Paper Details

ABSTRACT

Background

The phase II GIMEMA AML1718 trial demonstrated that venetoclax combined with fludarabine, high-dose cytarabine, and idarubicin (FLAI) is feasible and highly active in fit patients with newly diagnosed non-low-risk AML (Marconi et al., Blood Adv 2025). The GIMEMA AML1310 trial established MRD-driven risk-adapted intensive chemotherapy as a frontline strategy for younger adults with AML (Venditti et al.Blood 2019, Blood Adv 2024). However, randomized evidence demonstrating that the addition of venetoclax to intensive induction improves long-term survival over intensive chemotherapy alone in fit patients remains limited. We performed a propensity score-matched comparative analysis of the AML1718 and AML1310 trials to assess long-term clinical outcomes.

Methods

Patient-level data from AML1718 (venetoclax plus FLAI; n=124) and AML1310 (standard intensive chemotherapy; n=445) were analyzed. Since AML1718 enrolled only ELN2017 intermediate/high-risk AML, optimal 1:1 propensity score matching was performed using age, sex, and ELN2017 risk, generating two matched cohorts of 124 patients each. Endpoints included complete remission (CR), measurable residual disease (MRD) negativity, overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Cox models evaluating OS and DFS included allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a time-dependent covariate. Pre-specified subgroup analyses were performed according to ELN2017 risk.

Results

Before matching, AML1718 patients were older, more frequently classified as ELN high-risk, and underwent allo-HSCT more often than AML1310 patients. After matching, age, sex, and ELN risk were well balanced between cohorts, whereas allo-HSCT remained more frequent in AML1718 (60% vs 24%).

Venetoclax plus FLAI significantly improved CR (80% vs 63%; P=0.003) and MRD negativity (73% vs 49%; P=0.002). At 6 months, a higher proportion of AML1718 patients were alive in CR (70% vs 57%), with fewer cases of resistant disease or early death (P=0.030).

At 36 months, OS was 46% (95% CI, 37-57) in AML1718 versus 31% (95% CI, 23-41) in AML1310. In multivariable analysis including allo-HSCT as a time-dependent covariate, treatment in AML1718 was associated with improved OS (HR 0.69, 95% CI 0.50-0.95; P=0.023). DFS also favored AML1718 (49% [95% CI, 40-61] vs 35% [95% CI, 26-49]), although the difference was not statistically significant (HR 0.78, 95% CI 0.50-1.23; P=0.30).

The cumulative incidence of relapse was significantly lower with venetoclax (Gray's P=0.035), with 36-month CIR estimates of 29% (95% CI, 19-39) versus 48% (95% CI, 35-59), while NRM was similar between cohorts.

The survival benefit was primarily observed in ELN intermediate-risk AML, with significant improvements in OS (HR 0.37, 95% CI 0.22-0.60; P<0.001) and DFS (HR 0.49, 95% CI 0.27-0.86; P=0.014), together with a marked reduction in relapse (36-month CIR: 17% vs 53%; Gray's P=0.002). No statistically significant differences were observed in the ELN high-risk subgroup.

Conclusions

In this propensity score-matched comparison of two prospective GIMEMA trials, venetoclax combined with intensive FLAI significantly improved remission quality, reduced relapse, and prolonged overall survival compared with conventional intensive chemotherapy in fit patients with newly diagnosed intermediate/high-risk AML. The greatest benefit was observed in ELN intermediate-risk AML, whereas the effect was less evident in ELN high-risk disease, supporting further investigation of optimized treatment strategies for this subgroup. These observations prompt the question which approach is preferable between intensification (ven+iCHT) or de-escalation (Ven+HMA) for fit, high-risk AML patients. Since the prognostic role of MRD has been firmly established and intensification appears to provide a more in-depth MRD eradication, we need well-designed clinical trial to answer this question.