Conversations with Cancer Experts Series

MDS: How He Intend to Use Imetelstat in My Practice
Dr. Jesus Gonzalez Lugo MD
Assistant Professor
Hematologic Malignancies and Cellular Therapeutics

Kanas University Medical Center
SPEAKERS
Ravi Vij, Jesus Lugo

Ravi Vij  00:02
Hello, my name is Ravi Vij. I'm from my cancer Haven and today in our conversation with cancer expert series, we have Dr. Jesus Gonzalez Lugo assistant professor at Kansas University Medical Center in the hematological malignancy and cell therapeutics arena. And we are going to talk about a drug that is expected to be on the market in the near future for myelodysplastic syndrome. imetelstat and Dr. Luka will tell us how he intends to use it in his practice. So welcome, Jesus.

Jesus Lugo  00:36
Thank you very much, very happy to be here.

Ravi Vij  00:38
So before we get into the discussion on the drug, I just want the to help put in just very general broad strokes, how you segment your MDS, and we'll talk a little bit about what we have to offer these patients today and then get into a deep dive on a Imetelstat. So how do you segment your MDS?

Jesus Lugo  00:59
Sure. So, as we have it here, MDS, first we have to define what MDS is. So, I would have to say that MDS has three main components, and MDS has ineffective hematopoiesis. MDS has cytopenias, which has low blood counts, and also it has a risk of progression to acute myeloid leukemia, those are the three components of this. And low risk, basically are patients that mainly have the cytopenias, which is the low blood counts, mainly anemia, which is the more common most common things that these patients have.

And the high risk patients are the patients that have more risk to develop acute myeloid leukemia. We can do this by several risk scores. And but that is mainly the thing, the lower risk patients are the ones that many times we treat their symptoms and the high risk patients are the ones that we either transplant them because they have to go to an alllo stem cell transplant, because that is the way that we can we can detain their progression to leukemia, or we have to give them other types of medications such as a society or the side of being so we can decrease their progression.

Ravi Vij  02:26
So, obviously, we're going to hone down more today in this discussion to the low risk MDS subsets. So can you just give us just a broad general overview of how you approach your low risk MDS today, and then we'll talk about the agent Imetelstat, of course.

Jesus Lugo  02:42
So we have several things for low risk MDS. And in the current years, our armamentarium has increased. We have erythropoiesis stimulating agents, we have lustapercept, which actually has come to the frontline. Now, more very recently, this partnership actually with the COMMANDS trial now, I would suggest that it should go to the frontline, before erythropoiesis stimulating agents because of the groundbreaking COMMAND trial that works in about 60% of the patients compared to ESAs.

We have lenalidomide which works in patients that are 5 Q deleted, which is a subset of patients that have MDS. And like I mentioned HMAs, which we give in high risk patients. We can also give it in patients that are lower risk MDS, but we usually give it when we run out of options on patients when other options. We are, yeah, when we run out of options, like I mentioned, and then we have this very fascinating new agent Imetelstat.

Ravi Vij  03:56
Can you talk to us about the IMERGE study that has been the pivotal trial? And if I'm correct this drug, we're in June this year and may actually get approved if the FDA gives the green light in the next few weeks?

Jesus Lugo  04:12
Correct? That is what we're expecting. So it's going to be very exciting if it happens. So the IMERGE trial was an international double blind, randomized phase three trial, and it included patients with a lower risk MDS that were relapsed refractory to erythropoiesis stimulating agents or that were not able to get erythropoiesis stimulating agents because their Epo was more than 500.

And also this patients were transfusion dependent. Of course they didn't include patients that were deletion 5 Q, and they did not allow patients that had a prior lenalidomide or HMAs. The other thing that it's very important to mention is that this patients were transfusion dependent, but if you can see, these patients required four units or more of transfusions, this is very heavy transfusions, four to six units.

Many of these patients with other agents usually do not respond to anything. So that's something that I have to really, really clarify here. And this patients were randomized to to one to Imetelstat or placebo. The primary endpoint was eight week  transfusion independence, RBC transfusion independence, and secondary endpoints, you know, were 24, week RBC transfusion, independence and among others.

Ravi Vij  06:05
So it is an IV drug given every four weeks.

Jesus Lugo  06:08
Correct. It is an IV drug, and it is given every four weeks and for about two hours.

Ravi Vij  06:14
And so what, were the results like? You're excited about this, tell us what is exciting.

Jesus Lugo  06:22
I think this is extremely exciting. Because like I mentioned, these patients are heavily transfused patients, that you would think that they would not respond, because like I said, having four or six units, and this patients had some of them, the median was about six units at baseline that they were requiring, many of these patients don't respond to anything.

And you can see here as well, and um, the slide that we're showing the hemoglobin rise of these patients on the Imetalstat was 3.6. If you see on lustapercept some patients responded only up to like 1.5. So we are seeing I think that a very potent drug. So that is exciting. The other thing is that the it showed 40% of the patients responded at eight weeks versus 15% on on placebo. So that is something very good response.

Ravi Vij  07:30
It seems like you're saying these are heavily transfused patients more so than perhaps the most are perceived in the ESA trials. Is that fair to assume?  And how durable were the responses?

Jesus Lugo  07:54
Well, their responses, as you can, as you can see here, the responses go down with time. But some patients were able to respond up to a year.

Ravi Vij  08:09
That's done bad. So and then, obviously, you mentioned their various risk stratification schemas for MDS. And so how does this do for the various risk groups within the low overall low risk category?

Jesus Lugo  08:29
All right, I think I misspoke. I what I wanted to say some patients responded responded more than a year, not up to a year. So, yes, so patients that were IPSS low, versus patients that were IPSS intermediate. The patients that received Imetelstat you know, they still responded versus the patients that received placebo. Most of the patients that received placebo that were intermediate did not respond. Compared to the patients that received the Imetelstat everyone irrespective if they were low or intermediate, they responded. The patients that received placebo no response, basically.

Ravi Vij  09:19
And I guess, even using the more modern IPSS-R  system, the results were favorable.

Jesus Lugo  09:29
Correct. Also with the IPSSR patients with Imetelstat. When they were low, they responded and again, patients that were IPSS-R intermediate there is zero response on the placebo arm.

Ravi Vij  09:47
So obviously, a very marked improvement, and what about the cytogenetic risk categories divided by cytogenetic risk categories was there also better chance of Imetelstat doing the job?

Jesus Lugo  10:08
Yeah Imetelstat significantly increase the proportion of patients irrespective of the cytogenetic risk category as well, compared to placebo,

Ravi Vij  10:21
And this may be something that not as many people are familiar with what is IPSS- M.

Jesus Lugo  10:27
So, IPSS-M is a newer risk category that we have now, we used to have the IPSS, the IPSS-R. And now, the IPSS M is something that we have since 2022 is a new risk category that incorporates molecular markers. So, NGS is incorporated into the risk stratification and it can give us a more detailed risk stratification. So, some patients because of that, because of the risk, because of the NGS or because of the molecular mutations, they can, their stratification can change. So, some of them maybe are changed to intermediate some of that were intermediate go to high risk. So, that is something that can happen they can be recategorized

Ravi Vij  11:26
Seems as like this seemed to do the job even if you use the IPSS M system to categorize.

Jesus Lugo  11:35
So, as you can see here in this in this slide, what it says is that some patients were recategorized as IPSS M high risk, because the study did not use the IP SS M it used the IPSS. And using the IPSS M,  some of these patients were recategorized as high risk, and they still saw a response with a Imetalstat.

Ravi Vij  12:06
So, the other thing is that, unlike ESAs, and perhaps even luatapercept, which modifies you know, the cytokine mileu, perhaps this drug attacks the root biology of the disease and is perhaps disease modifying based on its effects on the mutational profile of the underlying disease is that what we take away?

Jesus Lugo  12:32
You know, I am very glad that you're mentioning this exactly. So, as you can see, here, it can, we were seeing that this has potential, disease modifying effect, because you can see that it can decrease actually DNMT3A or as ASXL1 allele frequencies. and they are correlated with longer transfusion independence. And this is very exciting, you know, because it opens up the door at also leading to prolonging maybe overall survival, maybe decreasing leukemia reduction in this patients. It's something that we have never looked into in patients that are lower risk, and maybe we now have may have the possibility to look into these things.

Ravi Vij  13:26
So and again, that has probably to do with how the drug works. As we said the ESAs and the lustapercept group of drugs seem to modify the cytokine milieu, how does Imetelstat work?

Jesus Lugo  13:42
Yeah, so Imetelstat has a very interesting mechanism of action is actually a first in class telomerase inhibitor. And you know, telomeres are nucleotides that are at the ends of the chromosomes. What they do is that they prevent the chromosomes from breaking during proliferation, and MDS actually has increased telomerase is which maintains telomeres and prevents cell death. And basically, what is does and a telomerase inhibitor is that it is selective at killing, while allowing a normal residual hematopoiesis to reemerge. So selective about killing specifically these cells theoretically.

Ravi Vij  14:41
So, I think there's been some talk about the toxicity profile of this drug. So what can you tell us about the side effects?

Jesus Lugo  14:51
Yeah, so the side effects of this drug. There have been some important thrombocytopenia s and neutropenia with this medication, grade three and grade four, compared to placebo, about 60s in the 60%. That you don't see with lustapercept and that you don't see with ESA s. What I can say, though, is that they are manageable are usually seen during the first or second cycles. And they are reversible.

But yes, it's something that we need to take into account. It's something that we will need to manage as well. And it's something that gets better with a dose reductions with delaying also delaying treatment, and it's something that we'll we'll also have to maybe give prophylactic antibiotics or prophylactic antivirals, antifungals to, to these patients. So new strategies and new things that we will have to do. But regardless, I think, and the other interesting thing that I have to say, though, is that even though they had this important neutropenia, and thrombocytopenia has, it did not correlate with infections or bleeding.

Ravi Vij  16:19
So as you seemingly mentioned, these seem to be sort of transient in the first cycle or two, and perhaps represent that you're getting rid of the malignant clone and the normal hematopoiesis is just taking some time to emerge. Is that possible? The the explanation for this observation?

Jesus Lugo  16:42
I think it could be, yes.

Ravi Vij  16:46
So then, how do we put this together? So we're having an increasing number of options? Where do you see if the drug is approved, as expected in the near future, using this in your own practice?

Jesus Lugo  17:04
I think right now, the way that we have to use it, or that I will use it is for patients that have failed erythropoiesis stimulating agents or patients that are not eligible to get them because their Epo is high or more than 500, that I know that they're not going to be able to respond to have a meaningful response to ESAs. I think as well that it will give us the ability to do more clinical trials in the very near future. Because as I said, I think it's a very potent drug, as we can see.

And we can take the example of lustapercept that it was only approved for patients that were ringed sideroblast, SF3B1, as a second line after they failed ESAs as well. And now, it was brought to the frontline. So maybe something similar might happen to Imetelstat and you know, in the future as well, I don't know, I think that we have to be thinking about other things right now.  Lustapercept as well.

There's a clinical trial, The ELEMENT trial that we're looking to give it up patients that are not even transfusion dependent. So we're looking at many other things. So I think that the future in lower risk MDS, even though we don't have as many options as other diseases, I think that the future is still bright, and we're getting many other options. And I am very happy for this patients. Because even though we call it low risk MDS, I think is sort of a misnomer, because these patients still have a lot of morbidity, because having a low hemoglobin gets you to having a very low quality of life.

Ravi Vij  19:09
So it seems like this drug does increment thehematocrit  great, but is perhaps not the drug to use if you develop multilineage or cytopenias, in which case HMA is maybe the preferred option. Is that how you look at it?

Jesus Lugo  19:28
Correct, I think that if you have multiple cytopenias, is something that you should not use, of course, you we need to take into account that it causes thrombocytopenia, and neutropenia. So I would only give it to patients that have good platelets that have good neutrophil accounts, good white cells, and I would only use it for anemia, correct.

For patients that have a other types of cytopenias I would, unfortunately still use HMAs. For patients that have thrombocytopenia, you know, it might still be controversial, but for patients that have isolated thrombocytopenia and low blasts, we can use a TPO receptor agonist . And then the other thing I would mention is that it is not studied yet, but I think that we have to also look at other subsets of patients, maybe patients that also have bone marrow fibrosis along with MDS, maybe it might not be the best idea to give this agent either because they might have a lot of cytopenias as well or cytopenia that might be brought up because they don't have that much reserve either because of the fibrosis.

Ravi Vij  20:56
So though it is being studied in myelofibrosis, and I think there's a pivotal trial that is seeking to show that it improves survival in patients with relapsed refractory myelofibrosis. So I guess they are venturing into areas other than MDS already.

Jesus Lugo  21:11
That is correct. We will see.

Ravi Vij  21:15
Well, I appreciate your willingness to come and educate our audience about Imetelstat and the exciting development. Hopefully we have this drug to give to patients in the very near future. And I hope I can count on you to come back and educate us about other exciting developments in this field.

Jesus Lugo  21:36
Thank you very much. It was a pleasure. And thank you for having me.

Ravi Vij  21:39
Thank you
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