NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia.
- Author:
Eun Sang YI
1
;
Young Bae CHOI
;
Rihwa CHOI
;
Na Hee LEE
;
Ji Won LEE
;
Keon Hee YOO
;
Ki Woong SUNG
;
Soo Youn LEE
;
Hong Hoe KOO
Author Information
- Publication Type:Original Article
- Keywords: NUDT15; Leukemia; 6-Thioguanylic acid; Thiopurine; 6-Mercaptopurine
- MeSH: 6-Mercaptopurine; Blood Cell Count; Child*; Humans; Leukemia; Leukopenia; Precursor Cell Lymphoblastic Leukemia-Lymphoma*; Thioguanine
- From:Cancer Research and Treatment 2018;50(3):872-882
- CountryRepublic of Korea
- Language:English
- 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. RESULTS: A 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. CONCLUSION: NUDT15 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.
