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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.

Author information

1
Department of Clinical Pharmacy, Centre for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
2
Department of Paediatrics, The University of Tokyo, Tokyo, Japan.
3
Department of Paediatrics, St. Luke's International Hospital, Tokyo, Japan.
4
Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University, Tokyo, Japan.
5
Centre for Clinical Epidemiology, St. Luke's Life Science Institute, Tokyo, Japan.
6
Department of General Paediatrics & Interdisciplinary Medicine, National Centre for Child Health and Development, Tokyo, Japan.
7
Department of Paediatrics, St. Marianna University School of Medicine, Kanagawa, Japan.
8
Department of Paediatrics, Teikyo University Hospital, Tokyo, Japan.
9
Department of Haematology/Oncology, Saitama Children's Medical Centre, Saitama, Japan.

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

PMID:
26033531
DOI:
10.1111/bjh.13518
[Indexed for MEDLINE]

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