Severe Thiopurine-Induced Myelosuppression in a Pediatric Acute Lymphoblastic Leukemia Patient With the NUDT15 *1/*6...

Variants in TPMT and NUDT15 genes that affect thiopurine metabolism can guide personalized dosing to minimize toxicity. Decreased or no appreciable NUDT15 activity demonstrates impaired breakdown of active thiopurine metabolites which can lead to severe adverse events including potentially life-threatening myelosuppression. Recently, the NUDT15*6 allele was re-classified from having uncertain function to no function by the Clinical Pharmacogenetics Implementation Consortium. Here, we present a pediatric patient with a NUDT15*1/*6 genotype who experienced significant thiopurine-induced myelosuppression. The patient is a 4-year-old female with standard risk-average precursor B-cell acute lymphoblastic leukemia treated per AALL1731. Exome sequencing determined TPMT*1/*1 (normal metabolizer) and NUDT15*1/*6 (indeterminate metabolizer). After 75 mg/m²/day mercaptopurine, myelosuppression necessitated a three-week delay prior to the next phase of therapy. With 60 mg/m²/day thioguanine in a subsequent phase of therapy, she was admitted twice for fever and neutropenia. In the final phase of therapy, mercaptopurine at standard dosing of 75 mg/m²/day caused severe neutropenia and thrombocytopenia with elevated metabolite levels that required stopping mercaptopurine. After neutrophil recovery, a trial of 50% standard dosing was not tolerated and her dose was reduced to 27%, which was tolerated. Among 339 patients with cancer, sequencing revealed an allele frequency of 0.88% for NUDT15*6. In a larger cohort sequenced for suspicion of rare genetic disease, the frequency of NUDT15*6 was 0.15% among 1011 unrelated individuals. This brief report supports the recent update that patients with the NUDT15*1/*6 genotype should be classified as intermediate metabolizers.