Venetoclax combined with a hypomethylating agent is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy; it has also become widely used in the relapsed/refractory (r/r) setting. In contrast to the VIALE-A trial, real-world data have shown less favorable outcomes. Recently, an increasing number of factors influencing treatment response have been identified.

We report data from 82 consecutive patients (48 male, 34 female) treated at the University Medical Center Ljubljana between 2021 and 2025. 65 patients received treatment as first-line therapy (median age: 74 years; range 50–87), and 17 patients in the r/r setting (median age: 67 years; range 56–88). The majority received azacitidine plus venetoclax; only 3 patients were treated with decitabine plus venetoclax. The first treatment cycle was typically administered in the hospital, with subsequent cycles given in an outpatient setting.

Among newly diagnosed AML patients, 25 (38%) were classified as favorable-risk, 7 (11%) as intermediate-risk, and 6 (9%) as adverse-risk according to the ELN 2024 prognostic classification system. In 27 (42%) patients, next-generation sequencing (NGS) was not performed. Thirty-four patients (52%) met the criteria for AML, myelodysplasia-related (AML-MR) according to the WHO 2022 classification: 17 had specific myelodysplasia-related gene mutations, 12 had specific myelodysplasia-related cytogenetic abnormalities, and 5 had a history of MDS. Additionally, 5 patients (7.7%) had secondary AML following a prior myeloproliferative neoplasm. Two patients presented with extramedullary disease.

The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate in the newly diagnosed AML group was 54%. The 2-month mortality was 6/65 (9%), and median overall survival was 9.9 months. Seven (11%) patients were refractory. The median number of treatment cycles was 4 (range 1–29).

Among the 17 r/r patients, 5 (29%) met the criteria for AML-MR, and 3 (18%) had secondary AML following a prior myeloproliferative neoplasm. According to the ELN 2024 risk stratification, 4 were favorable-risk, 3 intermediate-risk, and 1 adverse-risk; however, most patients could not be classified due to lack of NGS data. CR/CRi was achieved in 10/17 (59%) patients, and 3/17 (18%) patients were refractory. Patients received a median of 5.5 treatment cycles. Median survival was 13.4 months.

Median survival of the entire cohort (82 patients) was 11.1 months (median follow-up: 7.4 months), with no significant difference between first- and second-line treatment. When stratified by ELN 2024 risk classification, median survival was not reached in the favorable-risk group, was 9.8 months in the intermediate-risk group, and 12.5 months in the adverse-risk group. Patients who could not be classified according to ELN 2024 due to the lack of NGS data had the worst survival (8.7 months). Patients under 75 years of age had significantly better survival than those ≥75 years (13.3 vs. 6.2 months; p = 0.009). Patients with monocytic differentiation (n = 17) had shorter survival (8.3 months) compared to the others (11.1 months; p = NS).

Conclusions: Our data show poorer outcomes compared to the VIALE-A trial, even among patients treated in the first-line setting. However, outcomes for patients treated in the relapsed/refractory (r/r) setting were not inferior. Notably, our cohort included a significant proportion of patients with myelodysplasia-related AML and secondary AML arising from prior myeloproliferative neoplasms. There was a trend toward inferior outcomes in patients with monocytic differentiation. Survival was significantly shorter in patients aged ≥75 years. Improved diagnostics, including broader use of next-generation sequencing (NGS), may help better identify patients most likely to benefit from this treatment approach.

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2025
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