Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents
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 AML patients treated with front-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; 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 to existing HMA/VEN-specific models, our model demonstrated superior low- vs. intermediate-risk discrimination (31.9-month separation, p=0.002; HR=0.45, p=0.003), with comparable C-index. Our model supports personalized risk stratification for HMA/VEN-treated AML, pending broader validation.
Authors
- Rinzine Sammut (ORCID: https://orcid.org/0000-0003-3015-0846)
- Nicole D. Vincelette (ORCID: https://orcid.org/0000-0001-7627-6781)
- Somedeb Ball (ORCID: https://orcid.org/0000-0002-1754-1204)
- Eric Padron (ORCID: https://orcid.org/0000-0002-4707-7916)
- Andrew Tucker Kuykendall (ORCID: https://orcid.org/0000-0002-9040-7415)
- Sandrine Niyongere (ORCID: https://orcid.org/0000-0001-9254-0095)
- L Zhang
- T. Cluzeau
- Jungwon Moon (ORCID: https://orcid.org/0009-0007-5150-5817)
- Fatima Tuz Zahra (ORCID: https://orcid.org/0000-0001-5989-1117)
- Dimitrios Drekolias (ORCID: https://orcid.org/0000-0001-5905-4167)
- Tiffany N. Razabdouski (ORCID: https://orcid.org/0009-0008-5666-8575)
- Zhuoer Xie (ORCID: https://orcid.org/0000-0002-4742-3321)
- Rory Michael Shallis (ORCID: https://orcid.org/0000-0002-8542-2944)
- Xiaoqing Yu (ORCID: https://orcid.org/0000-0002-3255-9285)
- Chia-Ho Cheng
- Caroline Fileni
- Onyee Chan
- Qianxing Mo
- Kendra Sweet
- Alison R. Walker
- Jeffrey E. Lancet
- David A. Sallman
- Sura-Attha Umasangtongkul
- Kathy Mai
- Seongseok Yun
- Felyschia M. Lledo
- Rami S. Komrokji
- Dahui Qin
Institutions
- University of Maryland, Baltimore (US)
- Nova Southeastern University (US)
- Centre Hospitalier Universitaire de Nice (FR)
- Moffitt Cancer Center (US)
- University of Baltimore (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Blood Cancer Discovery
- Published
- 2026-02-11
- DOI
- https://doi.org/10.1158/2643-3230.bcd-25-0193
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00