Severe Thiopurine-Induced Myelosuppression in a Pediatric ALL Patient with the NUDT15 *1/*6 Genotype
Publication Date
9-2025
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Abstract
Introduction: Genetic variants in TPMT and NUDT15 that affect the metabolism of mercaptopurine (6MP) are routinely tested for to guide 6MP dosing. Nudix hydroxylase 15 (NUDT15) deficiency can cause myelosuppression when affected patients are treated with 6MP. The NUDT15 *6 allele is classified as having uncertain function by the Clinical Pharmacogenetics Implementation Consortium Guidelines given insufficient data to determine its phenotype. Here, we present the case of a pediatric patient with the NUDT15 *1/*6 genotype experiencing significant mercaptopurine-induced myelosuppression. Case Description: We present a 4-year-old female with standard risk-average precursor B-cell acute lymphoblastic leukemia treated per AALL1731. Exome sequencing reported TPMT *1/*1 (Normal Metabolizer) and NUDT15 *1/*6 (Indeterminate). In Maintenance Cycle 1, 6MP was started at standard dosing of 75 mg/m2/day. On Cycle 1 Day 29, her absolute neutrophil count (ANC) and platelets had decreased but remained within goal range. At that time, 6-thioguanine nucleotides (6-TGN) were at the higher end of normal at 445 pmol/8 x 108 RBC, and 6-methylmercaptopurine (6-MMP) was elevated at 9200 pmol/8 x 108 RBC. On Cycle 1 Day 47, she developed increased bruising and was found to have severe neutropenia with an ANC of 0.03 x 103 mcL and thrombocytopenia with platelets of 5 x 103 mcL. 6-TGN were relatively unchanged at 440 pmol/8 x 108 RBC, but 6-MMP had significantly increased to 16,177 pmol/8 x108 RBC. Given the degree of myelosuppression, 6MP was held. Her ANC and platelets did not recover until Cycle 1 Day 64, at which time 6MP was restarted at 50% of the original dose. She has not required any additional dose changes or disruption in Maintenance Cycle 2. Conclusions: This case suggests that patients with the NUDT15 *1/*6 genotype could be treated as intermediate metabolizers with higher risk of toxicity than those with wild-type NUDT15 and require dose reduction.
Disciplines
Oncology | Pediatrics
Recommended Citation
Fry, Jillian; August, Keith; Flatt, Terrie DO; and Ramsey, Laura B., "Severe Thiopurine-Induced Myelosuppression in a Pediatric ALL Patient with the NUDT15 *1/*6 Genotype" (2025). Posters. 477.
https://scholarlyexchange.childrensmercy.org/posters/477
Notes
Presented at the Children's Oncology Group (COG) Fall Meeting; New Orleans, LA; September 16-19, 2025.