{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:07:04Z","timestamp":1791313624399,"version":"4.3.1"},"reference-count":47,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:p>\n                    Mercaptopurine is a cornerstone of maintenance chemotherapy in childhood acute lymphoblastic leukemia (ALL). Its cytotoxic effects are mediated by 6\u2010thioguanine nucleotides (TGNs) incorporation into lymphocyte DNA. Thiopurine methyltransferase (TPMT) inactivates mercaptopurine, and deficiency resulting from genetic variants increases TGN exposure and hematopoietic toxicity. Although mercaptopurine\u2010dose reduction reduces toxicity risk without compromising relapse rate in patients with TPMT deficiency, dosing recommendations for those with moderately reduced activity (intermediate metabolizer (IM)) are less clear and their clinical impacts have yet to be established. This cohort study assessed the effect of TPMT IM status on mercaptopurine\u2010associated toxicity and TGN blood exposure in pediatric patients with ALL initiated on standard dose mercaptopurine. Of 88 patients studied (mean age 4.8\u2009years), 10 (11.4%) were TPMT IM, and all had undergone \u2265\u20093 cycles of maintenance therapy (80% completed). A larger proportion of TPMT IM than normal metabolizers (NM) had febrile neutropenia (FN) during the first two cycles of maintenance, reaching significance in the second cycle (57% vs. 15%, respectively; odds ratio\u00a0=\u00a07.33,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). Compared to NM, FN events occurred more frequently and with prolonged duration in IM in cycles 1 and 2 (adjusted\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). IM had a 2.46\u2010fold increased hazard ratio for FN, and about twofold higher TGN level than NM (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). Myelotoxicity was more common in IM than NM (86% vs. 42%, respectively) during cycle 2 (odds ratio\u00a0=\u00a08.2,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). TPMT IM initiated at a standard mercaptopurine dose are at greater risk for FN during early cycles of maintenance therapy, thus our findings support genotype\u2010guided dose adjustment to reduce toxicity.\n                  <\/jats:p>","DOI":"10.1002\/cpt.2894","type":"journal-article","created":{"date-parts":[[2023,3,18]],"date-time":"2023-03-18T07:18:50Z","timestamp":1679123930000},"page":"1326-1336","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Thiopurine Methyltransferase Intermediate Metabolizer Status and Thiopurine\u2010Associated Toxicity During Maintenance Therapy in Childhood Acute Lymphoblastic Leukemia"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1569-1580","authenticated-orcid":false,"given":"Ute I.","family":"Schwarz","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry University of 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School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantel","family":"Cacciotti","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Cairney","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serina","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2187-0051","authenticated-orcid":false,"given":"Jennifer","family":"Seelisch","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumitra","family":"Tole","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Wilejto","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rommel G.","family":"Tirona","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-1632","authenticated-orcid":false,"given":"Richard B.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"},{"name":"Department of Medicine, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra P.","family":"Zorzi","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Schulich School of Medicine and Dentistry University of Western Ontario  London Ontario 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