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

Abstract Background Although some acute myeloid leukemia (AML) patients achieve minimal residual disease (MRD) negativity following induction and consolidation therapy, many struggle with long-term remission, particularly those in intermediate and high-risk groups. High-risk AML patients who initially respond to treatment but are not eligible for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes. Consequently, maintenance therapy is crucial. Research has demonstrated that tyrosine kinase inhibitors (TKIs) not only inhibit the abnormal activation of the tyrosine kinase pathway but also reduce DNA methylation. The combination of second-generation TKIs with demethylating agents exhibits a significant synergistic effect in promoting apoptosis and reducing methylation levels. However, real-world reports on the use of azacitidine (AZA) and Dasatinib for maintenance in intermediate and high-risk AML patients are limited. We therefore conducted a study to evaluate the efficacy and safety of combining AZA with Dasatinib in the maintenance therapy of intermediate and high-risk AML patients. Methods In this single-center, prospective, randomized phase II trial, newly diagnosed AML patients aged 11 to 76 years with intermediate-high risk (ELN 2022 AML risk stratification) were assigned (2:1) to receive either AZA or AZA plus Dasatinib with negative MRD status after induction and consolidation therapy (NCT05042531). The AZA + Dasatinib group received AZA (75 mg/m²/day) via subcutaneous injection on days 1-5 and Dasatinib (20 mg orally) from days 1-28. The AZA group received only AZA on the same schedule. Maintenance therapy may be interrupted or delayed for grade 3/4 toxicity, with the AZA dose adjustable to 50 mg/m²/day or 37.5 mg/m²/day, while Dasatinib remains at 20 mg. The primary endpoint was overall survival (OS), with secondary endpoints being disease-free survival (DFS) and adverse events (AEs). Results From April 2020 to April 2024, 33 patients were randomly allocated into either AZA (n=22) or AZA plus Dasatinib (n=11). The intention-to-treat population included 30 patients (20 in the AZA group and 10 in the AZA plus Dasatinib group. The median age was 42 years (range, 21-60.5) in the AZA group and 49 years (range, 44.3-53) in the AZA + Dasatinib group, with 50% males in both groups. Morphological characteristics in the AZA group were M2 (50%), M4 (15%), and M5 (35%), while in the AZA + Dasatinib group, they were M2 (60%), M4 (20%), and M5 (20%). Both groups received a median of 12 cycles of AZA. Baseline characteristics were generally balanced between the groups. With a median follow-up of 24.5 months (range, 13.3 to 40 months). The median overall survival (mOS) was 26 months (95% confidence interval 18.9-33.1 months) in the AZA group, while the mOS was not reached in the AZA + Dasatinib group, which had a statistically significant difference (log-rank test, p = 0.038). The two-year OS value of the AZA + Dasatinib group is better than the AZA group (90% versus 79.5%). DFS did not differ between the groups (p=0.65). In terms of AEs, hematological AEs occurred in 65% (13/20) of the AZA group versus 90% (9/10) of the AZA + Dasatinib group (p=0.210), with grade ≥4 events at 20% in both groups. Non-hematological events were 20% (4/20) in the AZA group versus 40% (4/10) in the AZA + Dasatinib group (p=0.384), with no serious non-hematological events reported. Conclusions AZA in combination with low-dose Dasatinib as a maintenance treatment exhibits promising efficacy and is well-tolerated compared with AZA monotherapy in intermediate and high-risk AML patients. This combination may be a novel treatment option for AML patients.