https://www.onclive.com/view/emerging-d ... r-risk-mds
Frontline treatments that achieve transfusion independence are of paramount importance for patients with lower-risk myelodysplastic syndrome (MDS). Progress in the past few years has led to long-term management of the symptomatic events that may cause progression to high-risk MDS; however, emerging therapies change the history of lower-risk MDS.1
In a recent OncLive The Talk™ video program, Rami Komrokji, MD, led a discussion about practice-affirming updated findings with luspatercept-aamt (Reblozyl) as well as early impressions of the data on novel agents presented at the 64th American Society of Hematology (ASH) Meeting and Exposition.
Emerging Data Offer Alternatives for Patients With Lower-Risk MDS
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Re: Emerging Data Offer Alternatives for Patients With Lower-Risk MDS
Here since I know you want to cut right to the chase 
Komrokji: There are a few presentations of real-world data complementing what you discussed and data from the MEDALIST. A very consistent message to what’s published.
Dezern: It is fun to think about having novel options here. Historically, one of the reasons providers have pushed off the use of a new agent is because we have so few. That is changing and if we’re able to use luspatercept earlier, we can then bring in novel agents as they become available. I’m hopeful we can improve outcomes for our patients with MDS.
Imetelstat may be just that. It’s an interesting drug, with a different mechanism of action than what we’ve spoken about so far. It’s a telomerase inhibitor, and we believe [it] targets cells with high telomerase activity as well as those that have increased expression of the telomerase reverse transcriptase expression. This is a drug we’ve known about for a little while, and data from the phase 2 portion of IMerge [NCT02598661] has already been published a few years ago. At ASH, Uwe Platzbecker, MD, and colleagues went through to describe a very specific subset of those original patients and we can learn a fair amount from these data.9,10
What they looked at was the clinical benefit in patients who were non-del(5q), had not had thalidomide, and had not had an HMA. These patients became transfusion-independent for greater than 1 year on the trial receiving imetelstat. Ultimately, this was only 11 out of the original 38 patients who were in the early portion of the trial and met those very specific criteria. They fall into a group who many would consider having a high transfusion burden. They were getting approximately 6 units in the 8 weeks prior to the time of enrollment. All previously had ESAs, which is part of how they became eligible for the original trial. The data showed that the [median] duration of transfusion independence was approximately 92 weeks. The OS was almost 5 years, at a little less than 60 months. Thankfully, in terms of safety with this mechanism of action for imetelstat, none of the 11 patients progressed to acute myeloid leukemia. This may not surprise you given that they’re low risk and they responded to a drug.
What ties together many of the themes that we’ve been speaking about is that it looks like, at least from the data presented, that when these patients became transfusion independent, they had a reduction in the mutational burden of their SS3P1. This is a lower-risk group of patients, but if you’re truly changing the amount of that mutation that is causing the disease, that may be important. In over half of those who had mutational data, there was a greater than 50% reduction in that varietal frequency. It’s compelling data, hinting at a changing natural history.
I’m optimistic that this is an active drug.
Komrokji: The question would always be how do we think of sequencing those? We have now 2 active therapies, luspatercept and imetelstat.
Zeidan: That’s a great question and a very good problem to have. If you asked me 2 or 3 years ago, I would tell you 2023 was going to be the year of high-risk MDS. In turns out, 2023 is actually the year of lower-risk MDS. We have to see the full data, but COMMANDS’ primary end point has been met.7 We know the drug is very active in the second-line setting. With imetelstat, the data have been shared in quite a bit of detail in the news release and are quite compelling.9 It’s not common to see a transfusion-dependence rate that holds in the phase 3 at 38% with a compelling duration. The high-level summary of the safety was consistent with what all of us have seen before. If these data pass scrutiny and get approvals, that could be a major change in how we treat MDS. If we have the same discussion in 2024, it would be a very interesting discussion.
Assuming the trials are reviewed and are positive in terms of the regulatory assessment, luspatercept could potentially become a firstline option. I don’t think ESAs are going to go away. Certainly, they are going to be [useful in] patient subsets. One question that many of us will ask is how does ESA work if you give imetelstat? We don’t cure these patients; they are going to go through several therapies. One of our goals is to think of the total therapy. The second thing to think of is imetelstat use in the second-line setting, if that’s approved. It would be established as a post-CsA [cyclosporin A] failure. The question is going to be, do you use it before or after luspatercept?
Lower-risk MDS is looking like I think very exciting in the next few years. Patients are going to benefit from all these results.
Komrokji: There are a few presentations of real-world data complementing what you discussed and data from the MEDALIST. A very consistent message to what’s published.
Dezern: It is fun to think about having novel options here. Historically, one of the reasons providers have pushed off the use of a new agent is because we have so few. That is changing and if we’re able to use luspatercept earlier, we can then bring in novel agents as they become available. I’m hopeful we can improve outcomes for our patients with MDS.
Imetelstat may be just that. It’s an interesting drug, with a different mechanism of action than what we’ve spoken about so far. It’s a telomerase inhibitor, and we believe [it] targets cells with high telomerase activity as well as those that have increased expression of the telomerase reverse transcriptase expression. This is a drug we’ve known about for a little while, and data from the phase 2 portion of IMerge [NCT02598661] has already been published a few years ago. At ASH, Uwe Platzbecker, MD, and colleagues went through to describe a very specific subset of those original patients and we can learn a fair amount from these data.9,10
What they looked at was the clinical benefit in patients who were non-del(5q), had not had thalidomide, and had not had an HMA. These patients became transfusion-independent for greater than 1 year on the trial receiving imetelstat. Ultimately, this was only 11 out of the original 38 patients who were in the early portion of the trial and met those very specific criteria. They fall into a group who many would consider having a high transfusion burden. They were getting approximately 6 units in the 8 weeks prior to the time of enrollment. All previously had ESAs, which is part of how they became eligible for the original trial. The data showed that the [median] duration of transfusion independence was approximately 92 weeks. The OS was almost 5 years, at a little less than 60 months. Thankfully, in terms of safety with this mechanism of action for imetelstat, none of the 11 patients progressed to acute myeloid leukemia. This may not surprise you given that they’re low risk and they responded to a drug.
What ties together many of the themes that we’ve been speaking about is that it looks like, at least from the data presented, that when these patients became transfusion independent, they had a reduction in the mutational burden of their SS3P1. This is a lower-risk group of patients, but if you’re truly changing the amount of that mutation that is causing the disease, that may be important. In over half of those who had mutational data, there was a greater than 50% reduction in that varietal frequency. It’s compelling data, hinting at a changing natural history.
I’m optimistic that this is an active drug.
Komrokji: The question would always be how do we think of sequencing those? We have now 2 active therapies, luspatercept and imetelstat.
Zeidan: That’s a great question and a very good problem to have. If you asked me 2 or 3 years ago, I would tell you 2023 was going to be the year of high-risk MDS. In turns out, 2023 is actually the year of lower-risk MDS. We have to see the full data, but COMMANDS’ primary end point has been met.7 We know the drug is very active in the second-line setting. With imetelstat, the data have been shared in quite a bit of detail in the news release and are quite compelling.9 It’s not common to see a transfusion-dependence rate that holds in the phase 3 at 38% with a compelling duration. The high-level summary of the safety was consistent with what all of us have seen before. If these data pass scrutiny and get approvals, that could be a major change in how we treat MDS. If we have the same discussion in 2024, it would be a very interesting discussion.
Assuming the trials are reviewed and are positive in terms of the regulatory assessment, luspatercept could potentially become a firstline option. I don’t think ESAs are going to go away. Certainly, they are going to be [useful in] patient subsets. One question that many of us will ask is how does ESA work if you give imetelstat? We don’t cure these patients; they are going to go through several therapies. One of our goals is to think of the total therapy. The second thing to think of is imetelstat use in the second-line setting, if that’s approved. It would be established as a post-CsA [cyclosporin A] failure. The question is going to be, do you use it before or after luspatercept?
Lower-risk MDS is looking like I think very exciting in the next few years. Patients are going to benefit from all these results.
Re: Emerging Data Offer Alternatives for Patients With Lower-Risk MDS
Hopefully it won't be long until these KOL's are suggesting Imetelstat as Frontline. -Kmall