Background Venetoclax, a B-cell lymphoma 2 inhibitor, has achieved encouraging outcomes in the treatment of acute myeloid leukemia (AML). Homoharringtonine (HHT), a natural plant alkaloid derived from Cephalotaxus, demonstrates a significant anti-leukemic efficacy in AML. We reported that the combination of Venetoclax, Homoharringtonine, and Azacitidine (AZA) has been shown to prolong overall survival and increase the remission rate in AML patients (Jun L, Blood Cancer J. 2022). In this study, we further explore the efficacy and tolerability of the combination of Venetoclax, Homoharringtonine, Azacitidine (VAH), and Cytarabine (VAHA) in newly diagnosed AML patients.

Methods The clinical study was performed at Zhongda Hospital, Institute of Hematology, Southeast University. The AML patients were enrolled and assigned to unfit and fit groups based on the Ferrara Criteria. Patients who were assigned to unfit groups received the VAH regimen with venetoclax (100 mg on days 1,200mg d2,400mg on days 3–14), azacitidine (75 mg / m2on days 1–5), and HHT(1 mg/ m2on days 1–5). Patients who were assigned to fit groups received VAHA therapeutic regimen received venetoclax (100 mg on days 1, 200mg d2,400mg d3–d14), AZA (75 mg / m2on days 1–7), HHT (1 mg/ m2on days 1–7) and cytarabine (15mg / m2on days 1–7). The primary endpoint was a composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and overall survival. 69 de novo AML patients who received IA/DA regimens in our center were enrolled as control group. Patients were sequencedby our reported targeted exome-seq for human leukemia driver genes (Jun L, Blood Cancer J. 2022)

Results A total of 77 newly diagnosed AML patients were enrolled from 12 August 2023 to 8 May 2025 in this clinical study, including 65(84.4%) de novo AML patients and 12 (15.6%) secondary AML patients. 48/29 patients received the VAH/VAHA regimen, respectively. The CRc rate was 77.1% (37/48) in patients who received the VAH regimen and 86.2% (25/29) in patients who received the VAHA regimen. In patients with ELN favorable, intermediate, or poor risk, the CRc rate was 75%, 75%, 78.6% for the VAH regimen and 100%, 100%, 69.2% for the VAHA regimen, respectively. Moreover, we compared the efficacy between de novo AML patients who received the VAHA and IA/DA regimens in our institute; a significantly higher CRc was observed in VAHA regimen vs IA/DA regimen (95.7% vs. 63.8%, P=0.003).

A total of 314 mutations of 48 genes were detected in the 77 patients before treatment. The median mutation number was 4 (range 1～12) per patient. The most frequently genetic mutations wereFLT3 (22/77,28.6%), DNMT3A (20/77,25.9%) and TET2 (18/77,23.4%). The VAH scheme achieved high CRc in patients with mutated U2AF1(4/4,100%), RUNX1(8/9,88.9%), IDH2 (7/8,87.5%), while the VAHA regimen achieved high CRc in patients with RUNX1 (3/3,100%), IDH2 (2/2,100%), NPM1 (6/6,100%), CEBPA (9/9,100%), DNMT3A (4/4,100%). Comparing the median variant allele frequency (VAF) in 29 paired patients with pre-treatment and post-treatment, the VAF of FLT3 (23.62%vs.0 %, P=0.006), NPM1(28.86 % vs. 0%, P=0.008), and CEBPA (38.15%vs.0 %, P=0.028) mutations were significantly decreased upon the treatment.

During a median follow-up of 399 (range 21～608) days, 24 (31.2%) patients died. The most common causes of death were relapse/disease progression (n=17,70.8%), and infections (sepsis[n=5], pneumonia[n=2]). Patients who received the VAHA regimen had a longer survival than those who received the VAH regimen (median OS: not reached vs.399 days (95%CI 132.22～532.78, P=0.044). Moreover, de novo AML patients who received the VAHA regimen had a longer survival (median OS: not reached vs.465 days(95%CI 346.29～583.71), P=0.041) and relapse-free survival (median RFS: not reached vs. 344 days (95%CI 346.29～583.71), P=0.047) than those who received IA/DA regimen in our institute.

All patients were well tolerated by the regimens. No therapy-related death occurred, and no patients had grade 3-4 cardiac adverse events.

Conclusion: Both the VAH and VAHA regimens achieve high CRc rates with well-tolerance in newly diagnosed AML patients. Our results reveal that the VAHA regimen may act as the first-line treatment of newly diagnosed AML patients who are not suitable for intensive therapy.

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2025
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