111/bjh.13518