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. 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.

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

“…NUDT15 , another important gene with a similar pathway as TPMT , was first identified as a candidate gene by a genome‐wide association study (GWAS) of inflammatory bowel disease patients and in children with ALL . NUDT15 was associated with thiopurine‐related hematopoietic toxicity and has been confirmed in several other studies to be associated with thiopurine tolerance and/or thiopurine‐related toxicity in leukaemia patients . In this study, two SNPs of NUDT15 (rs116855232 and rs186364861) were identified in association with thiopurine metabolites and therapeutic interruption which confirmed and reflected previous findings on its association with thiopurine‐related hematopoietic toxicity (Tables ).…”

“…Clinical information including 6‐MP dosage (mg/body surface area/day), duration of 6‐MP treatment, and adverse effects related to treatment were investigated. The treatment protocol has been described in detail previously . Patients who were over 10 years of age or under 12 months or who had initial white blood cell (WBC) count of 50 × 10 9 L −1 or more were considered as high‐risk ALL patients (the others were standard risk ALL patients) according to the risk stratification criteria of the National Cancer Institute .…”

“…We defined the terms used to describe the adverse effects of thiopurine treatment as follows: leukopenia, WBC count <1.5 × 10 9 L −1 ; neutropenia, absolute neutrophil count <0.5 × 10 9 L −1 ; hepatotoxicity, ALT or AST enzyme activity >3 times the upper limit of the reference range and bilirubin >1.5 times the upper limit of the reference range after starting 6‐MP and during a stable disease state; and treatment interruption, any period in which 6‐MP therapy was discontinued due to an adverse drug reaction. Treatment was interrupted when patients showed significant hematopoietic toxicity (absolute neutrophil count below 0.5 × 10 9 L −1 or platelet count below 50 × 10 9 L −1 ) or serious infectious events . This study was approved by the Institutional Review Board of Samsung Medical Center (IRB file No.…”

Homozygous mutation in NUDT15 in childhood acute lymphoblastic leukemia with increased susceptibility to mercaptopurine toxicity: A case report

“…In a study of 404 Taiwan Chinese patients with ALL, 5 patients were homozygous (TT) for the NUDT15 variant and the maximal tolerable daily dose of 6-MP in this group was 9.4±3.7 mg/m 2 /day (24). A previous study demonstrated that 5 out of 182 Korean pediatric patients with ALL were homozygous for the NUDT15 variant and the lowest dose of 6-MP administered was 7.5 mg/m 2 /day (25). Previous studies suggest that a comprehensive pharmacogenetic model incorporating the specific genetic variation of NUDT15 may allow for further personalized thiopurine therapy (13,(23)(24)(25)(26).…”

“…A previous study demonstrated that 5 out of 182 Korean pediatric patients with ALL were homozygous for the NUDT15 variant and the lowest dose of 6-MP administered was 7.5 mg/m 2 /day (25). Previous studies suggest that a comprehensive pharmacogenetic model incorporating the specific genetic variation of NUDT15 may allow for further personalized thiopurine therapy (13,(23)(24)(25)(26). Although genetic testing prior to treatment revealed that the patient possessed the TPMT wild-type allele, the patient suffered from severe myelosuppression, in particular, neutropenia and hyperpigmentation, all of which led to a lung infection and treatment delay.…”