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Spotlight

This roundtable series discusses the use of therapy after or instead of erythropoiesis-stimulating agents in patients with low- to intermediate-1 risk myelodysplastic syndromes, as discussed by key opinion leaders at virtual live events and interviews.

Therapies for MDS With Transfusion-Dependent Anemia

Dr Yacoub discusses imetelstat patient selection in MDS

Patient Selection for Imetelstat Benefits from Considering AEs

Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center, discusses the adverse event (AE) profile of imetelstat (Rytelo) when treating patients with myelodysplastic syndromes (MDS).

The phase 3 IMerge trial (NCT02598661) led to this drug’s approval in patients with low- and intermediate-1 risk MDS and transfusion-dependent anemia requiring 4 or more red blood cell units over 8 weeks. They also had to receive prior erythropoiesis-stimulating agents. Yacoub says the AEs that stand out are cytopenias including considerable rates of grade 3 or higher thrombocytopenia and neutropenia. In addition to monitoring these toxicities closely and providing support when these AEs arise, he says patients should be selected to receive imetelstat only if they have sufficient reserves of platelets and neutrophils before treatment, making the therapy ideal for only certain patients.

There were also treatment-emergent nonhematologic AEs such as arthralgia/myalgia, headache, and fatigue, but few were grade 3 or higher. According to Yacoub, hematologists will generally be comfortable managing the other toxicities, but patient selection and close support are essential to address the hematologic AEs.

 This is a new drug that we're going to be learning [about], and obviously we have to build our own expertise and how we address those [AEs]. But the ones that stand out is the impact on blood counts. Imetelstat can cause significant thrombocytopenia and significant neutropenia, so we start with selecting patients who have some reserve in their platelet counts and their hemoglobin and their neutrophil count. That it is not a drug for everybody; it's a drug for select patients who have otherwise preserved platelets and neutrophils, and then meticulous follow-up for the platelet counts and the neutrophils and supporting patients accordingly. There are nonhematologic [AEs] as well that we probably will have to learn to manage as we go forward, but many of them are not prohibitive, and things that we are very comfortable addressing. I think the hematological [AEs] remain the most visible challenge that require the skills of the hematologists in delivering the therapy safely for the right subject.

Abdulraheem Yacoub, MD, discusses the adverse event profile of imetelstat when treating patients with myelodysplastic syndromes.

Patient Selection for Imetelstat Benefits From Considering AEs

Abdulraheem Yacoub, MD, discusses imetelstat as a newer and exciting option for patients with myelodysplastic syndromes.

Significance of New Therapeutic Options in MDS and Other Blood Cancers

Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center, discusses imetelstat (Rytelo) as a newer and exciting option for patients with myelodysplastic syndromes (MDS).

In low- and intermediate-1 risk MDS and transfusion-dependent anemia, Yacoub says imetelstat offers a significant improvement in a population with limited effective treatments. The use of this drug can delay the need for hypomethylating agents and chemotherapy to later lines of treatment.

Use of imetelstat is also being investigated in trials for other blood cancers such as acute myeloid leukemia, myelofibrosis, and juvenile myelomonocytic leukemia. According to Yacoub, the development of imetelstat is a significant achievement in the oncology community and a major advancement for patients with MDS.

 The field of MDS has been stagnant with fewer therapeutic options, but fortunately now imetelstat has become another tool we have for the patients. All the options we have right now have a percentage of likelihood of working that is not universal. All our options are under 50/50 to actually work, so to have another option for these patients that could result in a hematological improvement that is durable and impactful is very precious. Many patients are going to benefit from this, and it will also delay our need to use or commit patients to hypomethylating agents and chemotherapy.

 This premise in MDS might be transferable to other blood cancers, so additional clinical trials are underway to see the utility and the ability to apply the same concepts of benefit in MDS to other blood diseases. So hopefully there'll be additional benefits from imetelstat. In addition, this really is a remarkable scientific achievement. This is a novel mechanism of action. It is a Nobel Prize winning discovery, and to apply this fantastic science and be able to deliver therapeutics that build on that science is really a big scientific win for the field. We're all excited that we could build on that success and deliver therapy that actually works for our patients.

Mikkael A. Sekeres MD, MS, discusses when he decides to start therapy for anemia in patients with low-risk myelodysplastic syndromes.

Quality of Life Considered When Starting Treatment in MDS

Mikkael A. Sekeres MD, MS, professor of medicine and chief of the Division of Hematology, Leukemia Section at the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses when he decides to start therapy for anemia in patients with low-risk myelodysplastic syndromes (MDS).

If a patient is receiving at least red blood cell transfusion each month, Sekeres says that is when he will start them on treatment. Erythropoiesis-stimulating agents (ESAs) are the common option for patients who are transfusion dependent, but therapeutic choices will depend on the serum erythropoietin (EPO) level and level of red blood cell transfusion dependency.

According to Sekeres, patients with higher serum EPO level do not respond to ESAs as much as those with low serum EPO levels. Other options are available for these patients with high serum EPO levels, such as luspatercept-aamt (Reblozyl). If patients have already received or are ineligible for ESAs, imetelstat (Rytelo) is also an option.

We usually start therapies in patients when they become dependent on red blood cell transfusions. Now, how do we define that? Sometimes we'll say that a patient requires about 2 bags of blood every 8 weeks, or 1 bag of blood every month. And I think once my patients start to require a transfusion of a bag of blood a month or more frequently, it really starts to impact their quality of life. So that's when I start to consider treatments for transfusion-dependent anemia in my lower-risk patients with MDS.

 Now, one of the first treatments we often turn to are ESAs. Why? Well, they're relatively easy. They have a recognizable [adverse event] profile, and they're not a form of chemotherapy. So patients who aren't yet dependent on red blood cell transfusions or highly dependent on red blood cell transfusions, and patients who have a lower serum EPO level—we typically define lower as less than 200 IU/L—are more likely to respond to ESAs like [epoetin] or darbepoetin. On the other hand, patients [who] will have a higher serum EPO level, let's say a serum EPO level greater than 500 IU/L, who are already requiring frequent red blood cell transfusions, are less likely to respond to ESAs. So we start with the basics, and we start with what's easy, ESAs.

Mikkael A. Sekeres MD, MS, discusses transfusion independence rates with imetelstat in patients with low- to intermediate-1 risk myelodysplastic syndromes.

Transfusion Independence Sustained With Imetelstat in Low-Risk MDS

Mikkael A. Sekeres MD, MS, professor of medicine and chief of the Division of Hematology, Leukemia Section at the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses transfusion independence rates with imetelstat (Rytelo) in patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS).

On the phase 3 IMerge trial (NCT02598661), 118 patients and 60 patients were randomly assigned to imetelstat vs placebo, respectively. This double-blind trial, patients had to be erythropoiesis-stimulating agent relapsed, refractory, or ineligible and transfusion dependent.

 On this study, the 8-week transfusion independence rate was 40% for those who received imetelstat vs 15% for those who received placebo.... When you're looking at an 8-week duration of transfusion independence, you can get these false response rates to placebo in a lower-risk MDS population. So when we looked at 16-week duration of transfusion independence, which is how we've defined what we think should be a more clinically meaningful duration of transfusion independence in the 2018 revision to the International Working Group response criteria, the response rate to imetelstat was still 31% compared [with] only 7% in those patients who received placebo.

 One aspect of the response that I liked in the IMerge trial of imetelstat vs placebo was that the transfusion independence response rate seemed to hold pretty well even when you extended the duration of transfusion independence response from 8 weeks to 16 weeks. At 24 weeks, so almost 6 months of transfusion independence, it was still 28% in those patients who received imetelstat vs 3% in those patients who received placebo. So it continued to hold over time. When you look at the median duration of response, it was almost exactly 1 year in those patients who received imetelstat. So to summarize, what I would say is about one-third of patients receiving imetelstat had a transfusion independence response for a duration that we think is clinically meaningful, and the median duration of that response was also meaningful at approximately 1 year.

On June 6, 2024, the FDA approved imetelstat (Rytelo) for the treatment of adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia who require at least 4 red blood cell units over 8 weeks and have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESAs).

Findings from the phase 3 IMerge trial (NCT02598661) published in 

 support this approval as the study met its primary and key secondary end points.

 In the trial, those treated with imetelstat had significantly higher rates of red blood cell transfusion independence compared with those given placebo for at least 8 consecutive weeks. With imetelstat, this rate was 39.8% (95% CI, 30.9%-49.3%) vs 15.0% with placebo (95% CI, 7.1%-26.6%; 

 <.001). Rates of red blood cell transfusion independence for at least 24 weeks were 28.0% with imetelstat (95% CI, 20.1%-37.0%) and 3.3% with placebo (95% CI, 0.4%-11.5%; 

Moreover, red blood cell transfusion independence was durable and sustained in the imetelstat-treated population, with a median duration of approximately 1 year for 8-week responders and 1.5 years for 24-week responders, respectively.

For safety, the most frequently observed adverse events (AEs) consisted of laboratory abnormalities, including thrombocytopenia, decreased white blood cells, neutropenia, increased aspartate aminotransferase, increased alkaline phosphatase, increased alanine aminotransferase, fatigue, prolonged partial thromboplastin time, arthralgia/myalgia, COVID-19 infections, and headache.

“It is exciting to have another drug option that we can offer patients, and we need to keep working on it. We cannot rest on our laurels because we have 1 additional drug for patients with lower-risk MDS. We need a lot of new drugs that we can try to keep people eventually living longer,” stated Mikkael A. Sekeres MD, MS, in an interview with Targeted Oncology.

In the interview, Sekeres, professor of medicine and chief of the Division of Hematology, Leukemia Section at the University of Miami Health System, Sylvester Comprehensive Cancer Center, further discussed the approval of imetelstat for the treatment of patients with low- to intermediate-1 risk MDS.

Targeted Oncology: Can you explain the significance of the FDA approving imetelstat for this patient population?

 For patients who have lower-risk MDS, we do not have a lot of tools in our toolbox. We often, for somebody who has anemia, start with an ESA. That will work for somewhere between 20% and 40% of people. It will work for on average about a year. When that stops working, we will turn to luspatercept or sometimes we will use luspatercept upfront. And again, that will work on average in about 40% to 60% of people depending on when we use it and whether or not patients have ringsideoblasts or an 

 mutation. When that stops working, traditionally, we have turned to types of chemotherapy. With imetelstat, we have an option that comes between ESAs and luspatercept, and something that I would consider to be more traditional chemotherapy like a hypomethylating agent.

What are the primary differences between this agent and other treatments available?

When we have somebody who has lower-risk MDS with anemia, we start with drugs that have fewer AEs and have decent efficacy. Then we march along to where that efficacy and safety balance starts to shift. With ESAs, we have a lot of experience with them; they are not chemotherapy, they are hormonal therapy, and as I mentioned, they work and about 20% to 40% of people, but low-risk, moderate benefit.

When we get to imetelstat, we have a pretty decent benefit. It works for 40% of people, so 40% of people treated with imetelstat went at least an 8-week period without needing a blood transfusion whereas when they started the study, they needed at least 4 bags of blood transfused over an 8-week period. So [it was] a pretty dramatic decrease in their blood transfusion needs, 40% of people. On average, it lasted for about a year. That's all the good stuff about imetelstat. Some of the AEs are that it can cause low blood counts. The neutrophils, the white blood cells, can go down substantially, and people ask, can the platelets? Again, we think moderate benefit, but slightly higher risk than where we started with ESAs.

How are those AEs with imetelstat managed?

Some patients do not have those AEs. Some patients get a free ride. It is my favorite part of my day when the patient benefits from a drug and they do not have those sorts of AEs. For those who do, we have a couple of options. We can hold the drug and see if the AEs resolve and then restart it. We can also dose reduce and see if patients still get the benefit of being treated with imetelstat but without the cytopenias.

Should the findings on these AEs influence the use of the agent in clinical practice?

The ideal person for this drug would have lower-risk MDS, dependence on red blood cell transfusions, and isolated anemia. In other words…their white blood cells are relatively well preserved and their platelets are relatively well preserved. Again, the favorite part of my day is when I have a patient with MDS with limited cytopenias, but it’s not the most common part of my day. Most of my patients have some degree of cytopenias in addition to the anemia. I think it all depends on the degree of cytopenias they have. In other words, how much of a basement do we have to work with? If I have somebody who has thrombocytopenia with a platelet count of 90,000/µL, then I have more of a basement to use a drug that causes cytopenias than if I have a patient who walks through the door with a platelet count of 20,000/µL and who might be more hesitant to use drugs that affect the platelet count.

Can you elaborate on the design of the study and its role in supporting the FDA decision?

The IMerge trial, and I was on the steering committee for this study, was a randomized study. Patients were randomly assigned 2:1 to receive imetelstat vs placebo. It was double-blind and patients received the imetelstat as an injection once every 4 weeks. They were then followed over time. Being followed over time, what we were looking for was patients who achieved red blood cell transfusion independence. They started the study dependent on red blood cell transfusions of at least 4 bags of blood over an 8-week period, and transfusion independence means that went at least an 8-week period without needing a blood transfusion. That occurred in 40% of people who received imetelstat compared [with] 15% of people in the placebo group.

This of course begs the question, how can somebody receiving a placebo achieve transfusion independence? It speaks to the fact that an 8-week duration of transfusion independence is probably not robust enough. Then we start to look at how patients who went 16 weeks without a transfusion do. In other words, what percentage of those patients responded to imetelstat? What about 24 weeks or more, so almost 6 months or more? Rates were still much better in the imetelstat group with about 31% of patients going at least 16 weeks without requiring a transfusion, and then 28% of patients going at least 24 weeks without a transfusion. The fact that there was not that much of a drop off from the 40% at 8-week transfusion independence to 24 weeks of transfusion independence tells me that it is a drug that really does work pretty well.

What are the key takeaways of this trial for a community oncologist?

First of all, it is a drug that works in between 1 out of 4 and 4 out of 10 patients. And it depends on how you define work. If you go with an 8-week duration of transfusion independence, it works at about 40%. If you are going to a 24-week duration of transfusion independence, it works in 28% of patients. The second is that it is durable. In patients who did respond, they responded for about a year. That is really good for a trial in patients with lower-risk MDS. Compare that with about 31 or 32 weeks in patients who were treated with luspatercept after being exposed to an ESA in a similar population, or lenalidomide in patients with non­–deletion 5q in whom the duration of response was about 31 weeks. So, [it was] more durable than some other approaches after patients have been exposed to ESAs.

The final is to follow-up with patients for toxicity. We cannot just dose them on day 1 and then see our patients 4 weeks later without checking blood counts in between. I would check blood counts at least weekly as patients are being started on imetelstat to make sure we are identifying patients who develop cytopenias.

For patients, how does achieving red blood cell transfusion independence affect quality of life?

There is a base validity to it. It stinks to have to get a bag of blood. If you think about all the time somebody devotes to having to get that bag of blood—they wake up in the morning, get in their car, drive to the cancer center, park of the car, walk inside, register, get their blood drawn, see the doctor, and maybe go to a different area to get their transfusion. And then the transfusion can take between an hour and 2 hours, depending on a person's comorbidities. You have eaten up most of your day for 1 bag of blood. The folks entering this trial were getting a bag of blood on average every 2 weeks [with] at least some of them getting it weekly. At face value, avoiding that, I think, is a big deal. Equally importantly, we did do quality-of-life companion studies with this trial and in particular, patients experienced less fatigue when they were treated with an imetelstat than if they were treated with placebo. We have good data on patient-reported outcomes, hearing it from patients directly that they were benefiting from the drug.

What are the potential long-term implications?

With lower-risk MDS, we have a diagnosis that people will have for years, and none of the drugs that we use are curative. What we need to continue to do is to develop treatment options for patients. So we try one drug and maybe it works for a while and then stops working. We go to another drug, maybe that one does not work, then we go to another drug. Maybe that one works for a year or 2, and then it stops working. So we need to think about lower-risk MDS is chronic management where we cycle patients through drugs over the years.

Are there any ongoing or planned studies to further explore the benefits of this agent?

Imetelstat is being looked at in combinations and is being explored in patients who have higher-risk MDS to see if there are some benefits there.

What are your key takeaways regarding this approval?

It is exciting to have another drug option that we can offer patients, and we need to keep working on it. We cannot rest on our laurels because we have 1 additional drug for patients with lower risk MDS. We need a lot of new drugs that we can try to keep people eventually living longer.

1. Geron announces FDA approval of RYTELO™ (imetelstat), a first-in-class telomerase inhibitor, for the treatment of adult patients with lower-risk MDS with transfusion-dependent anemia. Geron Corporation. News release. June 6, 2024. Accessed June 18, 2024. 

2. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomized, double-blind, placebo-controlled, phase 3 trial. 

. 2024;403(10423)P249-260. doi:10.1016/S0140-6736(23)01724-5

Mikkael A. Sekeres MD, MS, further discussed the approval of imetelstat for the treatment of patients with low- to intermediate-1 risk myelodysplastic syndromes.