A Study to Assess the Efficacy of Venetoclax Combined with Homoharringtonine and Azacitidine in De Novo Acute Myeloid Leukemia

Background: Venetoclax, a B-cell lymphoma 2 inhibitor, achieves encouraging results in acute myeloid leukemia (AML)(Cancers 2022; 14:3456). A combination of Venetoclax with Azacitidine (AZA), a hypomethylating agent prolongs the overall survival and increases the incidence of remission in AML (New Engl J Med 2020; 383:617). Homoharringtonine (HHT) is a cytotoxic alkaloid; we previously reported the Aza+HHT-based regimen is a cost-effective first-line therapy with high efficacy and good tolerance for elderly/unfit AML (Blood Cancer J 2022; 12: 145). This study aimed to evaluate the clinical efficacy and tolerability of Venetoclax combined with AZA and HHT-based regimens in patients with de novo AML.

Methods: A total of 23 de novo AML（non-APL) patients who received the treatment of Venetoclax with Aza+HHT-based regimens were enrolled for the study between August 2023 and March 2024 at Zhongda Hospital, Institute of Hematology Southeast University. Patients were assigned into unfit and fit groups based on Ferrara Criteria. The scheme for 9 fit patients: Venetoclax (100mg on day 1, 200 mg on day 2, 400 mg on days 3-14), AZA (75 mg/m² on days 1-7), HHT (1 mg/m² on days 1-7) and cytarabine (15mg/m² SC every 12 hours on days1-7) (VAHA regimen); for 13 unfit patients: Venetoclax (100mg on day 1, 200 mg on day 2, 400 mg on days 3-10), AZA (75 mg/m² on days 1-5) and HHT (1 mg/m² on days 1-5) (VAH regimen). Disease assessments were performed with the modified International Working Group response criteria for AML after one treatment cycle (J Clin Oncol 2003; 21:4642). Patients in remission are given appropriate consolidation therapy based on NCCN guidelines. Criteria of disease assessments, and methods for gene mutation screening are described in our previous report (Blood Cancer J 2022; 12: 145)

Results: Complete remission or complete remission with incomplete count recovery (CR/CRi) was achieved in 82.6% (19/23) of the patients in the whole cohort, 88.9% (8/9) in group VAHA, and 78.6% (11/14) in group VAH, respectively. CR/CRi was achieved in 78.6% (11/14) of patients with adverse risk, and 88.9% (8/9) in patients with favorable/intermediate risk according to 2022ELN. Notably, the CRR was 85.7% (6/7) and 71.4% (5/7) in the VAHA and VAH groups with adverse risk, respectively, suggesting that the unfit regimen is also effective in overcoming poor prognostic markers. With a median follow-up of 211 days (range 46-322), the VAHA regimen had 290 days of median OS (95% CI not reached) and median RFS has not yet been reached. The VAH regimen had 242 days of median OS (95%CI not reached) and 182 days of median RFS (95%CI,140.0-191.0).

Upon the cycle 1 of induction therapy, high CR/CRi rates are achieved in patients with gene mutations of ASXL1 (100%,4/4), KIT (100%,2/2), IDH1/2 (100%,5/5), DNMT3A (100%,7/7), CEBPA (100%,3/3), NPM1 (85.7%, 6/7), and FLT3-ITD (74%,3/4). Gene mutations were also screened in 74% (14/19) of patients in CR after the 1^st cycle of treatment. Results showed that variant allele fractions (VAF) of IDH2, CEBPA, and NPM1 mutations were much lower post-treatment versus pre-treatment. The mutations in the genes for adverse molecular markers such as ASXL1, FLT3-ITD, KIT, and U2AF1 were undetectable in CR patients. 52.6% (10/19) patients in CR reached MRD negative after cycle 1 of treatment. All patients were tolerated for the regimens, with myelosuppression as the most common adverse event. No therapy-related death occurred.

Conclusion: This study showed the high clinical efficacy of Venetoclax with Aza+HHT-based regimens in patients with de novo AML, particularly in high-risk unfit patients. Our results reveal that Venetoclax with Aza+HHT-based regimens may be a new option for first-line treatment of AML patients who were ineligible for intensive therapy.

No relevant conflicts of interest to declare.