Efficacy and Safety of Azacitidine Plus Low-dose Dasatinib Maintenance Therapy for Patients with Intermediate and High-risk Acute Myeloid Leukemia: A Prospective, Randomized, Phase Ⅱ Clinical Trial

Technical Summary: Efficacy and Safety of Azacitidine Plus Low-dose Dasatinib Maintenance Therapy for Intermediate and High-risk AML

Problem Statement
Acute Myeloid Leukemia (AML) is characterized by a high recurrence rate, particularly among patients with intermediate and high-risk stratification. Despite achieving complete remission (CR) through induction and consolidation therapy, relapse rates for these patients can reach 60%, often resulting in a disease-free survival (DFS) of less than one year. While allogeneic stem cell transplantation (ASCT) offers a potential cure, it is inaccessible to many patients due to donor availability, age, comorbidities, or performance status. Consequently, maintenance therapy is critical for preventing relapse in non-transplant candidates. While azacitidine (AZA) monotherapy has demonstrated efficacy in improving prognosis, the potential synergistic benefits of combining AZA with second-generation tyrosine kinase inhibitors (TKIs) like Dasatinib for maintenance therapy remained unexplored in clinical trials. Dasatinib targets multiple kinases (BCR-ABL, c-KIT, FLT3, PDGFR, Src family) and has been shown to reduce DNA methylation levels and promote apoptosis, theoretically complementing the mechanism of demethylating agents.

Methodology
This study was a single-center, prospective, randomized, Phase II clinical trial (NCT05042531) conducted at the First Hospital of Lanzhou University.

• Participants: The study enrolled 33 newly diagnosed AML patients (aged 18–76) with intermediate or high-risk stratification (per 2022 ELN criteria) who achieved CR with negative minimal residual disease (MRD) following induction and consolidation therapy. Patients were ineligible for ASCT due to financial constraints, preference, or comorbidities.
• Intervention: Patients were randomized in a 2:1 ratio to receive one of two maintenance regimens for up to 12 cycles (28 days per cycle):
  1. Control Group: Azacitidine (AZA) 75 mg/m²/day subcutaneously on days 1–5.
  2. Experimental Group: AZA (75 mg/m²/day, days 1–5) combined with low-dose Dasatinib (20 mg orally, days 1–28).
     Note: The Dasatinib dose was reduced to 20 mg (from standard maintenance doses) to mitigate toxicity concerns and manage drug-drug interactions (e.g., with Paxlovid during the COVID-19 pandemic).
• Endpoints: The primary endpoint was Overall Survival (OS). Secondary endpoints included Disease-Free Survival (DFS), relapse rate, two-year mortality, and safety profiles (adverse events).
• Statistical Analysis: Survival distributions were analyzed using Kaplan-Meier methods and stratified log-rank tests. Baseline characteristics were compared using t-tests and chi-square tests.

Key Results

• Overall Survival (OS): The combination therapy demonstrated a statistically significant survival advantage. The median OS for the AZA monotherapy group was 26 months (95% CI: 18.9–33.1 months). In contrast, the median OS for the AZA + Dasatinib group was not reached at the time of analysis. This difference was statistically significant (p = 0.038). The 2-year OS rates were 79.5% for the AZA group and 90% for the combination group.
• Disease-Free Survival (DFS): There was no statistically significant difference in DFS between the two groups (p = 0.25). The median DFS was 24 months for the AZA group and not reached for the combination group. Relapse rates were 30% (6/20) in the AZA group and 20% (2/10) in the combination group. The authors attribute the lack of significant DFS difference to the small sample size and short follow-up duration.
• Safety and Tolerability: Hematological adverse events (AEs) were more frequent in the combination group (90% vs. 65%), though the difference was not statistically significant (p = 0.210). Neutropenia was the most common hematologic AE in both groups (Grade 3/4: 35% in AZA vs. 60% in combination). Non-hematologic AEs in the combination group included liver function impairment (30%), hyperuricemia (20%), and nausea (20%). Crucially, no patients discontinued treatment due to adverse reactions, and all toxicities were deemed manageable. Notably, pleural effusion, a known side effect of Dasatinib at higher doses, was not observed.

Significance and Claims
The paper claims that the combination of Azacitidine and low-dose Dasatinib as a maintenance treatment exhibits promising efficacy and is well-tolerated in intermediate and high-risk AML patients.

• Survival Benefit: The study provides evidence that adding low-dose Dasatinib to AZA maintenance significantly improves Overall Survival compared to AZA monotherapy in patients who are not candidates for transplantation.
• Feasibility: The regimen is presented as a feasible novel treatment option, with a safety profile that does not lead to treatment discontinuation despite the addition of a TKI.
• Mechanistic Rationale: The results support the hypothesis that combining a demethylating agent with a TKI targeting multiple kinases can enhance therapeutic outcomes in AML maintenance.
• Limitations and Modesty: The authors explicitly acknowledge limitations, including the small sample size (33 randomized, 30 treated) and the short follow-up period, which may explain the lack of significant DFS improvement. They do not claim the DFS benefit is absent, but rather that it requires validation in larger studies. The study concludes that while the OS benefit is significant, further large-scale clinical trials are necessary to confirm these findings and fully explore the DFS potential.