Prolonged venetoclax (VEN) plus hypomethylating agent (HMA) therapy in non-promyelocytic AML: A single-centre retrospective cohort study

Abstract Background: This retrospective study aimed to analyze and evaluate the progression-free survival (PFS) and overall survival (OS) of patients with newly diagnosed acute myeloid leukemia (AML, non-M3) who received long-term treatment with venetoclax (VEN) in combination with other chemotherapy drugs. The primary outcomes were PFS and OS. Methods: This single-center, retrospective study included 88 patients with newly diagnosed AML who received induction therapy with VEN-based regimens for 4 cycles or more. Baseline characteristics, including gender, age, ECOG score, pre-chemotherapy blood counts (such as white blood cell count, hemoglobin, and platelet count), abnormal karyotype, adverse karyotype, and risk gene mutations (ELN 2024 risk stratification for less-intensive), were also included. Patients were followed for relapse and overall survival, with data prospectively recorded. Finally, the Cox proportional hazards regression model was used to analyze and evaluate the factors influencing PFS and OS. Results: Among the 88 patients who received more than 4 cycles of treatment, 34 (38.6%) relapsed and 22 (25.0%) died during follow-up. In the analysis examining prognostic factors for PFS, age ≥ 60 years was a significant adverse prognostic factor (HR = 2.379, 95% CI: 1.041 - 5.438, p = 0.040), indicating that the risk of death in elderly patients was approximately 2.4 times that of non-elderly patients. NPM1 mutation was significantly associated with improved survival (HR = 0.055, 95% CI: 0.006 - 0.531, p = 0.012), suggesting that NPM1 mutation is an independent protective factor. In the analysis examining prognostic factors for OS, TP53 mutation was a significant independent adverse prognostic factor (HR = 4.743, 95% CI: 1.040 - 21.625, p = 0.044), indicating that the risk of death in TP53-mutated patients was approximately 4.7 times that of wild-type patients. Adverse karyotype was also significantly associated with poor survival outcomes (HR = 3.542, 95% CI: 1.029 - 12.190, p = 0.045). In the KMT2A rearrangement subtype, t(9;11)(p21.3;q23.3) (HR = 9.445, 95% CI: 1.360 - 65.584, p = 0.023) and KMT2A-tv11q23.3 (HR = 21.525, 95% CI: 1.512 - 306.415, p = 0.024) both significantly increased the risk of death, suggesting that they are strong independent risk factors. The 2024 ELN risk stratification did not reach statistical significance in this model (p = 0.125), which may be related to sample size or collinearity among variables. Conclusion: In summary, TP53 mutation, adverse karyotype, and KMT2A rearrangement (especially t(9;11) and KMT2A-tv11q23.3), and age ≥ 60 years are independent negative prognostic markers for AML patients, while NPM1 mutation improves survival outcomes. These findings can be used to guide clinical risk stratification and individualized treatment decisions. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Ethics statement This study was approved, and the written informed consent was waived by The Medical Ethics Committee of Qilu Hospital of Shandong University (KYLL-202502-054) due to the retrospective nature of the review, and confirmed that the data was anonymized and maintained with confidentiality. The study was conducted in accordance with the Declaration of Helsinki.