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Clinical Trial
. 2015 Oct;171(1):109-15.
doi: 10.1111/bjh.13518. Epub 2015 Jun 2.

Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia

Yoichi Tanaka  1 , Motohiro Kato  2 , Daisuke Hasegawa  3 , Kevin Y Urayama  4   5 , Hisaya Nakadate  6 , Kensuke Kondoh  7 , Kozue Nakamura  8 , Katsuyoshi Koh  9 , Takako Komiyama  1 , Atsushi Manabe  3
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Free article
Clinical Trial

Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia

Yoichi Tanaka et al. Br J Haematol. 2015 Oct.
Free article

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.

Keywords: 6-MP; Japanese; NUDT15; childhood acute lymphoblastic leukaemia; toxicities.

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