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Br J Haematol. 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.

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Department of Clinical Pharmacy, Centre for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
Department of Paediatrics, The University of Tokyo, Tokyo, Japan.
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.
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.
Department of General Paediatrics & Interdisciplinary Medicine, National Centre for Child Health and Development, Tokyo, Japan.
Department of Paediatrics, St. Marianna University School of Medicine, Kanagawa, Japan.
Department of Paediatrics, Teikyo University Hospital, Tokyo, Japan.
Department of Haematology/Oncology, Saitama Children's Medical Centre, Saitama, Japan.


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.


6-MP; Japanese; NUDT15; childhood acute lymphoblastic leukaemia; toxicities

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