Background:

Azacitidine (AZA) plus venetoclax (VEN) is the standard first-line treatment for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy (IC). While current recommendations favor continuous ≥21-day VEN cycles, real-world adaptations using shorter schedules are common, aiming to reduce hematologic toxicity and improve tolerability. However, evidence comparing a 7-day VEN schedule with “standard” ≥21-day VEN remains limited.

Methods:Data were retrospectively collected in the VENAURA registry (n = 775) from 10 different French centers (Saint-Etienne, Clermont-Ferrand, Grenoble, Lyon (Hopital Lyon Sud, Centre Léon Bérard), Nîmes, Villefranche sur Saône, Annecy, Valence, Roanne) in Auvergne Rhône Alpes (AURA) region, between January 2019 and February 2024. Patients were included if they received either 7 days or ≥21 days of VEN during cycle 1 in first-line treatment. Overall response rate was defined as in VIALE-A trial with a composite complete remission (CRc) combining complete remission (CR), complete remission with incomplete hematopoietic lineage recovery (CRi), morphological free leukemia state (MFLS).

Results:A total of 254 patients were eligible: 202 (80%) received standard VEN and 52 (20%) received the short-course regimen. Median age was 74 years (range 31–92); patients in the short-course group were significantly older (median 76 vs 73 years, p<0.001), with more patients aged ≥80 (29% vs 11%, p=0.002). ECOG ≥2 was similar (27% vs 37%, p=0.58). AML subtypes (de novo, secondary, myelodyplasia-related, therapy-related), mutation profiles (TP53, NPM1, IDH1/2, FLT3-ITD, NRAS, KRAS) and ELN 2024 risk group distribution were balanced between groups.

After the first treatment cycle, CRc was significantly lower in the short-course group compared to the standard group (40% vs 57%, p=0.048). When considering the best CRc achieved at any time during treatment, the short-course group also had significantly lower response rates (48% vs 74%, p<0.001).

The median number of cycles was 3 in both groups. Among responders (n=190), 66% (short-course) and 61% (standard) achieved best response during the first cycle (p=0.76).

Early mortality at 30 and 60 days was 5% and 8%, respectively, in the standard group, and 21% and 27% in the short-course group. With a median follow-up was 23 months, median OS was significantly shorter in the short-course group: 6 vs 13 months (p=0.0023), with a corresponding 2-year OS of 13% (95% CI 6–29) compared to 33% (27–42). Similarly, 2-year LFS was 11% (5–24) vs 24% (18–33) (p=0.0049) in short compared to standard group. Stratified by ELN 2024, 2-year OS and LFS were significantly better with standard VEN in favorable (OS: 40% vs 18%, p=0.02; LFS: 28% vs 17%, p=0.07) and intermediate risk (OS: 38% vs 17%, p=0.05; LFS: 35% vs 13%, p=0.05). In the adverse-risk group, -OS was 16% versus 25% (p=0.47) and LFS was 8% in both groups (p=0.37), with no statistically significant differences observed.

In uni-and multivariate analyses, short-course VEN was independently associated with inferior OS (HR 2.22, 95% CI 1.52–3.24, p<0.001) and LFS (HR 2.02, 1.41–2.91, p<0.001). Other independent predictors of poor survival included therapy-related AML (OS: HR 2.18, p=0.004; LFS: HR 1.94, p=0.009) and complex/monosomal karyotype (OS: HR 2.07, p=0.001; LFS: HR 1.55, p=0.042). Conversely, NPM1 mutation predicted improved LFS (HR 0.47, p=0.003), with a trend toward improved OS (HR 0.61, p=0.057). IDH1/2 mutations were also associated with favorable outcomes in univariable analysis (OS: p=0.013; LFS: HR 0.66, p=0.052). ELN 2024 risk classification was significantly associated with both OS (p<0.001) and LFS (p=0.002) in univariate analysis, but did not retain significance in multivariate models.

Conclusion:While 7-day VEN may appear feasible in selected patients, our data show inferior outcomes, particularly in those with favorable or intermediate ELN 2024 risk. These patients may benefit most from prolonged venetoclax exposure. Our study is limited by its retrospective nature and potential unmeasured differences in patient fitness. Although ECOG performance status was similar, patients in the short-course group were older and presented at least 1 exclusion criterion upon entry into a clinical trial, possibly reflecting greater frailty. Our findings do not support a generalized use of 7-day VEN schedules, and caution is warranted pending results from prospective randomized trials.

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2025
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