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Phase III Results Give Hope to People Living With Myelodysplastic Syndromes

June 01, 2023
by Michael Masciadrelli

Amer Zeidan, MBBS, medical director of the hematology early therapeutics research program at Yale Cancer Center and associate professor of medicine (hematology) at Yale School of Medicine, will reveal new data at the American Society of Clinical Oncology (ASCO) annual meeting from a phase III study evaluating the efficacy of imetelstat in red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndrome (LR-MDS) patients. Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The study results demonstrate significant and clinically meaningful efficacy, representing a potential breakthrough in the treatment of anemic LR-MDS.

Imetelstat, a telomerase inhibitor, was evaluated in patients who were heavily RBC transfusion-dependent LR-MDS and who were refractory or ineligible for erythropoiesis-stimulating agents (ESAs), but did not receive lenalidomide or hypomethylating agents (other drugs used to treat MDS). The phase III study, known as IMerge, enrolled a total of 178 patients. The findings from the study provide critical evidence supporting imetelstat's efficacy and safety profile. These results are expected to have a substantial impact on future treatment strategies for patients diagnosed with LR-MDS.

Dr. Zeidan, first and presenting author of the research at ASCO, answered questions on the study and its significance for patients living with MDS:

Q: What is the significance of this study?

A: “This is a very important study. Imetelstat is a first-in-class agent. It’s a first-in-class telomerase inhibitor, and this is the first time we have a phase III study of a drug in this class. We already completed the phase II study that was single arm that looked at a similar population of patients with lower risk MDS (myelodysplastic syndromes) who are heavily transfusion dependent, and the transfusion dependence rate with the drug was around 40%. Transfusions in MDS are associated with increased risk of complications, increased risk of death, not to mention healthcare utilization and costs. So, trying to reduce transfusions and ideally make patients transfusion independent is a very important goal of treatment in patients with lower risk MDS.

So the excellent activity of imetelstat in the phase II part of the study was taken to a phase III trial and what we have found in this study is what we actually expected based on the phase II trial: the transfusion dependence rate was much better with imetelstat compared to placebo, it was around 40% for an eight-week duration of transfusion dependence, the primary endpoint of the study, compared to 15% with a placebo; and most importantly, it was also durable. The median duration of transfusion independence for those who responded was more than 50 weeks. So clearly, a very positive study, very consistent with the phase II data. I think this drug could become an important option for patients.”

Q: What are the key findings from the data? What will you highlight at ASCO?

A: “During the ASCO presentation, we’ll discuss in detail, the efficacy of the drug in terms of transfusion independence, hematologic improvement, durability of response, but also looking within subgroups for patients based on the genetic profile. We will also discuss early signs of disease modification that we are seeing through reduction of variable allele frequency of important mutations that contribute to the pathogenesis of MDS. We'll also discuss the side effect profile and how the interruption of therapy has led to, I think, a manageable and reversible side-effect profile, mostly in the setting of liver enzyme abnormalities and cytopenias (a medical condition where there are a low number of red blood cells).”

Q: Are there other treatment options for this niche group of patients affected by this cancer?

A: “Yes, so myelodysplastic syndromes have been renamed neoplasms by the World Health Organization, the most recent classification to emphasize that it's a cancer. Many people think of MDS as an anemia or a pre-leukemia or a syndrome, but they are actually cancers. However, they differ in their severity. Patients in general are grouped into two big groups, lower risk and higher risk. In lower risk patients, those patients can live for years, but they have a lot of complications related to the low blood counts. That could be anemia, thrombocytopenia, or neutropenia, or a combination of these, but the most common use cytopenia is anemia. Anemia often is associated with reduced quality of life. The patient often needs regular transfusions. It's also associated with significant complications and high risk of death, as well as issues related to needing to go to the clinic frequently, healthcare utilization costs. Correction of anemia is very important. Historically, the only treatment we had was erythropoiesis stimulating agents for patients with lower risk MDS. In recent years, other drugs have been approved like lenalidomide, as well as hypomethylating agents and luspatercept. However, the response to these drugs is limited, and at some point, the patient will progress and will need additional treatment. I think imetelstat potentially could fill a very important gap there because those patients are generally not going to be cured without a bone marrow transplant, which is not something that's commonly done in MDS patients where the average age is in the early 70s. The goal is to try to improve quality of life in those lower risk MDS patients and make them transfusion independent as much as possible and that's generally achieved by sequential therapy. So you go from one agent to the next, while trying to maintain quality of life keeping the patient out of the hospital and minimizing complications of the treatment itself.”

Q: What is next in terms of research. What would you like done in future studies?

A: “This is a very important question. I think the next step is going to be focusing more on how to increase the overall durability of response as well as increased the rate of response. And I think that's going to be done by combining drugs. We have several active drugs now. So, figuring out how to combine them, and probably trying to treat patients earlier in their disease course will be important, so they don't even get to the point of becoming transfusion dependent. Several of those studies I think are going to happen over the next few years. And of course, there are other drugs that are being studied in phase I and phase II trials. Some of those hopefully will also lead to benefit to patients so that if we cannot cure the disease, we can for most patients at least improve their quality of life, make transfusions as least as possible, and also make sure they are out of the hospital and having a good quality of life.”

Q: What does the presentation at ASCO mean to you?

A: “It's one of the most gratifying moments for a clinical investigator when we hear a trial we worked on is positive. The reason why we do clinical trials is to help our patients. So have a positive trial and especially with an agent that you have worked on for years, and you have been very involved in the trial for a long time, not only in accruing patients, but also in the design and the conduct and oversight of the study and to have a trial being positive, especially for a randomized phase III trial, is a very good feeling, and the day when you hear that the results are positive is a day that you tend to remember for a very long time because what you have worked on did not only help your own patients, but hopefully if the drug gets approved, it's going to help many patients that you have not directly interacted with, which is I think is the most important mission of any clinical research. We are the face of the trial as clinical investigators, but we have a huge team here at Yale. A lot of coordinators, clinical research nurses, regulatory staff, and our nurse practitioners – all of them have been very important to the conduct of the trial here at Yale. This was a global study that happened in many countries, many centers, and it's a coordinated effort. So we are presenting the data on behalf of everybody and hoping that the regulatory review will be successful, and we have another option for our patients.”

Submitted by Renee Gaudette on June 01, 2023