Aza–Ven outperforms standard care for AML patients eligible for intensive chemotherapy

Standard initial treatment for acute myeloid leukemia (AML) patients varies based on age and fitness. Typically, younger and fit patients, under 65 years old, receive intensive induction chemotherapy (IC), commonly known as the “7+3” regimen, which consists of cytarabine and an anthracycline, followed by consolidation therapy, allogeneic stem-cell transplantation (HCT), or a combination of both [1]. In contrast, the standard for older or unfit patients has shifted toward lower-intensity but effective combinations of the BCL2 inhibitor venetoclax paired with the hypomethylating agent azacitidine (Aza‑Ven), based on the VIALE-A phase III data [2]. Results from the PARADIGM study presented at ASH 2025 challenged the current standard by testing whether Aza-Ven is superior to IC in fit patients [3].

The investigator-initiated, open-label, multicenter, phase II randomized trial enrolled previously untreated adult AML patients eligible for IC and randomized them 1:1 to receive Aza-Ven or IC (7+3 regimen or liposomal daunorubicin and cytarabine [CPX351]). Patients with t(15;17), acute promyelocytic leukemia, core binding factor alterations, FLT3 mutations, NPM1 mutations (if aged <60 years), BCR::ABL1 fusion or mixed phenotype AML were excluded from the study. Patients were allowed to proceed to HCT on both treatment arms following a response. The primary endpoint was event-free survival (EFS), with key secondary endpoints being response rates, overall survival (OS), toxicity, hospitalization metrics, and quality of life (QoL).

In total, 172 patients were enrolled (86 per treatment arm), with a median age of 64 years and 67% male. The majority of patients (72%) were in the adverse risk category (ELN 2022), and the distributions of risk category and mutation did not differ across arms. At a median follow-up of 21.9 months, the trial’s primary endpoint was met, showing that Aza-Ven extended the median EFS to 14.6 months compared with 6.15 months with IC (p = 0.0021). The 1-year EFS was 53.4% with Aza-Ven vs. 36.0% with IC.

Overall response rates were markedly different (88% for Aza-Ven vs. 62% for IC; p < 0.0001), as were composite remission rates (78% for Aza-Ven vs. 54% for IC; p = 0.0006). While complete remission rates were similar (56% vs. 49%; p = 0.2227), more patients treated with Aza-Ven proceeded to HCT (61% vs. 40%; p = 0.009), suggesting that Aza-Ven not only induces remissions but also preserves fitness for transplantation. Even after adjustment for HCT, the effect of Aza-Ven on EFS still remained protective (HR 0.67; p = 0.0302).

The secondary endpoint of OS was not statistically significant with a median OS of 21.5 months vs. 18.6 months with Aza-Ven vs. IC (p = 0.1873). The authors argued that, as many patients who start IC subsequently receive hypomethylating agent plus Ven, OS is a challenging endpoint to pursue and interpret in a setting where placebo control is not feasible.

The toxicity data and patient-reported outcomes also favored the Aza-Ven arm, with numerically fewer infections and bleeding events, significantly improved QoL and symptom burden during initial therapy, and less time in the hospital and the ICU. The ICU admission rates in the first 30 days and the 60-day mortality on the Aza-Ven arm were both 0% vs. 9.6% and 4.7% in the IC arm, respectively.

In conclusion, the phase II PARADIGM study met its primary endpoint, demonstrating significantly improved EFS with Aza-Ven vs. IC in functionally fit patients with newly diagnosed AML. Furthermore, PROs indicated that Aza-Ven improved QoL and was associated with reduced healthcare utilization. Together, these findings support the use of Aza-Ven in functionally fit patients with intermediate or adverse-risk, FLT3-wildtype AML.

Figure 1: Primary endpoint of event-free survival (EFS) for Aza-Ven (yellow) vs. IC (red)

REFERENCES

1. Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J 2021;11:41. https://doi.org/10.1038/s41408-021-00425-3.
2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383:617–29. https://doi.org/10.1056/NEJMoa2012971.
3. Fathi A. A Phase 2 Randomized Study Comparing Venetoclax and Azacitidine to Induction Chemotherapy for Newly Diagnosed Fit Adults With Acute Myeloid Leukemia. clinicaltrials.gov; 2025.

© 2026 Springer-Verlag GmbH, Impressum