Background: Primary refractory and relapsed/refractory acute myeloid leukemia (AML) are associated with dismal outcomes, posing great therapeutic challenges in AML management. This study aimed to evaluate the efficacy and safety of homoharringtonine (HHT) combined with venetoclax and azacitidine (VAH) in primary refractory and relapsed/refractory AML.

Methods: This retrospective study analyzed clinical data from 19 patients with primary refractory (non-response after first induction) or relapsed/refractory AML treated with the VAH regimen between March 2024 and July 2025 at our center. The VAH regimen included: venetoclax (oral; 100 mg Day1, 200 mg Day2, 400 mg Days 1-14), azacitidine (subcutaneous; 75 mg/m2 Days 1-7), and HHT (intravenous; 2 mg Days 1-5). Patients achieved complete remission (CR), CR with incomplete count recovery (CRi), partial remission (PR) or morphologic leukemia-free state (MLFS) received an additional cycle of VAH regimen. Patients achieving composite complete remission (CRc: CR + CRi) after two cycles proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT) if eligible and with a donor. Others received consolidation (VAH or high/intermediate-dose cytarabine) followed by maintenance as indicated. Primary endpoints were CRc and measurable residual disease (MRD) negativity (10-4). Secondary endpoints included relapse-free survival (RFS), overall survival (OS), and safety.

Results:Nineteen patients (median age 52 years, range 16-68) were included: 12 (63.2%) primary refractory and 7 (36.8%) relapsed/refractory. The overall CRc rate was 68.4% (13/19), 66.7% (8/12) in primary refractory AML and 71.4%(5/7) in relapsed/refractory AML. MRD negative was achieved in 42.1% (8/19) after VAH regimen therapy. According to the 2022 ELN risk stratification, 2 patients (10.5%) were classified as favorable, 2 patients (10.5%) as intermediate, and 15 patients (79.0%) as adverse-risk. The results of molecular subgroup analysis to CRc rate was 73.3% (11/15) in the ELN adverse-risk group. In the cytogenetic subgroups,CRc rate was 71.4% (5/7) in the poor-risk group. With VAH regimen, high CRc rates were achieved in patients with gene mutations of FLT3-ITD (100%, 3/3), ASXL1 (100%, 2/2), IDH2 (100%, 2/2), EZH2 (100%,2/2), KIT (75%, 3/4), DNMT3A (75%, 3/4), RUNX1 (66.7%, 2/3). These results suggestted that the VAH regimen significantly overcame the negative impact of poor prognostic markers. With a median follow-up of 135 days (95%CI, 115.8-154.2), 2 patients(10.5%) proceeded allo-HSCT. The median RFS was 108 days (95%CI: 50.5-165.5). Median OS was not reached. All patients tolerated the VAH regimen, the most common grade ≥3 AEs (CTCAE v5.0) included anemia (79.0%), neutropenia (68.4%), thrombocytopenia (63.2%), febrile neutropenia (52.5%), gastrointestinal reactions (26.3%), pneumonia (15.8%) and sepsis (10.5%). No treatment-related deaths occurred.

Conclusion: This study demonstrated high promising efficacy and safety of VAH regimen in primary refractory and relapsed/refractory AML patients, particularly in high-risk primary refractory and relapsed/refractory AML patients who were intolerant for intensive therapy. The VAH regimen significantly improved the response rates and overcome the negative impact of specific genetic patterns.

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2025
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