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

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.

• Authors: Eun Sang Yi, Young Bae Choi, Rihwa Choi, Na Hee Lee, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Soo-Youn Lee, Hong Hoe Koo
• Journal: Cancer research and treatment (Cancer Res Treat) Vol. 50 Issue 3 Pg. 872-882 (Jul 2018) ISSN: 2005-9256 [Electronic] Korea (South)
• PMID: 28903549 (Publication Type: Journal Article)

Chemical References

• Guanine Nucleotides
• Thionucleotides
• 6-thioguanylic acid
• Mercaptopurine
• NUDT15 protein, human
• Pyrophosphatases

Topics

• Adolescent
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Guanine Nucleotides (toxicity)
• Humans
• Infant
• Male
• Mercaptopurine (administration & dosage, adverse effects)
• Pharmacogenomic Variants
• Polymorphism, Single Nucleotide
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy)
• Pyrophosphatases (genetics)
• Republic of Korea
• Retrospective Studies
• Sequence Analysis, DNA
• Thionucleotides (toxicity)
• Young Adult