Cancer Res Treat.  2018 Jul;50(3):872-882. 10.4143/crt.2017.283.

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

• Yi ES
• Choi YB
• Choi R
• Lee NH
• Lee JW
• Yoo KH
• Sung KW
• Lee SY
• Koo HH

• KMID: 2417876
• DOI: http://doi.org/10.4143/crt.2017.283

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.

Keyword

NUDT15; Leukemia; 6-Thioguanylic acid; Thiopurine; 6-Mercaptopurine

MeSH Terms

6-Mercaptopurine
Blood Cell Count
Child*
Humans
Leukemia
Leukopenia
Precursor Cell Lymphoblastic Leukemia-Lymphoma*
Thioguanine
6-Mercaptopurine
Thioguanine

Figure

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  Fig. 1. Study population. Patients were classified into normal-, intermediate-, low-activity groups according to the number of variant alleles. 6-MP, 6-mercaptopurine; HCT, hematopoietic stem cell transplantation; TPMT, thiopurine S-methyltransferase.

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  Fig. 2. Daily 6-mercaptopurine (6-MP) dose and clinical features of the groups. (A) Daily 6-MP dose. (B) Therapy interruption days. (C) Incidence of febrile neutropenia.

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  Fig. 3. Lowest level of complete blood cell counts in the groups. (A) Lowest white blood cell (WBC) counts. (B) Lowest absolute neutrophil counts (ANCs). (C) Lowest hemoglobin (Hb) levels. (D) Lowest platelet (Plt) counts.

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  Fig. 4. Duration of leukopenia in the various groups. WBC, white blood cell.

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  Fig. 5. 6-Thioguanine nucleotide (6-TGN) levels and 6-mercaptopurine (6-MP) doses of the study population. RBC, red blood cell.

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  Fig. 6. Ratio of the 6-thioguanine nucleotide (6-TGN) level to 6-mercaptopurine (6-MP) dose between the groups.

Reference

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