Work

Omacetaxine and azacitidine for untreated patients with myelodysplastic syndromes and excess blasts: a phase I/II clinical trial

Year: 2025

Type: article

Abstract: Background Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB) have poor long-term outcomes. Our preclinical studies showed MDS-EB stem cells are dependent upon protein synthesis. We designed a phase 1/2 clinical trial to examine the safety/efficacy of the protein synthesis inhibitor omacetaxine mepesuccinate (oma) with the hypomethylating agent (HMA) azacitidine (aza) for patients with untreated MDS-EB. Methods Enrollment occurred from September 2018 to March 2024 and the study was registered at clinicaltrials.gov (NCT03564873). The phase 1 primary endpoint was to determine the maximum tolerated dose (MTD) and the phase 2 primary endpoint was to determine the overall response rate. Aza 75 mg/m 2 was administered daily and oma twice daily days 1–7. Oma was escalated in three cohorts: 0.75 mg/m 2 , 1.0 mg/m 2 and 1.25 mg/m 2 , with a de-escalation cohort (0.5 mg/m 2 ), to find the maximum tolerated dose (MTD). Responders who tolerated therapy could continue sequential cycles. Those who did not respond, progressed, had significant toxicity or proceeded to allogeneic stem cell transplantation (ASCT) discontinued. Findings The MTD of oma was 0.5 mg/m 2 ; dose limiting toxicities included hypoxia, respiratory failure, gastrointestinal bleed and gout. Common adverse events included thrombocytopenia, anemia, neutropenia and febrile neutropenia. Overall response rate was 13/24 (54%) with four complete remissions (CR). Ten patients were bridged to ASCT. With median follow-up time of 3.5 years, median response duration and progression-free survival were 719 and 92 days, respectively. Median overall survival was 1.5 years. Interpretation The MTD of oma in MDS-EB has been established. Responses, including CRs, occurred rapidly. This therapeutic combination, conceived based on data that it targets the malignant stem cell population, could be further studied for patients with MDS-EB but high toxicity needs to be taken into account. Funding HYPERLINCI, Edward P. Evans Foundation, Leukemia and Lymphoma Society Career Development Program, VA Merit, V-Foundation.

Source: EClinicalMedicine

DOI: 10.1016/j.eclinm.2025.103546