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We analyzed 506 patients with AML treated with first-line HMA\/VEN at Moffitt Cancer Center to develop a genetics-based prognostic model. In multivariate analysis, mutations in TP53, KRAS, JAK2, U2AF1, CBL, and cytogenetic lesions del(7q)\/\u22127, del(17p)\/\u221217\/i(17q), del(20q), and MECOM rearrangements predicted inferior OS, whereas IDH1\/2 mutations were favorable. A point-based system stratified patients into low-, intermediate-, and high-risk groups with median OS of 54.2, 22.3, and 7.5 months, respectively [P &amp;lt; 0.0001; concordance index (C-index) 0.648]. External validation (n = 126) retained prognostic separation (median OS 24.7, 17.4, and 4.3 months, P = 0.0005; C-index 0.626). Compared with existing HMA\/VEN-specific models, our model demonstrated superior low- versus intermediate-risk discrimination (31.9-month separation, P = 0.002; hazard ratio = 0.45, P = 0.003), with a comparable C-index. Our model supports personalized risk stratification for HMA\/VEN-treated AML, pending broader validation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study identifies key mutational and cytogenetic markers associated with treatment response and OS in patients with AML receiving HMA\/VEN therapy. By integrating these genetic markers, our new prognostic model offers improved risk stratification, guiding personalized treatment strategies for patients ineligible for intensive chemotherapy.<\/jats:p>\n                    <jats:p>See related commentary by Lachowiez and Loghavi, p. 339<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2643-3230.bcd-25-0193","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T21:38:41Z","timestamp":1770845921000},"page":"403-413","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents"],"prefix":"10.1158","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-4167","authenticated-orcid":false,"given":"Dimitrios","family":"Drekolias","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01xf75524","id-type":"ROR","asserted-by":"publisher"}],"name":"H. 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