Omacetaxine and Venetoclax Show Benefits in MDS, No Improvement in AML

A phase 1b/2 trial (NCT04874194) revealed that the combination treatment of omacetaxine and venetoclax (Venclexta) in patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with RUNX1 mutation showed safety but no statistically meaningful benefits in the AML arm. However, the combination proved clinical benefit in the MDS arm.¹

A total of 24 patients were enrolled in the study (n = 22 with AML; n = 2 with MDS). The median age of patients was 72, and 71% of patients were male. The RUNX1 mutation was confirmed in all patients, with a median variant allele frequency of 41%. Of the total patients, 5 had 2 RUNX1 mutations and 1 patient had 3 distinct RUNX1 mutations.

Of the 21 efficacy-evaluable patients, 19 had AML and 2 had MDS. None of the 19 patients with AML responded to omacetaxine and venetoclax. The 2 patients with MDS both responded, achieving complete response (CR) with unilineage and bilineage recovery, respectively.

The median overall survival (OS) among the total number of patients was 4 months (95% CI, 3–9), and the 1-year OS rate was 17% (95% CI,7%–41%).

Patients received a median of 1 cycle of omacetaxine and venetoclax therapy, and treatment was generally well-tolerated. The most common treatment-related adverse events (AEs) of any grade included infections and fatigue. There were no tumor lysis syndrome events reported. Mortality rates at 30 and 60 days were 8% and 21%, respectively. All deaths within 60 days were attributable to progressive AML.

Patients were treated with 1.25 mg of omacetaxine daily for 3 days and 400 mg of venetoclax daily for 14 days.

Co-occurring mutations in patients were common, specifically in ASXL1 (46%), SRSF2 (33%), TET2 (33%), and PTPN11 (21%). The median number of mutations per patient, including RUNX1, was 5.

The majority of patients with relapsed/refractory AML (64%) were considered secondary AML due to either therapy-related AML in 9 patients and/or antecedent hematologic neoplasm in 12 patients. The 2 patients with MDS were classified as MDS with excess blasts 1 and 2, respectively.

Patients were heavily pretreated, with a median number of 4 previous lines of therapy.

“Consistent with the responses seen in the 2 patients with RUNX1 MDS treated with [omacetaxine and venetoclax], our correlative data demonstrate that MDS cells harboring RUNX1 are preferentially sensitized to the in vivo [omacetaxine]-mediated protein translation inhibition,” wrote DiNardo et al, authors of the study.¹ 

A phase 1 study (NCT04926285)² is currently evaluating the safety and efficacy of venetoclax with escalating doses omacetax in patients with AML.

The authors concluded that the results from this trial should encourage further research into OM-based combinations in myeloid malignancies, specifically in patients with a RUNX1 mutation in MDS, and less in patients with heavily pretreated RUNX1 mutation in AML.¹ 

REFERENCES:

1.DiNardo C, Jen WY, Montalban-Bravo G, et al. Omacetaxine and venetoclax in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome with mutant RUNX1. Blood Neoplasia.2025;2(4):100145.doi:10.1016/j.bneo.2025.100145

2.Safety and Efficacy of Venetoclax With Escalating Doses of Omacetaxine in Patients With Acute Myeloid Leukemia Safety and Efficacy of Venetoclax With Escalating Doses of Omacetaxine in Patients With Acute Myeloid Leukemia (AML) (VEN-OM). ClincialTrials.gov. Updated June 8, 2025. Accessed October 27, 2025. https://clinicaltrials.gov/study/NCT04926285