OncLive recently interviewed Daniel Pollyea, MD, MS, about the current treatment landscape for higher-risk myelodysplastic syndromes (HR-MDS), along with exciting new data from a Phase 2 trial of pevonedistat plus hypomethylating agent (HMA) azacitidine. Pollyea touched on many aspects of the existing therapies for this rare disease. He also highlighted the importance of this possible new treatment option, labeling it as a “glimmer of hope.”

Interviewing Daniel Pollyea, MD, MS

Pollyea is the clinical director of Leukemia Services at the University of Colorado and the UCHealth Blood Disorders and Cell Therapies Center. He spoke with OncLive about the current treatment options for HR-MDS patients, starting with HMAs.

These treatments are the current standard of care for MDS patients with recently diagnosed or relapsed disease, along with those with lower- and higher-risk disease. In fact, HMAs are typically the only option for the majority of MDS patients. This is disheartening when considering their low efficacy.

The interview then moved on to transfusions and their role in the treatment of MDS. Pollyea labeled them as “very important,” noting how they improve patients’ quality of life (QOL), extend lives, and even save lives. While they are helpful in supportive care, it is also necessary to point out their flaws. Patients often do not prefer transfusions due to the hours they must spend at facilities.

Because of this, doctors aim to treat their patients to the point where they no longer require transfusions. When MDS patients achieve this goal, their QOL typically improves.

Unmet Needs

Unfortunately, MDS patients as a whole face an unmet medical need regardless of relapse, time of diagnosis, and disease risk. Pollyea did acknowledge that lower-risk MDS patients do have the FDA-approved option Reblozyl, so these patients may face less of an unmet need. However, there must be improvements in MDS research as a whole.

Promising Therapies

While there is an unmet need for MDS patients, there are a number of therapies currently in development that seem promising. A Phase 3 study is evaluating Venetoclax paired with azacitidine, and it has shown positive results for newly diagnosed HR-MDS patients. Additionally, preliminary data points to this combination as a viable option for HMA-failure MDS.

Magrolimab is a CD47-directed antibody that has shown positive results in preliminary trials, pointing to another possible treatment options for MDS patients. Pollyea then brought up pevonedistat, which is very exciting in regard to its ongoing research.

Pevonedistat for MDS

Medical professionals are very excited by the results they have seen in trials of pevonedistat plus azacitidine. This first-in-class NEDD8-activating enzyme inhibitor was shown to be more effective when combined with azacitidine than when azacitidine was administered alone.

The Phase 2 study’s primary endpoint was event-free survival (EFS), which sits at 21 months for patients with HR-MDS/chronic myelomonocytic leukemia and low-blast acute myelogenous leukemia (AML) taking pevonedistat plus azacitidine. This can be compared to 16.6 months in the patients receiving only azacitidine. Further results include:

• Overall survival of 21.8 months for the pevonedistat group vs. 19 months in the azacitidine group
• Tolerable safety profile
• Promising response rate and duration of response data

These data points are very exciting, and other research has even pointed to pevonedistat’s possible utility in AML treatment. In the end, medical professionals and patients alike cannot wait to see the future of this treatment combination.

Looking Forward

Pollyea stated that if pevonedistat receives FDA approval, it will most likely be used in combination with HMAs. All studies to date have evaluated the investigational treatment plus an HMA. At the end of the day, “we are stuck with HMAs as the backbone,” says Pollyea.

About MDS

MDS are a group of conditions that stop the bone marrow from producing the correct amount of blood cells. Medical professionals aren’t exactly sure why this happens, but they suspect that a genetic predisposition plays a role, as do environmental triggers like chemotherapy or exposure to certain chemicals. Symptoms include shortness of breath, chest pain, heart palpitations, pale skin, easy bruising and bleeding, and being more prone to infection. MDS also often progresses into acute myeloid leukemia (AML).