Recent Updates in Lower-Risk MDS

In the myelodysplastic syndrome [MDS] treatment space, ongoing research and evolving guidelines are informing clinical practice and impacting treatment decisions. In this Precision Medicine Perspectives series titled “Recent Updates in the Management of Lower-Risk Myelodysplastic Syndrome,” Amer Zeidan, MBBS, MHS, an associate professor of medicine at Yale University, reviews recent clinical trial data, discusses the updated WHO and ICC guidelines, and applies it all to the clinical decision-making process.

Targeted Oncology™: Could you provide a brief overview of lower-risk MDS and how the disease landscape has changed over time?

Amer Zeidan, MBBS, MHS: Lower-risk myelodysplastic syndrome is an evolving area because we historically have defined lower- vs higher-risk MDS based on a number of clinical and molecular data points. This has been evolving with the introduction of the molecular IPSS [International Prognostic Scoring System]. We are seeing some migration from lower risk to higher risk, but lower-risk MDS still constitutes most of the cases of patients with MDS.

It's important to remember that myelodysplastic syndromes are cancers. This is why the 2022 WHO classification called them myelodysplastic neoplasms. Even when they have lower risk, most patients will eventually die from myelodysplastic syndrome. This is important to realize because those patients are often underdiagnosed and sometimes undertreated. But we have more novel therapies and drugs that have been shown to improve quality of life, so it's important to diagnose and treat the condition.

Targeted Oncology: Given the updated guidelines for the WHO and the ICC [International Consensus Classification], how do you currently diagnose and classify MDS? What tools are you using in practice?

Amer Zeidan, MBBS, MHS: Myelodysplastic syndromes have historically been risk-stratified using the International Prognostic Scoring System, which depends on the blast percentage in the bone marrow, the blood counts, and the cytogenic abnormalities. Historically, this was revised in 2012, where the revised version of the IPSS, the IPSS-R, was published. This introduced 5 risk categories, instead of 4, relying on better cutoffs of the same variables—blast count, cytogenetics, and blood counts—to better risk stratify.

Most recently, in 2022, the molecular IPSS was introduced, which finally incorporated the recurrent somatic abnormalities that are often seen in patients with MDS but had not been formally accounted for in the previous classification systems. The molecular IPSS, or IPSS-M, uses 6 risk groups. The lower 3 risk groups—moderate-low, low, and very low—now constitute what we call lower-risk MDS. Together, these patients only have a median survival of around 5 to 6 years, which is actually pretty good because most of those patients are in their 70s. The median age of diagnosis of MDS is 72. But they have significant compromise to quality of life. Often, they have severe anemia and they need transfusions often. In patients with lower-risk MDS, we still recommend treatment most of the time, except in the occasional patients where the blood counts aren’t severe enough to cause symptoms, where they can be observed.

Targeted Oncology: What does the current treatment landscape for lower-risk MDS look like? What are the unmet needs in lower-risk MDS?

Amer Zeidan, MBBS, MHS: In lower-risk MDS, the main problem is anemia, which occurs in more than 90% of patients. In most patients, anemia will worsen, and patients will require blood cell transfusions most of the time. Around half of the 90%, around 40% of patients, will become dependent on regular blood cell transfusions. This has been associated with worse outcomes, inferior survival, and complications of chronic transfusions, such as iron overload and its complications, as well as increased cardiac abnormalities and risk factors. Treatment of anemia is a major component of the treatment of patients with MDS.

Historically, the most commonly used agents were erythropoiesis stimulating agents [ESAs], which come in 2 big groups: short-acting and long-acting. The short-acting, such as erythropoietin [Procrit], is given every week. Usually, the dose is somewhere between 40,000 and 80,000 international units. The long-acting version, such as darbepoetin, is given every 3 weeks, and the dose can be 300 to 500 micrograms.

Those are effective in around 40% of unselected patients, where they lead to transfusion independence. More recent studies have shown that the transfusion independence rate is closer to 30% with these drugs. It’s important to note that they work better in patients who have lower transfusion needs or minimal anemia, as well as in patients who have a lower erythropoietin level.

Often, ESAs will not work around 60% of the time. If they work, the median duration of response is around 12 to 18 months, so you often will need something after ESA, either as primary failure or secondary failure of ESA. Historically, we did not have a lot of great options except in patients who have deletion 5q, who were treated with lenalidomide, which is a very effective oral pill that leads to transfusion independence in around two-thirds of patients. Most of those patients will achieve cytogenic remissions. The problem is that deletion 5q only happens in around 10% of patients with MDS, so most patients did not have a great option until 2020, when luspatercept was approved.

Luspatercept essentially is a ligand trap. It's a modified or recombinant protein that targets the transforming growth factor pathway ligands from the circulation. This is a pathway that's hyperactivated in lower-risk MDS and leads to effective erythropoiesis, especially in the late differentiation part of red blood cell development. Using this drug, which is given by subcutaneous injection every 3 weeks, leads to transfusion independence around 40% of the time. But it doesn't last for a long time in terms of a median duration of response in patients after ESA failure. The median duration of response was around 32 weeks. It seems to work in patients with ring sideroblasts, which is around 20% to 25% of patients with MDS.

Luspatercept is now approved in the frontline setting as a first-line treatment for lower-risk MDS based on the COMMANDS trial [NCT03682536]. Other options include hypomethylating agents, which can be given in lower doses, as well as immunosuppressive treatments in selected patients. All of these are reasonable options for the management of anemia. Some patients with lower-risk MDS will have thrombocytopenia, and they can be treated with thrombopoietin mimetics or hypomethylating agents.

Targeted Oncology: Could you review recent updates for luspatercept, the IMerge [NCT02598661] trial, and KER-050?

Amer Zeidan, MBBS, MHS: This year 2023 was very important for lower-risk MDS because several therapies are moving forward to clinical practice and are already changing the standard of care. The COMMANDS trial tested 2 questions in a big, randomized trial. The first question was whether luspatercept—a transforming growth factor pathway modifier given subcutaneously every 2 weeks—works better than erythropoiesis stimulating agents in patients who don’t have ring sideroblasts. The trial allowed patients with and without ring sideroblasts as well as patients in the frontline setting, the first treatment for patients with lower-risk MDS. What the trial showed is—it was a positive trial—luspatercept-led transfusion independence among patients who were red blood cell transfusion–dependent at baseline of 60% compared with 30%.

Based on this, the FDA approved the use of luspatercept in the frontline setting regardless of whether the patient has ring sideroblasts for patients with lower-risk MDS who have symptomatic anemia and may require red blood cell transfusions for the management of anemia. This was the wording from the FDA label. The COMMANDS clinical trial specifically tested patients who are transfusion dependent. The patient had to require 2 or more units in the preceding 8 weeks before coming onto the trial. There will be another trial called ELEMENT [ELEMENT-MDS, NCT05949684], which will look at patients who have symptomatic anemia but who aren’t yet transfusion dependent. It will also include patients who have ring sideroblasts and patients who don’t have ring sideroblasts.

The COMMANDS data were impressive because the drug was active across all subtypes, regardless of the EPO level or the degree of the transfusion burden. In patients with ring sideroblasts, it was very effective. In patients without ring sideroblasts, the rate of transfusion dependence was somewhat similar between luspatercept and ESA. However, the durability of the response was better with luspatercept. Luspatercept is going to become a standard of care in the frontline sitting for anemic patients with lower-risk MDS who need transfusions, regardless of whether they have ring sideroblasts.

Another very promising drug is imetelstat. Imetelstat is a first-in-class telomerase inhibitor that's given intravenously every 4 weeks. This drug was tested in the IMerge trial, which was a randomized phase 3 trial against placebo. It had a very similar design to the MEDALIST trial [NCT02631070] that led to the approval of luspatercept, except that this trial didn’t require patients to be ring-sideroblast positive. This trial required the patient to be very heavily transfusion dependent. This trial was restricted to patients with lower-risk MDS who had received 4 or more units in the preceding 8 weeks. The median transfusion burden was 6 units.

The drug beat placebo with a 40% rate of transfusion dependence compared with 15% with placebo. It worked across all subgroups, whether patients had ring sideroblasts or not. It also worked quite well in patients with significant transfusion dependency. For example, the median burden of transfusion was 6 units. This is a patient getting almost a unit of blood every week. And 40% of those patients became transfusion independent, which is quite good. The durability was good; the median duration with imetelstat was 51 weeks. We also see a significant rise in the mean hemoglobin; the mean hemoglobin rise for responders in the imetelstat arm was 3.5 g. Those are patients who are going from 8 g/dL to 11.5 g/dL, which is quite a significant rise. You don't often see that in patients with MDS. Lastly, we are seeing early signs of disease modification in the form of reduction of some of the recurrent somatic gene mutations that we see in MDS, such as SF3B1 and TET2.

Overall, the drug is very promising. Certainly, it can cause cytopenias, mostly in the form of grade 3 and higher thrombocytopenia and neutropenia, but they’re generally manageable by dose reduction or dose delays, treatment interruption. With good management, as was done in the IMerge phase 3 trial, they didn’t lead to increase in the clinical consequences of severe cytopenia, such as febrile neutropenia or grade 3 or higher bleeding or infection.

It's a drug that certainly is very clinically active. The cytopenias are manageable. There was no concerning signal with the liver enzymes. This drug potentially could also become a standard care in the second-line setting. The company has announced that they have submitted application to the FDA, which has been accepted and is currently under review. I suspect we should hear the decision from the FDA sometime in 2024, and hopefully the drug will be approved for use in the standard care setting.

Then there are other agents, such as pyruvate kinase agonists as well as other versions of drugs that work on the transforming growth factor pathway similar to luspatercept, for example a drug called KER-050. There are some subtle differences from the luspatercept phase 2 data. It was a small number of patients but was quite promising. Additional data will be important to see how well this drug works and if it differentiates itself from luspatercept.

Targeted Oncology: What is the future outlook for the treatment landscape in lower-risk MDS?

Amer Zeidan, MBBS, MHS: We had significant improvements in lower-risk MDS management. One thing that needs to be studied is trying to move some of those therapies into an earlier line. The ELEMENT trial is going to study luspatercept in patients who are not transfusion dependent. That would be very important, as well as combinations. For example, combining effective drugs such as luspatercept and lenalidomide or luspatercept with ESA. This will be important because these drugs have different toxicities and potentially could be synergistic together. Hopefully that will increase the transfusion independence rate and prolong the duration of response.

Ultimately, I think some of our trials should aim to complete resolution of the anemia and even potentially try to prolong survival. At this point, we do not have a treatment that has been shown in a randomized trial to prolong survival in lower-risk MDS. Another area that will need additional data is the activity of imetelstat after luspatercept. Because luspatercept is probably now going to be used much more in the frontline setting. The IMerge study had a very small number of patients who have received luspatercept. I don't think there's any theoretical reason to suspect imetelstat would not work after luspatercept, but it would be nice to show data over the next years to better understand not only the combinations but the best sequencing of treatments for patients. Overall, we are seeing very nice progress in lower-risk MDS, and hopefully that will also be reflected soon in higher-risk MDS.