NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia.

Content Provider	Europe PMC
Author	Yi, Eun Sang Choi, Young Bae Choi, Rihwa Lee, Na Hee Lee, Ji Won Yoo, Keon Hee Sung, Ki Woong Lee, Soo-Youn Koo, Hong Hoe
Copyright Year	2018
Abstract	Purpose We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL).Materials and Methods Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated. ResultsA total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group.ConclusionNUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.
ISSN	15982998
Journal	Cancer Research and Treatment : Official Journal of Korean Cancer Association
Volume Number	50
PubMed Central reference number	PMC6056957
Issue Number	3
PubMed reference number	28903549
e-ISSN	20059256
DOI	10.4143/crt.2017.283
Language	English
Publisher	Korean Cancer Association
Publisher Date	2017-09-13
Access Restriction	Open
Rights License	This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright © 2018 by the Korean Cancer Association
Subject Keyword	NUDT15 Leukemia 6-Thioguanylic acid Thiopurine 6-Mercaptopurine
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology