Gaps in the Current Treatment Landscape of Myelodysplastic Syndromes

Amer Zeidan, MD, Yale School of Medicine, Yale University, New Haven, CT, discusses the methods he uses to manage treatment for patients with myelodysplastic neoplasms (MDS) who are not eligible for bone marrow transplants. He also provides updates on recent clinical trials and drug treatment options, particularly for higher-risk patients with MDS, and treatment gaps that still remain.

Transcript:

My name is Amer Zeidan. I'm an Associate Professor of Medicine at Yale University, and I specialize in the management of myeloid cancers, especially acute myeloid leukemia and myelodysplastic syndromes. So I'm the research leader for the disease aligned research team for myeloid blood cancers, as well as the early therapeutics research and an Assistant Director of the clinical trials office at Yale.

There has been a lot of progress in MDS management. However, most of the patients with MDS are not going to be cured except with a bone marrow transplantation. So the only way to cure patients with MDS currently is a bone marrow transplant. We generally recommend doing that for patients with higher risk disease, the patients who have more aggressive MDS. However, because the median age at which patients with MDS are diagnosed is generally in the early 70s, so most patients are generally older and cannot undergo transplant. They have multiple medical problems or they have limited donors. So that takes out more than 90% of patients with MDS out of the transplant question.

So when we talk about non-transplant management of MDS, you are really talking about the bulk of patients. This is not a small patient population. This is almost 90% of patients with MDS [that] are not going to undergo curative potential type of therapy such as bone marrow transplant. So the main options right now are dependent on the risk status of the patients. So there's lower risk and then there's higher risk. And you can use a number of tools to risk stratify patients, basically advise them on their expected survival as well as expected chance of progression to acute myeloid leukemia. And based on those numbers, we recommend treatment for lower-risk patients or higher-risk patients. For lower-risk patients, generally they can live multiple years and generally the treatment goal is to maintain quality of life or improve it, reduce the risk of complications from low blood counts and cytopenias, and try to optimize the patient time outside of the hospital.

In higher-risk MDS patients on the other hand, those patients generally have limited survival. Sometimes it's not beyond one to two years with the standard treatments without a bone marrow transplant. And the goal is to try to modify the disease’s natural course, meaning that you're trying to prolong survival. You are trying sometimes to cure the disease if you can take the patient to a transplant or, ideally, try to at least minimize the complications and optimize the patient time, improving their quality of life.

So we have some drugs that have been approved for this for high-risk MDS, hypomethylating agents. But one of the most important unmet needs are that those hypomethylating agents don't work particularly well. While they can improve the blood counts, and they can reduce the risks of complications of cytopenias, and can cause remissions, generally their survival advantage is limited. In randomized clinical trial, for example with azacitidine, the median survival was 24 months. But when we look at the real-life setting in studies that we and others have done, the real-life advantage, or the real benefit of hypomethylating agents in terms of overall survival, is somewhere between 11 to 18 months. So generally, patients are not expecting multiple years of survival on those drugs.

So trying to optimize hypomethylating agents by adding another drug, what we call combination-based treatment, has been a major goal in management of MDS. And there has been a number of drugs that have been tested, but, unfortunately, have not been successful. The standard of care continues to be single agent hypomethylating agents, and there are three of them: IV azacitidine, IV decitabine, and oral decitabine or decitabine/cedazuridine. And there are a number of clinical trials right now with promising agents that are being added to those hypomethylating agents, including large randomized Phase 3 trials. So we have randomized clinical trials looking at the addition of anti-TIM-3 antibody called sabatolimab, anti-CD47 drug called magrolimab, and venetoclax, which is an oral BCL2 inhibitor, in addition to tamibarotene, which is also, this is a RARA agonist, R-A-R-A agonist agent. So all of these are large randomized trials. If any of them [are] positive, it could change the landscape of management of higher-risk MDS.

The second area I think where there is significant deficiency is the management after those hypomethylating agents fail, what we call HMA failure setting; this is a very also difficult setting to treat. The average survival for high risk MDS patients after HMA failure is around six months, so generally we need new drugs. There have been a number of drugs that have been studied, but again, nothing approved. There is no standard of care in that setting. So many drugs are being studied, and hopefully some of those will prove to be beneficial for patients. In lower-risk MDS patients, historically the treatment has been focused on improving anemia. That usually happens with erythropoietic stimulating agents in lower-risk MDS patients, but many times those ESAs don't work very well, especially for patients who have a lot of blood transfusion needs or the patients who have high erythropoietin level.

But most recently there has been a number of active agents that have been studied. One of them is luspatercept, which is a transforming growth factor pathway ligand trap. And this drug, which is given subcutaneously every three weeks, [has] been shown to improve the rate of transfusion independence in MDS after ESA failure. Another drug called imetelstat just had a press release that is also very active after ESA failure. So the lower-risk MDS field is certainly looking more promising. I think a lot of the next steps in MDS management is going to focus on combinations that can improve survival, that can hopefully be given orally as much as possible so that you can minimize the patient time in the clinics and optimize their quality of life.