Combinations May Confer Benefit in MDS Management

Mikkael A. Sekeres, MD, MS

Although investigational agents are showing promise for patients with low-risk myelodysplastic syndrome (MDS), physicians are still seeking combinations that will enhance responses for patients with high-risk disease, explained Mikkael A. Sekeres, MD.

Azacitidine and decitabine are FDA approved for patients with low- and high-risk disease; however, Sekeres said that physicians are less reliant on hypomethylating agents for low-risk than they are for those with high-risk disease.

Checkpoint inhibitors have yet to show significant activity in the paradigm, but Sekeres cited antithymocyte globulin as an increasingly utilized immune approach for low-risk patients.

Additionally, phase III findings from the MEDALIST trial showed that patients with low-to-intermediate risk MDS who were refractory to or unable to receive an erythropoietin-stimulating agent (ESA) reported a significant improvement in red blood cell transfusion independence of at least 8 consecutive weeks of the first 24 weeks in those who received luspatercept versus placebo.¹ This was reported by the drug manufacturers, Celgene and Acceleron Pharma Inc, in June 2018. The companies plan to submit regulatory applications to the FDA in early 2019.

For high-risk patients, lenalidomide (Revlimid) and vorinostat were explored in combination with azacitidine, but the azacitidine-based combinations demonstrated similar efficacy to azacitidine alone.² An ongoing phase III trial, however, is evaluating the efficacy and safety of frontline pevonedistat and azacitidine versus azacitidine monotherapy in high-risk patients ineligible for transplant (NCT03268954).

“One of the biggest challenges with MDS is that it's a complicated disease,” said Sekeres. “We're going to have to continue to experiment with combination therapies and work with both doctors and patients at sticking with those therapies for multiple cycles to see whether or not they work.”

OncLive: How do physicians classify MDS?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Sekeres, professor of medicine, director, Leukemia Program, Cleveland Clinic Taussig Cancer Institute, discussed the characteristics of MDS and the evolving armamentarium of treatment.Sekeres: MDS is often divided into lower-risk and higher-risk categories. Patients who have lower-risk MDS often don't have a high blast percentage and have only 0 or 1 cytopenias. They have relatively good-risk cytogenetics, meaning a normal karyotype of -Y, deletion 5q, or deletion 20q. Patients who have higher-risk MDS often have excess blasts, multiple cytopenias, and poor-risk cytogenetics, which is defined as a chromosome 7 abnormality or complex cytogenetics.

We make this distinction because it is our way of staging MDS and determining what therapies people should receive. Those who have an isolated anemia might be treated with ESAs or even lenalidomide, particularly when they have the deletion 5q abnormality.

Some things on the horizon include the drug luspatercept, which is a TGF-beta inhibitor. In preliminary studies, it has been shown to have an overall response rate (ORR) of approximately 40% to 45%. We often treat patients with lower-risk MDS who have multiple cytopenias with truncated doses of hypomethylating agents. This comes from a study through the MDS Clinical Research Consortium, where we showed that patients who received 3 days of decitabine or 3 days of azacitidine had an ORR of about 50%.

What we have increasingly been doing is treating patients with multiple cytopenias and lower-risk disease with immune approaches such as anti-thymocyte globulin. A phase II study conducted in the United States and a phase III study conducted in Europe showed a response approximately one-third [of patients] that lasted for almost 1.5 years in patients with these MDS subtypes.

For those who have higher-risk disease, we tend to treat them with hypomethylating agents—– either azacitidine or decitabine. Azacitidine is the only drug that has been shown prospectively to improve overall survival (OS) in patients with higher-risk disease. We have participated in clinical trials in which we've added drugs to azacitidine to see if they work even better. Some of those drugs have included lenalidomide, which resulted in an ORR of almost 50% in patients with higher-risk disease. Additionally, these patients had a significantly higher ORR in patients with chronic myelomonocytic leukemia compared with azacitidine alone. There are ongoing trials with azacitidine and pevonedistat, which is a neddylation inhibitor.

Where is research headed now?

What is the role of stem cell transplant in this paradigm?

What are some of the biggest challenges with MDS?

There are also studies that are looking at combinations of the IDH inhibitors as well as studies that are looking at checkpoint inhibitors. Those studies will be presented at the 2018 ASH Annual Meeting.A lot of clinical trials are focusing on patients with MDS who have already been exposed to a hypomethylating agent. For patients with lower-risk disease who have already received a hypomethylating agent, their median survival is less than 1.5 years. Technically, we would say that they have lower-risk disease, but in truth based on their survival, it's closer to a higher-risk disease. Patients who have higher-risk MDS who have already been exposed to a hypomethylating agent have a median survival of 4.5 to 6 months. The future of clinical trials is going to focus on this group of patients who have already been treated with a hypomethylating agent, and frankly are quite desperate for a better therapy.For patients who have higher-risk disease, we discuss transplantation at diagnosis. Transplantation is the only cure for MDS. Though azacitidine may prolong overall survival, every therapy we have will ultimately fail our patients. We also will consider [transplant] in patients with lower-risk disease but who have high-risk molecular abnormalities, such as p53 or multiple molecular abnormalities.One of the biggest challenges with MDS is that it's a complicated disease. In chronic myeloid leukemia, the BCR-ABL translocation causes the leukemia, so it's reasonable to think that a drug could target that abnormality and make a significant impact on survival. In fact, that's what has happened with multiple tyrosine kinase inhibitors. With MDS, the typical patient at diagnosis may have 3, 4, or 5 molecular abnormalities, so to think that we can develop 1 drug that will target an abnormality is really full hearty.

References

1. Celgene and Acceleron announce luspatercept achieved primary and key secondary endpoints in phase III ‘MEDALIST’ study in patients with low-to-intermediate risk myelodysplastic syndromes. businesswire.com/news/home/20180628006306/en. Accessed October 9, 2018.
2. Sekeres M, Othus M, List A, et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol. 2017;35(24):2745-2753.