Novel Agents Needed to Expand Treatment Options for Patients With High-Risk MDS

The monoclonal antibody magrolimab represents a potential step forward in the treatment of patients with high-risk myelodysplastic syndrome (MDS), where the current standard of care of azacitidine or decitabine fails to generate significant responses, according to Dan Pollyea, MD, MS.

Magrolimab will be evaluated in combination with azacitidine vs azacitidine alone in previously untreated patients with high-risk MDS in the phase 3 ENHANCE trial (NCT04313881). The novel agent is designed to block CD47, a key “do not eat me” signal that is often overexpressed on tumor cells, and the agent induces tumor phagocytosis and eliminates leukemia stem cells.1

“There’s a real acute need to do better and to develop more effective treatments for these [patients],” Pollyea said.

In an interview with OncLive^®, Pollyea, the clinical director of Leukemia Services, the Robert H. Allen, MD, chair in Hematology Research, and an associate professor of medicine in Division of Hematology at the University of Colorado School of Medicine, discussed the difficulties in developing new agents for the treatment of high-risk MDS, the objective of the ENHANCE trial, and the potential for other therapies to emerge in the treatment paradigm.

OncLive^®: What is the current treatment landscape for patients with high-risk MDS?

Pollyea: A newly diagnosed patient with high-risk MDS does need treatment. That is usually an established fact and does separate higher-risk MDS from lower-risk MDS, which sometimes doesn’t need to be treated and is unique among malignancies. But a newly diagnosed [patient with] high-risk MDS is typically treated with a hypomethylating agent, and there are two of those: azacitidine and decitabine. Those are the standard-of-care treatment approaches for this disease.

What are some of the most pressing needs for this patient population?

We, as a community, need to develop better treatments for this disease in this population because the standard of care, we can all acknowledge, is not sufficient for our expectations for these patients. Single-agent hypomethylating agents [such as] azacitidine and decitabine have lower response rates than we would like. They take a long time to work, if they are going to work [at all]. And there are some considerable toxicities with these treatments.

What has been the biggest challenge in terms of developing novel agents for patients with high-risk MDS? What are the challenges of enrolling clinical trials?

A big limitation has been [our] limited ability to understand this disease. We haven’t had a good, sophisticated understanding of what makes this disease tick for many years. I would argue that’s changing. But we on the clinical side are only in our infancy in catching up with this, understanding it, and exploiting these weaknesses in the disease.

This is a disease that typically involves older patients, many of whom have considerable comorbidities. That makes any sort of treatment, especially any treatments with considerable toxicities, difficult for these patients to withstand. Historically, we have been excluding patients with MDS with increased [bone marrow] blasts from receiving effective treatments because we have considered this disease to be different than acute myeloid leukemia [AML]. There have been aggressive efforts to develop treatments for AML in the past 10 years that have borne a lot of fruit, but [patients with] MDS have been excluded from [these clinical trials], even though biologically, I think we can all agree, they essentially have disease that’s not [significantly] different.

That’s been a limitation in terms of being able to get these patients into clinical trials that have effective treatments. We’ve had a lot of obstacles.

From what understanding there is about MDS, what makes this disease particularly difficult to treat?

It is a disease that does cause failure of the bone marrow that makes patients more susceptible to infectious complications, makes them oftentimes dependent on transfusion support, and makes them quite tired, fatigued, and prone to bleeding complications. It’s a disease that can evolve to acute leukemia. These are all major challenges with respect to the intensity or complications of a disease.

One agent under investigation for the treatment of high-risk MDS is magrolimab. What should be known about this agent, and what makes it unique from other monoclonal antibodies or other agents in MDS?

Magrolimab is an exciting drug. It blocks a target called CD47, which, under normal circumstances, is part of the body’s way of surveilling for cells that shouldn’t be there. It’s one of the ways the immune system works properly to clear out malignant cells, and these malignant cells can hide [from the immune system] by overexpressing CD47.

[With magrolimab], the hope is that you can restore this balance by blocking CD47 and unmasking these MDS cells to be recognized and destroyed by your immune system. It’s an exciting way to potentially harness the immune system to eradicate this disease.

The ENHANCE trial will evaluate magrolimab in combination with azacitidine. What was the rationale of combining these agents?

The early clinical trials have shown more promise with magrolimab’s activity in combination with azacitidine. There are a variety of reasons why these two drugs might have an additive or synergistic property. That’s been the strategy fairly early in the development of [magrolimab]. The earlier phase clinical trials have been done with this combination. There’s been some enthusiasm about what we’re seeing there.

The rationale for comparing the combination with azacitidine alone is that azacitidine is the standard of care in this population. For us to make an achievement and an advancement in [the treatment of MDS], we have to show that a new therapy is better than the standard of care.

If data do prove to be positive in the ENHANCE trial, what could magrolimab potentially provide for this patient population?

Any therapy that can improve outcomes over azacitidine alone would be welcome in our field. It would represent a significant advance in our ability to treat [patients with high-risk MDS]. This is what we are hoping for, to have new therapies that can do better than our historical standard of care. And we’re excited to see how things go with this and some other drugs, as well.

Are there any other agents under investigation in high-risk MDS that you’re intrigued by?

All of us are excited about venetoclax [Venclexta] with azacitidine compared with azacitidine alone, [which is being evaluated in a similar study, the phase 3 VERONA trial (NCT04401748)], for patients with high-risk MDS.

Then there’s another clinical trial, [the phase 3 SELECT-MDS trial (NCT04797780)], that’s of high interest for patients with MDS who overexpress retinoic acid receptor alpha [RARA]. [Newly diagnosed patients with high-risk, RARA-positive MDS] are being given azacitidine plus an agonist, or a binder of that RARA target, called tamibarotene [formerly SY-1425]. There’s hope that for the subset of patients with MDS that overexpress [RARA], this combination could be effective. There are several strategies out there that are promising, and we’re very hopeful for them.

Reference

Sallman D, Malki MA, Asch A, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in MDS patients: phase 1b results. Presented at: 2020 EHA Congress; June 11-21, 2020; Virtual. Abstract S187. Accessed July 27, 2022. https://bit.ly/3cN755Z