{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T11:57:31Z","timestamp":1785585451957,"version":"3.56.0"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100019591","name":"Harry T. Mangurian, Jr. Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019591","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2026,9]]},"abstract":"ABSTRACT<\/jats:title>\n \n Frameshift mutations in exon 12 of nucleophosmin 1 (\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n ) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable\u2010risk in the absence of\n FLT3<\/jats:italic>\n \u2010ITD. In the European LeukemiaNet (ELN) 2024 risk\u2010classification for patients treated with hypomethylating agents plus venetoclax (HMA\u2009+\u2009VEN),\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n is not considered favorable when co\u2010occurring with signaling gene (SG) mutations (i.e.,\n FLT3<\/jats:italic>\n \u2010ITD,\n NRAS<\/jats:italic>\n ,\n KRAS<\/jats:italic>\n ). However, due to limited numbers in the original analysis, the prognostic impact of\n SG<\/jats:italic>\n mutations in\n NPM1<\/jats:italic>\n \u2010mutant AML remains unclear. We evaluated the prognostic significance of\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n with and without SG mutations in two independent cohorts of patients \u2265\u200960\u2009years with ELN 2024 favorable\u2010 or intermediate\u2010risk AML treated with HMA\u2009+\u2009VEN. Cohort 1 included 322 patients treated in the academic setting.\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n (\n n<\/jats:italic>\n \u2009=\u200961) was associated with a nonsignificantly longer overall survival (OS) compared to\n NPM1<\/jats:italic>\n wild\u2010type (\n NPM1<\/jats:italic>\n wt<\/jats:sup>\n ) (median, 53.05 vs. 17.03\u2009months,\n p<\/jats:italic>\n \u2009=\u20090.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n subgroup. Cohort 2 included 816 patients from a real\u2010world community\u2010treated cohort.\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n (\n n<\/jats:italic>\n \u2009=\u2009124) had a longer OS compared with\n NPM1<\/jats:italic>\n wt<\/jats:sup>\n (median, 15.3 vs. 14.4\u2009months,\n p<\/jats:italic>\n \u2009=\u20090.03). In MVA,\n NRAS, KRAS<\/jats:italic>\n , and\n FLT3<\/jats:italic>\n \u2010ITD were independent unfavorable prognostic factors;\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n with, compared to without, SG co\u2010mutation had a shorter OS (median, 9.4 vs. 31.6\u2009months,\n p<\/jats:italic>\n \u2009=\u20090.001). These findings suggest SG mutations negate the favorable impact of\n NPM1<\/jats:italic>\n mut<\/jats:sup>\n in older patients treated with HMA\u2009+\u2009VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high\u2010risk subgroup.\n <\/jats:p>","DOI":"10.1002\/ajh.70419","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:15:51Z","timestamp":1783052151000},"page":"2246-2257","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Signaling Mutations Negate the Favorable Impact of\n \n NPM1<\/i>\n <\/scp>\n Mutations in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Treated With\n VEN<\/scp>\n \/\n HMA<\/scp>"],"prefix":"10.1002","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7128-1255","authenticated-orcid":false,"given":"Fieke W.","family":"Hoff","sequence":"first","affiliation":[{"name":"National Heart, Lung, and Blood Institute National Institutes of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9014-1514","authenticated-orcid":false,"given":"Joshua F.","family":"Zeidner","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Medicine, Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geeta","family":"Torlapati","sequence":"additional","affiliation":[{"name":"The James Cancer Hospital The Ohio State University Columbus Ohio USA"},{"name":"Clara D. Bloomfield Center for Leukemia Outcomes Research The Ohio State University Comprehensive Cancer Center Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deedra","family":"Nicolet","sequence":"additional","affiliation":[{"name":"The James Cancer Hospital The Ohio State University Columbus Ohio USA"},{"name":"Clara D. Bloomfield Center for Leukemia Outcomes Research The Ohio State University Comprehensive Cancer Center Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Mr\u00f3zek","sequence":"additional","affiliation":[{"name":"The James Cancer Hospital The Ohio State University Columbus Ohio USA"},{"name":"Clara D. 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