Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents

Year: 2026

Type: article

Abstract: Venetoclax (VEN) combined with hypomethylating agents (HMA) improves outcomes for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, yet overall survival (OS) remains variable. 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)/-7, del(17p)/-17/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 < 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. SIGNIFICANCE: 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. See related commentary by Lachowiez and Loghavi, p. 339.

Source: Blood Cancer Discovery

DOI: 10.1158/2643-3230.bcd-25-0193

Institutions: University of South Florida, Moffitt Cancer Center, Centre Hospitalier Universitaire de Nice, Nova Southeastern University, Vanderbilt University Medical Center, University of Maryland, Baltimore

Language: English

Topic: Acute Myeloid Leukemia Research

Subfield: Hematology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: American Society of Hematology, American Society of Clinical Oncology, National Cancer Institute

Awards: G4710175517, Tumor suppressor roles of TFEB in the development and maintenance of myeloid leukemia, The oncogenic roles of alarmins and monocytes in triple negative myelofibrosis, Moffitt Cancer Center Support Grant

OpenAlex ID: W7128624541