Omacetaxine and Azacitidine for Newly Diagnosed Patients with Myelodysplastic Syndromes and Excess Blasts
Authors: Pollyea Daniel A , Stevens Brett M , Abbott Diana , Amaya Maria L , Gutman Jonathan , Kent Andrew , McMahon Christine M. , Schwartz Marc , Smith Clayton , Dell-Martin Jessica , Sohalski Connor , Ellis Alexandra , Haag Mary , Schowinsky Jeffrey , Pan Zenggang , Patel Sweta B , Ransom Monica , Gillen Austin E , Pietras Eric M. , Jordan Craig T 
Published: December 2024

Background
Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB) have poor long-term outcomes. Hypomethylating agents (HMA) are the only approved therapies; more efficacious and rationally designed treatment are needed. Previously we identified a stem cell population in MDS and reported its unique dependency on protein synthesis. This led us to design a phase 1/2 study of the protein synthesis inhibitor omacetaxine mepesuccinate (oma) with the HMA azacitidine (aza) for newly diagnosed MDS-EB. We report clinical outcomes and detailed correlative data from this single-institution trial (NCT03564873).
Methods
Subjects were eligible if they had MDS-EB, no prior therapy and adequate organ function. Aza 75 mg/m2 was administered d1-7. Oma was administered subcutaneously BID d1-7. Three oma dose escalation cohorts (0.75 mg/m2, 1.0 mg/m2, 1.25 mg/m2) with a de-escalation cohort (0.5 mg/m2) were planned in a 3+3 design. Responders who tolerated therapy could continue to receive serial treatment cycles. Non responders, those who progressed, had significant treatment related toxicity or proceeded to allogeneic stem cell transplantation (ASCT) came off study. Correlative endpoints used techniques detailed below.
Clinical Results
Nine subjects were required to complete phase 1. The median number of cycles was 2 (1-3). Two of the first 3 subjects in cohort 1 experienced DLT (grade 3 hypoxia/grade 4 respiratory failure), requiring de-escalation. In cohort 0, 1/6 had DLT (grade 4 GI bleed/grade 3 gout). The MTD was 0.5mg/m2 SC oma BID d1-7 with aza. Fifteen additional subjects enrolled at the MTD. Of the 24 total, median age was 70, median blasts were 10% and median IPSS-M score was 1.5. The most common grade &gt;2 AEs were leukopenia (N=14), thrombocytopenia, (N=14) anemia (N=9), and febrile neutropenia (N=9); the most common SAEs were febrile neutropenia (N=9), infection/pneumonia (N=5), fever (N=3) and sepsis (N=3). There were two grade 5 events, both sepsis. The overall response rate was 15/24 (63%) with 4 complete remissions. Responses occurred after a median of 1 cycle (1-3). Hematologic improvement (HI) occurred in 10/24 (42%). The median number of cycles was 1 (1-3). Ten subjects were bridged to ASCT; of these 2 relapsed after transplant. Five responders did not bridge to transplant; 3 died of disease progression. Five of 15 responders experienced disease progression; median response duration was 621 days (19-1771) and median progression free survival was 125 days (35-1806). Fifteen subjects have died, from disease progression (N=9), ASCT related mortality (N=3), sepsis (N=2) and pulmonary hypertension (N=1); median overall survival was 438 days.
Correlative Studies
To gain insight into factors associated with responses, we profiled baseline marrow specimens from responders (N=7) and non-responders (N=5) at single-cell resolution using flow cytometry and Cellular Indexing of Transcriptomes and Epitopes (CITE)-seq. CITE-seq from malignant stem cell populations showed responders had increased protein synthesis signatures, consistent with our preclinical studies, as well as enrichment for NF-kB and pro-inflammatory pathways. In contrast, non-responders had elevation of several metabolic pathways associated with cellular energetics, indicating a fundamentally distinct physiological state that we hypothesize influenced therapeutic response to this regimen.
Conclusions
Oma/aza in newly diagnosed MDS-EB can be safely administered; higher and more rapid rates of response and HI were observed compared to expectations for HMA alone. A significant number of patients were successfully bridged to ASCT and they had generally favorable long-term outcomes. Given the rapid responses and likelihood of progression without a transplant, oma/aza might best be utilized as a bridge to ASCT for appropriate patients. Correlative studies revealed significant inter-patient heterogeneity in the baseline stem cell population demonstrating two molecular phenotypes, one of which, involving increased protein synthesis and inflammation, was responsive to oma/aza. Collectively, our data identify oma/aza as a promising stem cell-directed therapy for newly diagnosed MDS-EB.