{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:34:37Z","timestamp":1791516877156,"version":"4.3.4"},"reference-count":36,"publisher":"American Society of Hematology","issue":"15","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,8]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>NPM1-mutated acute myeloid leukemia (AML) is genetically well defined, but clinical outcomes remain heterogeneous, suggesting that quantitative clonal features may refine current risk stratification. We analyzed 688 intensively treated NPM1-mutated (NPM1mut) AML integrating variant allele frequency (VAF), mutation order, and clonal architecture inferred by PyClone and ClonEvol. Comutations were present in 97% of patients (median, 3 per case), dominated by DNMT3A (49%), FLT3-ITD (46%), TET2 (22%), and IDH2 (20%). Prognostic modeling of NPM1 VAF identified an optimal cutoff of 31.44%, defining NPM1high and NPM1low groups. NPM1low correlated with splicing-related alterations and independently predicted inferior overall survival (hazard ratio [HR], 1.46; P = .037) and relapse-free survival (HR, 1.40; P = .036). Gene-specific VAF analyses revealed divergent effects across partners: high DNMT3A, FLT3-OTHER (non-ITD\/TKD), KRAS, and PTPN11 burdens were adverse, whereas high IDH2 VAF was protective. Combined models showed that patients with NPM1high and favorable comutation VAFs had the best outcomes, whereas dual unfavorable burdens conferred the poorest survival. Mutation ordering inferred from VAFs positioned NPM1 after epigenetic and splicing lesions but before signaling and transcription-factor mutations. Noncanonical orders, such as early FLT3-OTHER\/TKD or WT1 before NPM1, significantly stratified outcomes. Clonal reconstruction revealed predominantly linear evolutionary trajectories (84.3%), with increased mutational burden and clonal diversity associating with inferior survival. Notably, intraclonal colocalization of NPM1 with IDH1 or TET2 was associated with improved outcomes, whereas colocalization with WT1 predicted dismal prognosis. These results demonstrate that quantitative and structural dimensions of clonality refine the biological and prognostic landscape of NPM1-mutated AML beyond mutational status alone.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2026033576","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T17:07:42Z","timestamp":1780938462000},"page":"1911-1924","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Prognostic impact of variant allele frequency in intensively treated patients with\n                    <i>NPM1<\/i>\n                    -mutated AML: a PETHEMA study"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2097-4796","authenticated-orcid":false,"given":"Jos\u00e9 Vicente","family":"Gil","sequence":"first","affiliation":[{"name":"1Grupo Acreditado de Investigaci\u00f3n en Hematolog\u00eda, Instituto de Investigaci\u00f3n Sanitaria La Fe, Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8144-7995","authenticated-orcid":false,"given":"Claudia","family":"Sargas","sequence":"additional","affiliation":[{"name":"1Grupo Acreditado de Investigaci\u00f3n en Hematolog\u00eda, Instituto de Investigaci\u00f3n Sanitaria La Fe, Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Ayala","sequence":"additional","affiliation":[{"name":"2Hospital Universitario 12 de Octubre, Centro Nacional de Investigaciones Oncol\u00f3gicas, Universidad Complutense, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5834-9510","authenticated-orcid":false,"given":"Norma Carmen","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[{"name":"3Servicio de Hematolog\u00eda, Hospital Universitario de Salamanca\/Instituto de Investigaci\u00f3n Biom\u00e9dica de Salamanca, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer, Centro de Investigaci\u00f3n del C\u00e1ncer-Instituto de Biolog\u00eda Molecular y C\u00e9lular del C\u00e1ncer, Universidad de Salamanca-Consejo Superior de Investigaciones Cient\u00edficas, Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Antonio","family":"P\u00e9rez-Sim\u00f3n","sequence":"additional","affiliation":[{"name":"4Hospital Universitario Virgen del Roc\u00edo, Instituto de Biomedicina de Sevilla\/Consejo Superior de Investigaciones Cient\u00edficas, Universidad de Sevilla, Seville, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Teresa","family":"G\u00f3mez-Casares","sequence":"additional","affiliation":[{"name":"5Servicio de Hematolog\u00eda, Hospital Universitario de Gran Canaria Dr. Negr\u00edn, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, 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