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

Summary

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/m² was administered daily and oma twice daily days 1–7. Oma was escalated in three cohorts: 0.75 mg/m², 1.0 mg/m² and 1.25 mg/m², with a de-escalation cohort (0.5 mg/m²), 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/m²; 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.

Research in context.

Evidence before this study

This clinical trial is the first to combine the protein synthesis inhibitor omacetaxine mepesuccinate with azacitidine for previously untreated patients with myelodysplastic syndromes (MDS) with excess blasts (EB). We searched PubMed and ClinicalTrials.gov from July 1, 2014 to December 1, 2024 for prior evidence of such a combination in this population and did not find any that met these search criteria. The clinical trial was developed based on pre-clinical data suggesting this combination could be effective in this population. This paper, published September 12, 2018, showed that protein synthesis inhibition could target MDS stem cells and inspired this clinical strategy.

Added value of this study

With this study we follow up on a promising hypothesis related to a new therapeutic direction, the targeting of an MDS stem cell population through protein synthesis inhibition, with a clinical trial in patients with this disease. We have detailed the toxicity profile of a novel drug combination, established the recommended dose for future studies, and report preliminary efficacy of this combination.

Implications of all the available evidence

It is possible to use omacetaxine mepesuccinate with azacitidine to target a malignant stem cell population in MDS with excess blasts. Further studies with this regimen or other similar regimens can now be planned or designed to potentially understand this mechanism, and how it can positively impact patients more optimally while avoiding adverse events.

Introduction

Patients with myelodysplastic syndromes (MDS) with excess blasts (MDS-EB)¹ have poor long term outcomes.² Currently the only approved therapeutic option for these patients is a hypomethylating agent (HMA). The HMA azacitidine (aza) was superior to best supportive care for high-risk, newly diagnosed MDS-EB patients, but efficacy with this agent is limited: the overall response rate (ORR) was 29% with a complete remission (CR) rate of 17%.³ In addition, a median time of 64 days to achieve a response was required.⁴ More potent, effective and rationally designed therapeutic strategies for this disease are needed. Recently, we determined that the BCL-2 inhibitor venetoclax targets the leukemia stem cell (LSC) compartment of a related myeloid malignancy, acute myeloid leukemia (AML).⁵ Widespread use of this agent has resulted in frequent, deep and durable remissions for patients with this disease.⁶ Given the biological similarities between AML and MDS-EB,⁷ we investigated whether a stem cell population exists in MDS-EB; we were indeed able to identify these cells, and found they showed distinct activation of oxidative phosphorylation and protein synthesis machinery. Furthermore, targeting protein synthesis showed eradication of the MDS stem cell population in primary patient specimens.⁸ This observation led us to design this phase 1/2 study of the protein synthesis inhibitor omacetaxine mepesuccinate (oma) with aza for untreated patients with MDS-EB. Here we report the clinical outcomes of this novel therapeutic combination.

Methods

Patients were eligible if they had MDS-EB, no prior therapy with a hypomethylating agent, an Eastern Cooperative Oncology Group performance status⁹ of ≤2, adequate organ function, and no uncontrolled diabetes or systemic infection. All patients received antimicrobial prophylaxis.

Aza 75 mg/m² intravenously was administered daily on days 1–7. Oma was administered subcutaneously (SC), twice daily, on days 1–7. A cycle was defined as a 28-day period. There were three planned dose escalation cohorts of oma; 0.75 mg/m², 1.0 mg/m² and 1.25 mg/m², with a dose de-escalation cohort (0.5 mg/m²). Dose escalation to find the maximum tolerated dose (MTD) was performed in a 3 + 3 fashion in which the first three patients were assigned to cohort 1; in the absence of dose limiting toxicity (DLT), escalation to the next cohort was permitted. If one of the first three patients in a cohort had DLT, a total of six patients were enrolled in that cohort; the cohort in which >1 patient experienced DLT was the maximally administered dose. The MTD was the cohort in which ≤1/6 patients had a DLT event. DLT was defined as the occurrence, in the first cycle of treatment, of: grade ≥3 non-hematologic toxicity, excluding grade ≥3 infection, fever or electrolyte abnormalities that resolved to < grade 2 in <72 h; absolute neutrophil count <500/μL or platelet count <10 × 10⁹/L for >42 days in cycle one for patients who achieved a CR or marrow CR; any treatment related death.

Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Serious AEs (SAEs) were defined as AEs that were life threatening, or resulted in death, hospitalization or prolongation of hospitalization. Bone marrow biopsies occurred at baseline, cycle 1 day 8, cycle 1 day 28 and again at the conclusion of cycle 4, 6 and every 6 cycles thereafter. Response assessments, hematologic improvement and transfusion independence were protocol defined per the 2006 International Working Group (IWG)¹⁰; for this report we have also updated these definitions using the 2023 version.¹¹ Patients who responded and tolerated therapy could continue to receive sequential cycles of treatment indefinitely. Those who did not respond, progressed, had significant treatment related toxicity or proceeded to allogeneic stem cell transplantation (ASCT) came off the study.

Statistics

Kaplan–Meier survival analysis was used to calculate median survival times and accompanying 95% confidence intervals for overall survival (OS), progression-free survival (PFS), and duration of response among responders. OS was defined as time between the baseline assessment date and death date, or censor date for patients still alive. PFS was defined as time between the baseline assessment and date of relapse, date of death, date of first assessment among non-responders, or date of censoring among responders. Duration of response for responders was defined as time between the date of the first response and relapse or date of death. Reverse Kaplan–Meier analysis was used to calculate median follow-up time. For the phase II study, sample size was determined based on an alternative hypothesis of an ORR of 40% compared with a null hypothesis of a 20% ORR,¹² using a Simon two-stage minimax design for phase II studies,¹³ with a significance level of 0.05 and a power of 80%. The primary objective of Phase 1 was to determine the MTD of oma in combination with aza; the primary objective of phase 2 was to determine the ORR of the combination.

Ethics

This single-institution investigator-initiated protocol was approved by the Colorado Multiple Institutional Review Board (#17-2215) and is included as a Supplemental file; patients were treated in accordance with the Declaration of Helsinki and the study was registered at clinicaltrials.gov (NCT03564873). Informed consent was obtained from all study patients.

Role of funding sources

Teva provided oma and financial support for the clinical trial and had input into the study design. Teva and other funding sources had no additional roles in the study, including data collection, analysis, interpretation or writing of the manuscript.

Results

Between September 2018 and March 2024, 24 patients were enrolled (Fig. 1). Nine patients were required to complete the phase 1 study. Baseline factors are listed in Table 1. Ten (42%) were male. The median age was 70 (range 53–80) and the median baseline blast percentage was 10% (range 6%–17%). The median molecular international prognostic scoring system (IPSS-M)¹⁴ score was 1.51 (very high risk) and 4 (17%) had TP53 mutations. Per the revised IPSS,¹⁵ cytogenetics were classified as good (N = 5), intermediate (N = 7), poor (N = 2) and very poor (N = 10). Four had MDS with increased blasts (IB)1 and 15 had MDS-IB2.¹⁶

Fig. 1.

CONSORT flow chart.

Table 1.

Baseline characteristics of all patients and their outcomes.

Patient	Age	Sex	Cohort	Baseline Blasts (%)	WHO Classification	Mutations (VAF%)	Cyto Category per IPSS-R	IPSS-M	Best Response Per 2006 IWG	Best Response Per 2023 IWG	Bridged to Transplant with Study Therapy	Relapse
001	74	M	1	12	MDS-IB2	STAG2 56% U2AF1 44%	Intermediate	1.79 (Very High)	Marrow CR	No Response	Y	N
002	76	M	1	7	MDS-IB1	RUNX1 9% U2AF110% BCOR 23% STAG2 22%	Good	1.66 (Very High)	Marrow CR with HI	CRL (CRuni)	Y	N
003	61	F	1	7	MDS-IB1	None	Very Poor	1.22 (High)	Marrow CR with HI	CRL (CRuni)	N	Y
004	70	F	0	9.5	MDS-IB2	ASXL1 34% SRSF2 42% STAG2 30%	Intermediate	1.18 (High)	Marrow CR with HI	CRL (CRbi)	Y	N
005	57	M	0	13	MDS-IB2	DNMT3A 45% SETBP1 48% SRSF2 47% TET2 45% SCF3R 60%	Poor	2.52 (Very High)	Marrow CR	CRL (CRuni)	Y	N
006	70	F	0	10	MDS-IB2	RUNX1 8% PHF6 7%	Very Poor	0.65 (High)	No response	No Response	N	N/A
007	73	M	0	13.5	MDS-IB2	SF3B1 20%	Intermediate	0.45 (Moderate Low)	CR	CR	Y	N
008	74	F	0	11	MDS-IB2	TP53 44%	Very Poor	1.04 (High)	Marrow CR	CRL (CRuni)	N	Y
009	73	M	0	8	MDS-IB1	DDX41 17% DDX41 22% DDX41 51% JAK2 15% CBL 5%	Good	0.72 (High)	Marrow CR	CRL (CRuni)	Y	N
010	71	F	Expansion	17	MDS-IB2	ASXL1 9% CBL 12% CBL 11% SF3B1 35%	Poor	3.15 (Very High)	No Response	HI-N	N	N
011	76	M	Expansion	15	MDS-IB2	TET2 35% NF1 25% NF1 19% SRSF2 32% ASXL1 28% TET2 33%	Good	0.48 (Moderate High)	Marrow CR	CRL (CRuni)	N	Y
012	70	F	Expansion	13	MDS-IB2	NRAS 10% NRAS 10% TP53 63%	Very Poor	3.76 (Very High)	No Response	No Response	N	N/A
013	75	F	Expansion	7.5	MDS-IB1	TP53 55% DNMT3A 31%	Very Poor	1.11 (High)	No Response	No Response	N	N/A
014	70	M	Expansion	12	MDS-IB2	ASXL1 43% RUNX1 48% CSF3R 48%	Very Poor	1.34 (High)	No Response	No Response	N	N/A
015	59	M	Expansion	10	MDS-IB2	U2AF1 26% BCOR 19% ETV6 11%	Intermediate	1.30 (High)	Marrow CR	No Response	Y	N
016	69	F	Expansion	6	MDS-IB1	DNMT3A 42% TP53 73% U2AF1 43%	Very Poor	3.64 (Very High)	No Response	No Response	N	N/A
017	53	F	Expansion	10	MDS-IB2	No Mutations	Intermediate	1.06 (High)	No Response	No Response	N	N/A
018	80	M	Expansion	15	MDS-IB2	NRAS 6% DNMT3A 20% U2AF1 30% BCORL1 33% RUNX1 19% BCOR 31%	Good	3.30 (Very High)	CR	CR	Y	N
019	63	M	Expansion	12	MDS-IB2	KIT 17% NRAS 19%	Intermediate	1.51 (Very High)	Marrow CR with HI	CRL (CRuni)	N	Y
020	70	F	Expansion	10	MDS-IB2	TP53 46%	Very Poor	1.71 (Very High)	CR	CR	Y	Y
021	70	F	Expansion	10	MDS-IB2	TET2 47% TET2 13% RUNX1 20% DNMT3A 44% CEBPA 35% BCOR 43% CALR 50%	Good	2.02 (Very High)	No Response	No Response	N	n/a
022	63	M	Expansion	9	MDS-IB1	SF3B1 40% TP53 78%	Very Poor	2.66 (Very High)	Marrow CR	No Response	Y	Y
023	62	F	Expansion	10	MDS-IB2	TP53 35% TP53 36%	Very Poor	3.26 (Very High)	No Response	No Response	N	n/a
024	76	M	Expansion	15	MDS-IB2	No Mutations	Intermediate	1.51 (Very High)	CR	CR	N	N

EB = excess blasts; IPSS-R = revised international prognostic scoring system; CR = complete remission; HI = hematologic improvement; CR_L = CR with limited count recovery; CR_uni = unilineage; CR_bi = bilineage; N/A = not applicable due to not having had a response; WHO = World Health Organization; MDS-IB1 = MDS with increased blasts 1; MDS-IB2 = MDS with increased blasts 2; VAF% = variant allele frequency %.

Two patients experienced DLT events (grade 3 hypoxia and grade 4 respiratory failure) within the first three enrolled in cohort 1, requiring de-escalation to cohort 0. In cohort 0, 1/6 patients had a DLT event (grade 4 gastrointestinal bleed and grade 3 gout flare, occurring in the same patient). Therefore, the MTD was established as 0.5 mg/m² SC omacetaxine BID on days 1–7 along with azacitidine 75 mg/m² IV daily on days 1–7. Fifteen additional patients were enrolled at the MTD; all 24 are presented in the safety and efficacy analysis and detailed in Table 1. Five-hundred-and-six AEs were reported, including 36 SAEs. The most common grade >2 AEs regardless of attribution were thrombocytopenia (N = 17), anemia (N = 11), neutropenia (N = 8) and febrile neutropenia (N = 6); the most common SAEs were febrile neutropenia (N = 6), infection/pneumonia (N = 5), fever (N = 3) and sepsis (N = 3). There were two grade 5 events, both due to sepsis and deemed unrelated; one patient died within 30 days of treatment of sepsis and one patient died within 60 days of treatment from disease progression. Grade >2 AEs are listed in Table 2.

Table 2.

Grade > 2 adverse events and serious adverse events, regardless of attribution, and the number of patients who experienced each event.

Event	Grade 3	Grade 4	Grade 5
Hematologic adverse events
Thrombocytopenia	10	7	0
Febrile neutropenia	5	1	0
Anemia	10	1	0
Neutropenia	3	5	0
Non-hematologic adverse events
Systemic inflammatory response syndrome/Sepsis	1	4	2
Pneumonia	2	1	0
COVID-19 infection	1	0	0
Sinusitis	1	0	0
Skin infection	2	0	0
Urinary tract infection	1	0	0
Stridor	1	0	0
Hypoxia/respiratory failure/dyspnea	5	1	0
Acute kidney injury	2	0	0
Dysphagia	2	0	0
Hypotension	4	0	0
Hypertension	1	0	0
Hypophosphatemia	3	0	0
Hypocalcemia	1	0	0
Hypokalemia	1	0	0
Hyponatremia	2	0	0
Hyperglycemia	1	0	0
Arthralgia	1	0	0
Cardiac arrythmia	2	0	0
Edema	2	0	0
Gout	1	0	0
Encephalopathy	2	0	0
Fatigue	2	0	0
Chest pain	0	1	0
Fever	2	0	0
Intracranial hemorrhage/stroke	2	0	0
Gastrointestinal bleed	1	1	0
Muscle weakness	0	1	0
Pleural effusion	0	1	0

Highest grade of each event per patient is recorded once.

The median follow up time for all patients was 3.5 years (95% confidence internal [CI] 1.8, 4.9). Per 2023 IWG criteria,¹¹ the ORR was 13/24 (54%) with N = 4 CR, N = 8 CR with limited count recovery (CR_L) and N = 1 Hematologic Improvement. Using 2006 IWG¹⁰ criteria, the ORR was 15/24 (63%) (Table 3). The median total number of cycles received was 1 (1-3). Responses occurred quickly, after a median of 1 cycle (1-3). Ten patients were bridged to ASCT due to responses that occurred as a result of oma/aza; of these, 2 have relapsed. A total of 6/15 (40%) responders experienced disease progression. Of the 9 non-responders per 2006 IWG criteria, 8 received second-line salvage therapy. Seven received venetoclax with azacitidine; one received intensive chemotherapy with fludarabine, cytarabine, growth factor and idarubicin (FLAG-Ida). Six proceeded to ASCT. Median response duration was 2 years (95% CI 73 days, Not Reached). Using 2023 IWG response criteria, median progression free survival was 92 days (95% CI: 41, 611) (Fig. 2, left). Fifteen patients have died, from disease progression (N = 9), transplant related mortality (N = 3), sepsis (N = 2) and pulmonary hypertension (N = 1). Median OS was 1.5 years (Fig. 2, right); 3 years for those who had an ASCT and 7.3 months for those who did not. Individual patient outcomes are summarized in Fig. 3.

Table 3.

Responses.

	2006 IWG Criteria	2023 IWG Criteria
Complete remission	4 (17%)	4 (17%)
Complete remission with limited count recovery (CRL)	N/A	8 (33%)
CR Bilineage (CRbi)	N/A	1 (4%)
CRL Unilineage (CRuni)	N/A	7 (29%)
Hematologic improvement-neutrophil response	N/A	1 (4%)
Marrow CR	11 (46%)	N/A
Erythroid Response	3	N/A
Platelet Response	2	N/A
Neutrophil Response	0	N/A
Overall response	15 (63%)	13 (54%)
No response	9 (38%)	11 (46%)

Fig. 2.

Outcomes of phase 1/2 clinical trial of omacetaxine and azacitidine for previously untreated myelodysplastic syndrome with excess blasts patients. A) Progression-free survival; B) overall survival.

Fig. 3.

Swim lane plot showing individual patient response and outcomes. CR = complete remission; CR_L = CR with limited count recovery; CR_uni = unilineage; CR_bi = bilineage; HI-N = hematologic improvement, neutrophils.

Discussion

Effective treatment of MDS-EB remains a major challenge.^2,17, 18, 19, 20, 21 Standard-of-care regimens employing HMAs exhibit suboptimal response rates and require a median of 4–6 cycles to achieve,^3,22,23 indicating that HMAs alone are unlikely to effectively target the malignant stem cells that serve as a reservoir for disease. However, recent efforts to add therapies to an HMA backbone in newly-diagnosed higher-risk MDS have not succeeded. A study that randomized patients to receive aza, aza with lenalidomide or aza with vorinostat did not result in improved response rates.²⁴ The addition of the NEDD-8 activating enzyme inhibitor pevonedistat with aza did improve response rates but not event-free survival.²⁵ The TP53 targeting therapy eprenetapopt,²⁶ T-cell immunoglobulin domain and mucin domain −2 (TIM-3) inhibitor sabatolimab²⁷ and CD47-targeting monoclonal antibody magrolimab²⁸ also either failed definitive studies or are no longer being developed. Currently, a definitive trial of the BCL-2 inhibitor venetoclax with aza awaits publication (NCT04401748); the phase 1b results were recently published and were promising²⁹ but a press release on June 16, 2025 stated the study did not meet its primary endpoint of OS. Notably, venetoclax has stem-cell targeting properties in AML,^5,30,31 and therefore, we focused on the augmentation of aza backbone therapies with novel strategies to target MDS stem cells.

Therefore, to rationally investigate other potential aza partners we exhaustively characterized the biological properties of primary human MDS stem cell populations.⁸ We established that MDS stem cells exhibited high rates of protein translation and, using the translation inhibitor omacetaxine mepesuccinate in preclinical in vivo models of high-risk MDS, showed specific targeting of MDS stem cells that significantly augmented the activity of aza,⁸ hence providing preclinical rationale for our trial. In this pilot study, we were able to establish the MTD of this combination. Response rates of roughly 50% in this small series would favorably compare to historical studies establishing aza as the standard of care^3,4 and more recent control arms that have employed aza alone.^25,27 A relatively high rate of patients proceeded to ASCT but despite this, there are few long-term survivors. This may be a reflection of the small sample size and relatively high-risk population. However, it is notable that three patients died of transplant-related mortality. While no obvious associations with this outcome and the study exist, there may be as-yet unknown associations.

Those who proceeded to ASCT had a longer OS; these patients had a higher response rate (70%) than those who did not proceed to ASCT (43%). The median number of cycles administered is lower than other studies; patients moved quickly to ASCT in some cases, and in others, once they achieved remission, were maintained on aza alone.

This was a small, single-center study, and these results would need to be investigated in a larger population for more enthusiasm to be reasonable. In addition, the toxicity impact of adding a second agent to HMAs in this population can be considerable, and was a limitation in this trial. However, employing this type of stem-cell directed strategy to a group of MDS-EB patients who are being steered toward ASCT, allowing for ideally deeper pre-ASCT responses that can translate into better post-ASCT options, could be viable.

Contributors

DAP designed the clinical trial, recruited and treated patients, verified the underlying data and contributed to data analysis. DA led data analysis and verified the underlying data. MA, JAG, AK, CM, MS, CS, JD-M, CS and recruited and treated patients and contributed to data analysis. JD-M and CS verified the underlying data. MH, JS and ZP contributed data. BMS, SBP, MR, AG, CTJ and EMP performed correlative work and related data analysis. DAP, EMP, BMS and CTJ wrote and edited the manuscript. All authors read and approved the final version of the manuscript.

Data sharing statement

Data collected for this study, including de-identified individual patient data and a data dictionary defining each field in the set, can be made available on reasonable request and after signing appropriate data sharing agreements. Please send data access requests to the corresponding author. Such requests must be approved by the respective ethics boards and appropriate data custodians.

Declaration of interests

Teva supplied omacetaxine and financial support for the clinical trial in the form of payments made to the University of Colorado. CS receives salary and equity for OncoVerity and consulting fees from RefinedScience. CM served on an advisory board for Syndax and Kura and serves on a safety monitoring committee for Kura. DA has served on a data safety monitoring board for Merck. DAP received consulting fees from Abbvie, Gilead and Syros.