{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:48:55Z","timestamp":1782272935098,"version":"3.54.5"},"reference-count":28,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,6]]},"abstract":"ABSTRACT<\/jats:title>\n \n Variants in\n TPMT<\/jats:italic>\n and\n NUDT15<\/jats:italic>\n genes that affect thiopurine metabolism can guide personalized dosing to minimize toxicity. Decreased or no appreciable\n NUDT15<\/jats:italic>\n activity demonstrates impaired breakdown of active thiopurine metabolites which can lead to severe adverse events including potentially life\u2010threatening myelosuppression. Recently, the\n NUDT15*6<\/jats:italic>\n allele was re\u2010classified from having uncertain function to no function by the Clinical Pharmacogenetics Implementation Consortium. Here, we present a pediatric patient with a\n NUDT15*1\/*6<\/jats:italic>\n genotype who experienced significant thiopurine\u2010induced myelosuppression. The patient is a 4\u2010year\u2010old female with standard risk\u2010average precursor B\u2010cell acute lymphoblastic leukemia treated per AALL1731. Exome sequencing determined\n TPMT*1\/*1<\/jats:italic>\n (normal metabolizer) and\n NUDT15*1\/*6<\/jats:italic>\n (indeterminate metabolizer). After 75\u2009mg\/m\n 2<\/jats:sup>\n \/day mercaptopurine, myelosuppression necessitated a three\u2010week delay prior to the next phase of therapy. With 60\u2009mg\/m\n 2<\/jats:sup>\n \/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\u2009mg\/m\n 2<\/jats:sup>\n \/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\n NUDT15*6<\/jats:italic>\n . In a larger cohort sequenced for suspicion of rare genetic disease, the frequency of\n NUDT15*6<\/jats:italic>\n was 0.15% among 1011 unrelated individuals. This brief report supports the recent update that patients with the\n NUDT15*1\/*6<\/jats:italic>\n genotype should be classified as intermediate metabolizers.\n <\/jats:p>","DOI":"10.1111\/cts.70639","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T03:16:38Z","timestamp":1781320598000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Severe Thiopurine\u2010Induced Myelosuppression in a Pediatric Acute Lymphoblastic Leukemia Patient With the\n NUDT15 *1\/*6<\/i>\n Genotype: A Brief Report"],"prefix":"10.1111","volume":"19","author":[{"given":"Jillian","family":"Fry","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology\/BMT Children's Mercy Kansas City Kansas City USA"},{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3044-5521","authenticated-orcid":false,"given":"Erin C.","family":"Boone","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0203-0196","authenticated-orcid":false,"given":"Wendy Y.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7953-4616","authenticated-orcid":false,"given":"Shobana","family":"John","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Lansdon","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Children's Mercy Kansas City Kansas City USA"},{"name":"Division of Laboratory Genetics and Genomics Children's Mercy Kansas City Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Midhat S.","family":"Farooqi","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Children's Mercy Kansas City Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byunggil","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine Children's Mercy Kansas City Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-1893","authenticated-orcid":false,"given":"Andrea","family":"Gaedigk","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"August","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/BMT Children's Mercy Kansas City Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terrie G.","family":"Flatt","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology\/BMT Children's Mercy Kansas City Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6417-3961","authenticated-orcid":false,"given":"Laura B.","family":"Ramsey","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation Children's Mercy Research Institute Kansas City USA"},{"name":"School of Medicine University of Missouri Kansas City USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007691-200404000-00018"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00054725-200402001-00008"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra020021"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2009.069252"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.59.4671"},{"key":"e_1_2_9_7_1","unstructured":"M.L.Appell \u201cTPMT nomenclature committee (TPMT alleles) \u201d(2025) 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