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Phase 3 Trials in High-Risk MDS Highlight Future Directions


A recent review emphasizes a need for novel therapies, summarizes current phase 3 clinical trials, and suggests several considerations for future trials in high-risk myelodysplastic syndromes (MDS).

Although treatment with a hypomethylating agent (HMA) is the standard for patients with myelodysplastic syndromes (MDS), single-agent HMAs only partially impact the course of the disease. A review published in The Lancet Haematology emphasizes a need for novel agents or combinations, summarizes current phase 3 clinical trials for untreated high-risk MDS, and suggests several considerations for future trials.

MDS comprises a group of myeloid disorders characterized by bone marrow failure, causing peripheral blood cytopenia. MDS has the potential to transform into acute myeloid leukemia (AML), with patients classified as low-risk or high-risk based on the International Prognostic Scoring System or IPSS-Revised. These systems are based on blast percentages in bone marrow, severity of cytopenia, and the type of cytogenetic alteration present.

While MDS is complex, there is evidence in support of significant epigenetic deregulation as well as genes that are known to be mutated in patients with MDS. These findings have helped improve diagnosis, prognostication, and treatment decisions.

Three HMAs—azacitidine, decitabine, and oral decitabine-cedazuridine—are currently FDA approved for the treatment of MDS, with the most recent approval, decitabine-cedazuridine, in 2020. No novel drugs or combinations have shown better responses or overall survival outcomes in MDS compared with single-agent HMAs in randomized trials. Despite some promising phase 1 and phase 2 trial results, recent phase 3 trials of 2 combinations, eprenetapopt plus azacitidine and pevonedistat plus azacitidine, had negative results when compared with single-agent azacitidine.

The review, written by Guillermo Garcia-Manero, MD, chief of the myelodysplastic syndromes section in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, includes data surrounding 5 next-generation therapeutic combinations being tested in phase 3 trials, although only one study, the PANTHER trial of azacitidine plus the NEDD8 inhibitor pevonedistat (NCT03268954), is already published. Additional data included in the review were presented at meetings or included in press releases.

Azacitidine and the anti-TP53 agents such as eprenetapopt is one combination that showed significant clinical activity in phase 1 and phase 2 trials. However, results of a randomized phase 3 trial (NCT03745716) of 154 patients found that the complete response rate in the combination group was not significantly superior to that of the azacitidine monotherapy group.

Azacitidine and pevonedistat was safe and showed clinical activity in a phase 1 AML trial, and phase 2 results that included MDS patients led to the design of the PANTHER trial. While many expected this combination to outperform the single-agent azacitidine treatment group, it was not more effective than the monotherapy cohort group.

Azacitidine and venetoclax, a BCL-2 inhibitor, is a combination approved for use in AML that showed positive results in phase 1 research and is now being studied in the phase 3 VERONA trial (NCT04401748) with primary end points of complete remission (CR) and overall survival (OS).

The combination of azacitidine and the TIM-3–targeted immune checkpoint inhibitor sabatolimab is another treatment strategy that has shown clinical activity and is expected to have more results available in both MDS and AML soon. Initial data on azacitidine and magrolimab, an anti-CD47 antibody, were promising, and the ENHANCE trial (NCT04313881) aims to assess the end points of CR and OS.

Considering the negative outcomes reported in recent phase 3 research, Garcia-Manero also highlights potential pitfalls of the major ongoing phase 3 trials in the realm of MDS research and potential suggestions for future study designs. While he does not have access to detailed data from these studies, one possible pitfall was overestimated activity in early phase 1 and 2 research. Sample sizes, statistical assumptions, trial designs, and a lack of molecular stratification of MDS in these studies may also be contributing factors, he proposes.

To improve outcomes in future trials in high-risk MDS, Garcia-Manero suggests higher powered studies, as smaller trials such as the eprenetapopt and azacitidine trial have generally been less successful. Excluding CR as a main end point is another potential strategy to improve outcomes, as CR may not equate OS. The CR rate with HMA monotherapy in 2022 is also not clear, he notes. Finally, he recommends running blinded studies and designing studies for specific molecular subtypes of MDS and leaving those patients out of more general studies.

“If these recommendations were to be considered, it will be the responsibility of investigators, sponsors, and authorities to implement them in the design of clinical trials in high-risk myelodysplastic syndromes,” Garcia-Manero concluded.


Garcia-Manero G. Current status of phase 3 clinical trials in high-risk myelodysplastic syndromes: pitfalls and recommendations. Lancet Haematol. Published online October 7, 2022. doi:10.1016/S2352-3026(22)00265-4

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