A Phase II Study of Omacetaxine Mepesuccinate for Patients with Higher-Risk Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia after Failure of Hypomethylating Agents

Abstract

Background: The outcome of patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4-6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. Methods: We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m2 subcutaneously every 12 hours for 3 consecutive days on a 4-7 week schedule. The primary endpoints were the overall response rate (ORR) and OS. Findings: Forty-two patients were enrolled with a median age of 76 years. The ORR was 33%. Patients with diploid cytogenetics were more likely to respond to OM than were those with cytogenetic abnormalities (58% versus 23%, respectively; P=0.03). Overall, the median OS was 7.5 months and 1-year OS rate was 25%. Patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 versus 6.8 months, respectively; P=0.01). Two patients had ongoing response to OM of 2 years or longer (both MDS with diploid cytogenetics and RUNX1 mutation). The most common grade ≥3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). Interpretation: Overall, OM was safe and active in patients with MDS or CMML who experienced HMA failure. These results support the further development of OM in this setting. Clinical Trial Registry: The trial was registered at ClinicalTrials.gov with the identifier NCT02159872. Funding: This trial was funded by the MD Anderson Cancer Center Support Grant CA016672. Disclosure of Conflicts of Interest: The authors report no relevant conflicts of interest. Ethics Approval Statement: This study was approved by the Institutional Review Board of The University of Texas MD Anderson Cancer Center.