Evolving Treatment Landscape in Lower-Risk MDS

At the 2023 European Hematology Association Congress, follow-up data from the IMerge clinical trial [NCT02598661] were presented, looking at imetelstat in patients with lower-risk myelodysplastic syndrome [MDS]. In this Precision Medicine Perspectives series titled “Recent Updates in the Management of Lower-Risk Myelodysplastic Syndrome,” Eytan M. Stein, MD, reviews key data updates and discusses their potential clinical implications in the overall treatment landscape.

Targeted Oncology™: What are the options available for first-line treatment for patients with lower-risk MDS? What is the rationale for use and their mechanism of action?

Eytan M. Stein, MD: When we think about patients with low-risk myelodysplastic syndrome, we’re primarily thinking about patients with myelodysplastic syndrome with a unilineage dysplasia, which tends to be anemia. Although it’s not synonymous with having a patient who has isolated anemia, most patients with lower-risk myelodysplastic syndromes who need treatment tend to have isolated anemia. The treatments focus on those particular patients and what we can do to make those patients less anemic and less transfusion dependent.

Patients with 5q-deleted myelodysplastic syndrome—that’s a special category—receive a medication called lenalidomide. But in patients with non–5q-deleted myelodysplastic syndrome, the first-line therapy―when we can get it―is to give a medication that is an [erythropoiesis]-stimulating agent. The theory behind that is that if you boost the amount of erythropoietin or recombinant erythropoietin in a patient’s body, that will stimulate the bone marrow to produce more red cells and therefore allow the patient to have less anemia and therefore fewer transfusions.

Targeted Oncology: What are the treatment options for patients with lower-risk MDS who progress on first-line treatment, and what is their rationale for use? How do you determine treatment? What factors influence your decision to initiate second-line treatment?

Eytan M. Stein, MD: The question becomes: If you’ve got a patient who is on an [erythropoiesis]-stimulating agent or perhaps their endogenous erythropoietin levels are so high that you don’t expect an [erythropoiesis]-stimulating agent to work in the first line, what would a second-line treatment be for those patients? In 2023, or at least in the first half of 2023, the way we think about this is we look to see whether the patient has a myelodysplastic syndrome that has something called ring sideroblasts in it. Patients with myelodysplastic syndromes with ring sideroblasts seem to respond to a relatively new medication called luspatercept. Luspatercept is given by subcutaneous injection once every 3 weeks. And in those patients who have ring sideroblasts, about a third to half will develop transfusion independence by getting luspatercept. It becomes a little more difficult in patients who do not have ring sideroblasts because the treatments we have in that setting unfortunately are not as good as they should be.

There are 2 major treatments that we think about. One is trying lenalidomide in combination with [erythropoiesis]-stimulating agents, even in the patients who do not have a 5q deletion, because about 20% to 30% of those patients will become transfusion independent. The second thing that we sometimes try is..[moving] on to giving hypomethylating agents. Hypomethylating agents are typically used for intermediate- and higher-risk myelodysplastic syndrome. However, if your back is up against the wall and you don’t have other things to do for a patient who’s got lower-risk MDS [myelodysplastic syndromes], we often try hypomethylating agents in those patients.

When I think about what influences a decision to transition a patient to second-line treatment, it really comes down to their burden of transfusions. If a patient has received an [erythropoiesis]-stimulating agent for 8 weeks or so, is not responding to that [erythropoiesis]-stimulating agent, and is needing 1 or 2 units of packed red blood cells every 1 to 2 weeks, that’s a patient whom I certainly move on to a second-line treatment to try to decrease their need for packed red blood cell transfusions.

Targeted Oncology: What were the primary and secondary end points from the 1-year follow-up data of the IMerge trial that were recently presented at EHA [2023 European Hematology Association Congress]? Describe the IMerge trial and the mechanism of action of imetelstat.

Eytan M. Stein, MD: Imetelstat is part of a class of drugs called telomerase inhibitors. What’s interesting about these drugs is they were actually first explored in a different myeloid malignancy called myelofibrosis, but then it became clear after that exploration had been done that they might also lead to improvement in anemia in patients with lower-risk myelodysplastic syndromes.

The IMerge study looked at patients who were relapsed or refractory to erythropoiesis-stimulating agents, that first-line treatment that we talked about a second ago. It asked the question: Is it worthwhile to give these patients imetelstat, and will that help improve the patient’s transfusion independence in the second-line setting? This was a randomized phase 3 study where patients were [randomly assigned] to receive either imetelstat or placebo, with the primary end point of the study looking at the rate of 8-week transfusion independence. That means that they look at how many patients are able to be free of transfusions for 8 weeks or longer.

This is obviously an area that is important because we talked about how in the second line of therapy in a patient who had not responded to an [erythropoiesis]-stimulating agent, if they have ring sideroblasts, you would give them luspatercept, but most patients do not have ring sideroblasts. There is this very large group of patients who don’t have great options. We talked about giving them a hypomethylating agent or giving them lenalidomide, but those aren’t great options. They have a lot of adverse effects. Imetelstat is exciting because it potentially offers another option to these patients.

Targeted Oncology: What was the durability of response from the 1-year follow-up of the IMerge trial. How did the efficacy compare across the subgroups at 8 weeks, 24 weeks, and a year?

Eytan M. Stein, MD: The results of the IMerge study are actually quite promising, favoring imetelstat. The rate of 8-week transfusion independence was higher with imetelstat than with placebo. The median duration of transfusion independence was almost a year, 51.6 weeks with imetelstat compared with only 13 weeks with placebo. When you look at the 24-week rate of transfusion independence—so that is how many patients were free of transfusions for 24 weeks continuously—the rate of 24-week transfusion independence with imetelstat was 28%. It was only 3.3% in patients receiving placebo. Overall, the rate of transfusion independence, even at longer periods of time, ends up significantly favoring patients who get imetelstat. Even at a year, the [percentage] of patients who were transfusion independent with imetelstat [was] 17.8% compared with only 1.7% of the group of patients who received placebo.

To boil this down, what that means is that at 8 weeks, it’s clearly better to be receiving imetelstat than to be receiving placebo. That’s great to begin with. But what’s perhaps more exciting is that some of these rates of transfusion independence end up lasting a very long period of time. For the patient who is transfusion dependent, being free of transfusions for a year or even longer greatly affects their quality of life. This ends up being something that at least seems to be better than placebo.

Targeted Oncology: What is the impact of imetelstat on hemoglobin level?

Eytan M. Stein, MD: The impact of imetelstat on hemoglobin level is significant. The way we know that it’s significant is that these patients end up becoming transfusion independent. If you’re transfusion independent, that typically means that your hemoglobin is at least above 7 g/dL, usually above 8 or 9, or even going closer to 10 g/dL. The decrease in the number of transfusions is a reflection of the improvement in the hemoglobin level.

Targeted Oncology: How might these data affect your decisions in clinical practice? What are some clinical implications of these data?

Eytan M. Stein, MD: The data in the IMerge study [are] quite exciting because [they] now move imetelstat probably into the second line for treatment of patients with lower-risk MDS who are anemic and transfusion dependent. The treatment algorithm would therefore potentially become starting with an [erythropoiesis]-stimulating agent, and if a patient relapses or is refractory to an [erythropoiesis]-stimulating agent, if they have ring sideroblasts, they would go on and get luspatercept. If they do not have ring sideroblasts, which is the bulk of the patients, they will end up getting imetelstat. And then if the imetelstat or luspatercept stops working, then you go on and get something else after that. I think it puts imetelstat in a relatively early line of therapy, and that is good for patients because it gives them more options.