Amer Zeidan:

Good morning, good afternoon, good evening. Welcome everybody to a new episode of MDS Sessions at VJHemOnc. My name is Amer Zeidan and I’m an Associate Professor of Medicine at Yale University and it’s really a true pleasure to come today and discuss a very evolving area, which has been after many years of lack of new drugs, have been seeing a lot of new developments and promising drugs. So to do a very good coverage of this area, I’m joined by two very good friends and excellent experts in myeloid malignancies, Dr. Valeria Santini from the University of Florence in Italy, and Dr. Courtney DiNardo from the MD Anderson Group. We’ll be discussing some of the new agents that are currently approved and some of the ones that are in late testing in the clinical trial field. And also, we’ll make the discussion somewhat oriented to the clinical practice.

Thank you so much, Valeria and Courtney, for joining me.

Valeria Santini:

Thank you.

Courtney DiNardo:

Happy to be here. Thank you so much.

Amer Zeidan:

Thank you. So maybe we can start with you, Valeria. You have made important contributions to several of the drugs that are approved. Historically maybe we can start with your view about this field, since you have been seeing some of the slow developments over the last 15, 20 years. What do you think has helped in getting, finally, some drugs beyond ESA and lenalidomide clearly after all these years of waiting?

Valeria Santini:

Thank you for giving me this historical perspective because it’s quite interesting. First of all, I just want to stress the fact that our patients with low-risk MDS mainly have anemia that leads to transfusion dependence. And this is something that affects profoundly the quality of life and also the general health of patients. So this has been a worry for many years, but we couldn’t find any really effective drug. As you may know, almost 10 years ago, we tried to consolidate the data indicating that lenalidomide could have some effect in patients with low-risk MDS, transfusion dependent but not carrying del(5q). And this was indicating less than 30% of response. So indeed, there was a signal that the treatment with lenalidomide could work, especially in some subset of low-risk patients with low production of erythropoietin, but still not really satisfying, 27% of response, and not very long-lasting. So we couldn’t find actually specific biomarkers that were indicating the responsive patients, and therefore the research went on in different ways completely. And there were actually in a couple of Phase II trials, some studies that were carried on because of just serendipity observation. So luspatercept and more so sotatercept were two ligands of activating receptor 2B that were observed to be increasing hemoglobin levels in patients treated for metastatic solid tumor. So this observation led to the trials in myelodysplastic syndromes in which anemia was the most important fact. So it was a very initial observation, a completely different pathway to stimulate and to block, in fact, more than stimulate, with the two drugs. And in fact, luspatercept in the Phase II in all comers low-risk MDS induced a response, especially in the patients with ring sideroblast. And that’s why we went on in this way only with the luspatercept study in ring sideroblast low-risk MDS patients with transfusion independence. And in these cases we reached, as it is known I suppose, nearly 50% of transfusion independence longer than eight weeks.

So this was a very important and relevant result because, as I mentioned before, we had no alternative for these patients. By the way, patients with a long expectancy of survival with transfusion dependence lasting for many years, so it was really a pace forward, a very important one. And as you know, the approval of the drug reached both FDA and EMA in consent in 2020. So this was, I think, a very important achievement after many years. So the important thing is that, for the first time, we could really show a consistent and persistent effect of a drug in terms of transfusion independence. Now we know with a long follow-up that a substantial, although small, proportion of patients can still be in transfusion independence continuously for more than one year. So, just triggering a completely different pathway led to indeed a very important result.

And another, I don’t want to spend too much time to explain to you how important it is to become transfusion independent. Still we are not able to do it for all patients with luspatercept, and other drugs have been tested like imetelstat, not yet approved, but a very interesting drug that has a completely different mechanism of action. The mechanism of action seems to be, seems to be I say because it has to be proven that is the real one in terms of inducing response, the inhibition of telomerase activity.

And with imetelstat, the results were also very interesting because the patients were compared to placebo and the patients were the same subgroup of patients treated in the Phase II of luspatercept. So transfusion dependent, all comers, low-risk MDS patients. And the drug, given intravenously every four weeks compared to placebo, could indeed induce transfusion independence in nearly 40% of cases, which was, again, a very important result that has been recently published. This response is maintained, again, is maintained for six months and then in 18% of cases more than one year continuously. So these patients have really a substantial advantage by being treated with imetelstat. I was a little bit looking for my words, discussing the mechanism of action. It has not been demonstrated clearly, but what seems quite clear is that the baseline telomerase activity or the telomerase length overall as well as H third level, does not seem to correlate with a response. That’s why we think that maybe there is something else than telomerase inhibition.

Amer Zeidan:

Yeah, thank you so much, Valeria. This is a great historical perspective. I think you alluded very well to the fact that it’s not uncommon in the MDS field to actually get drugs approved and then we figure out the mechanism of action, as happened with lenalidomide and potentially with imetelstat. However, I think the most important aspect, as you mentioned, is that we had a very long period between 2006, when lenalidomide was approved in the U.S., until 2020 when we had the first drug approved after 15 years, which is somewhat similar to what happened in AML.

Courtney has been a leader in drug development in AML and many, many years, 40 years with no drugs, and then 10, 11 drugs approved within six years. So hoping for a similar scenario in MDS. So we’re going to go through the details of these drugs and mechanisms and the data in a little bit, but just to backtrack for a second, Courtney, in your clinic this issue of what is lower-risk MDS and what is higher-risk MDS has been kind of a moving target. Every few years we seem to get these new prognostic tools and we are seeing more and more patients shift between these risk categories. So today in your clinic, when you see a patient, how do you conceptually decide on the treatment? We still think of patients in a binary way, either lower-risk or higher-risk.

Courtney DiNardo:

Yeah, no, I think that’s one of the most important questions is trying to figure out what risk classification your patient has so you know how to best treat the patient. And I think, you’re right, it has changed, from IPSS to the revised IPSS to now using the molecular IPSS version. And I think, actually, I saw a patient in clinic yesterday who was referred to me and had transfusion-dependent anemia, had sustained white count, sustained platelet count, and did have excess blasts, and had five different high-risk mutations. And so this patient was billed as a low-risk MDS patient. But when you incorporate the MDS model, they’re actually quite a high-risk patient that may benefit from a hypomethylating, for instance, hypomethylating agent instead of luspatercept or an ESA. And so I think it’s just really important to make sure people are aware that the molecular IPSS model is a very straightforward program on the website. So I think one of the most important things I do when I’m teaching people in the clinic, the fellows, the residents coming through, is just to make sure to always be using that to identify the updated risk.

And I think it’s really important also, just going back to your statement about we knew about deletion (5q) and lenalidomide and then it’s just been years and years without additional therapy. What’s really important is that that population of patients with ring sideroblast often correlating with SF3B1 mutations, right? So the knowledge of that SF3B1 mutation really can help you identify that luspatercept may be a particularly beneficial treatment option.

Amer Zeidan:

Yeah, thank you Courtney. And I think this is very important. In my mind, I always felt that lower-risk MDS somewhat has been underestimated in terms of its severity when people call it lower-risk MDS. And I do agree that most of those patients will die from MDS, even whether it’s lower or higher risk, most of them will die from the disease rather than with the disease. And I think being transfusion dependent, even if you score lower-risk, is certainly a big problem.

Valeria, maybe we can go through your current paradigm right now. I know there are differences in the approval of the drugs between the U.S. and Europe, but let’s say, I believe luspatercept got approval, but it’s, I guess the-

Valeria Santini:

No, no. Luspatercept is approved in Europe and it has been approved only for secondline. So refractory/relapsed after ESA transfusion-dependent patients, and it’s available. Some countries have restriction in terms of, how do you say, price. But otherwise, it is approved everywhere.

Amer Zeidan:

So, let’s assume it’s approved in the frontline setting. How do you approach your patients right now knowing you have ESA, you have hypomethylating agents, you have luspatercept and lenalidomide?

Valeria Santini:

That’s a complex question, although I think it’s a very interesting one because it’s what we will face in the next few days and weeks. So, I will first of all try to delineate the molecular characteristics of the patient. And as Courtney just outlined, I think I will evaluate the patient with IPSS-M. This is greatly helpful, not only to establish the prognosis, but also to understand which somatic mutations are targetable. Then, as a matter of fact, we are used to treating our patients with anemia, with erythropoietin-stimulating agents in firstline. We have been doing it for decades with really very good optimization of the treatment. I would anyhow select patients on the basis of some very well-known parameters. So you can start with ESA only if patients have a relatively recent diagnosis of MDS, if they are not transfusion dependent, and especially if they do not have multiple somatic mutations that are correlated with the absence of response. In that case, I would certainly opt more for luspatercept had I the possibility to treat in firstline.
I would not go in firstline with a treatment with hypomethylating agents unless this patient has also other cytopenias, like thrombocytopenia especially, that can be responsive to hypomethylating agents. Having said so, I also have to stress the fact that in Europe we are not able to use, unless off-label, the hypomethylating agents in lower-risk MDS patients, although we know that they are effective, they’re effective both in firstline and in secondline.

I’d rather then consider very carefully the patient that I see when I’m sure that these are lower-risk patients for the parameters I just mentioned. So it’s a very careful selection that should be done every time we consider treating a patient. And we should, just to tell you what I think is paramount importance is to treat early. You don’t have to wait too much to treat these patients because whichever treatment you choose, you have to be on time to treat them and not wait too long.

Amer Zeidan:

So before I go to Courtney, just to make sure for the frontline, so your approach is still being selective in terms of which patients to use in the frontline setting. You would not be giving luspatercept across the board for all anemic transfusion-dependent lower-risk patients.

Valeria Santini:

No.

Amer Zeidan:

You still look at EPO level and ring sideroblast and all of these factors, right?

Valeria Santini:

Yes, I do not exclude the fact that some patients without ring sideroblasts can respond very well. But what has been shown in the COMMANDS trial is what has been observed in transfusion-dependent patients. And in our optimization of therapy of patients, we do not treat a patient with ESA when they are transfusion-dependent. So this is a second step. We treat them earlier, we treat them before they become transfusion-dependent. So, the great activity of luspatercept in firstline has been demonstrated in transfusion-dependent patients, and this is why it has been shown also to be, in some cases, superior to ESAs. So still I have a very careful and conservative, if you wish, way to select patients for treatment.

Amer Zeidan:

So Courtney, before we go to the secondline, I just wanted to see your thoughts from the U.S. perspective on
the frontline management of anemic patients with lower-risk MDS. Is it different than what Valeria outlined?

Courtney DiNardo:

Not so different. I think, again, what we haven’t highlighted yet is the fact that even though these are lower-risk MDS patients who have kind of a sustained neutrophil count and sustained platelet count, these patients that have profound anemia oftentimes are not only needing transfusions, but just the level of fatigue is really debilitating for a lot of these MDS patients. And so from, you’re right, I do a lot of AML and so I’ll see a patient with lower-risk MDS and say, “Oh, you’re going to do great.” But really patients can be feeling, this disease can come with quite a toll in terms of quality of life and energy level and fatigue in particular. And so when we have a patient that fits that low-risk MDS, isolated anemia, if they have ring sideroblasts and an SF3B1 mutation, then it’s clear, right? It’s so obvious for us in the U.S. that have access to luspatercept that that is the frontline treatment of choice.

But as Valeria was mentioning, based on the COMMANDS study, even if they don’t have that phenotype, that luspatercept is reasonable as a frontline option over and above ESA therapy. And so when you start lumping up subgroups and looking specifically, you didn’t see that clear statistical win of luspatercept. But when you look across the board at those forest plots and everything, what favors luspatercept versus what seems to favor ESAs, really I think luspatercept for all the various different subgroups really seems on par or better. And so there’s still a little bit of debate, I think, should you use an ESA first or luspatercept first in those non-ring sideroblast, non-SF3B1 patients. But I think either are appropriate and we are more and more choosing luspatercept for those patients.

Amer Zeidan:

Yeah. So I think there’s a general consensus that RAS-positive patients should be getting the drug in the frontline setting. I do wonder about how the activity of ESA will be after luspatercept in the frontline. So I think this is an important question to answer clinically. I don’t have any specific preclinical or theoretical reasons why ESA would underperform significantly after luspatercept. I guess, in general, most drugs secondline, thirdline would do less than frontline. But the bigger question in my mind is giving luspat followed by ESA versus giving ESA followed by luspat. But I agree with both of you that I’m not as concerned in the RAS-positive patients, but it’s certainly a very important question in the RAS-negative. These patients are going to be on therapy for probably the rest of their lives with one drug after the other and trying not to burn your bridges, as they say, in terms of subsequent therapy.

So Valeria, I think you touched on this point, which I think is very important, is the idea of treating patients earlier and earlier now that we finally have effective drugs. We still are challenged by the fact that we cannot say with certainty that any drug we give for lower-risk MDS patients will improve their survival, will reduce progression to acute myeloid leukemia. We still think of all the treatments that we give for these patients as palliative. And this is I think the major pushback against trying to treat patients before they are transfusion-dependent, before they are significantly symptomatic. So how do you go about this when you make that decision for your patients, whether it’s ESA or luspatercept or even with lenalidomide, which we have some nice data within that setting.

Valeria Santini:

Well, that’s a very important point. In fact, it has been shown that even ESAs when determining a good response and increasing hemoglobin can prolong survival, overall survival. This is a concept that is quite intuitive if you think that you have remodeling of the cardiac muscles already when your hemoglobin level is around 10. That means that, in fact, there is an impairment, there can be an impairment in the long run, in the long term for cardiac functioning. And this is only one of the problems.
Of course, this becomes more and more evident if you become transfusion-dependent. And treatment with luspatercept has shown a prolongation of survival, significant prolongation of survival, if you become transfusion-independent. So I do think that the sooner you treat, the sooner you avoid and the better you avoid complications related to anemia. Long-term anemia can indeed induce a lot of problems besides weakness, asthenia, fatigue. Just think about cognitive impairment in elderly patients like our MDS are.
If you have chronic anemia, your cognitive functions are, of course, decreased. And this is one thing. And if you have a cognitive impairment, your expectancy of life can be, of course, decreased. The sooner the better for any treatment. We learned it many years ago for ESAs. The sooner you treat, the best results you obtain. And of course the quality of life of the patient is improved because you have also more patients who respond, a higher response rate. The same is true for all the drugs, even for hypomethylating agents. So I think that we should really keep in mind this concept. Then you don’t have to wait until the patient has really very important symptoms, asthenia or other correlating symptoms, but you have to think of increasing hemoglobin on time.

Amer Zeidan:

Yeah. And I fully agree with you. Conceptually I always wondered if our bodies are basically working with a hemoglobin of 12 or 13 at least, then normally why would someone be normally living with a hemoglobin of eight or nine? It must have some bad effects and improving that should help. But clearly, I think the lack of very definitive data from randomized trials I think has been a challenge to try to move the field, I think to not only correction of anemia but complete resolution, which I think probably is going to be the next big frontier in MDS.

Courtney, to close on the frontline therapy before we go to the secondline therapy, you have pioneered a lot of work with the IDH inhibitors in AML. And that’s, I guess, one of the nice things about working across both diseases is using some of those therapies across AML and MDS. The Moffitt group has shown that some lower-risk MDS patients who have severe neutropenia seem to be enriched for IDH mutations, which I guess could make sense because it’s a differentiation block. But are there cases where you would use IDH inhibitors as a frontline treatment in patients with lower-risk MDS or you only use them after failure of the more traditional drugs that we discussed?

Courtney DiNardo:

It is definitely true that IDH mutations are quite rare in MDS at all. Right? And in general, IDH mutations, when they are present in MDS, are more frequently associated with higher-risk MDS. And you do, you see this phenotype where there’s a lower white count, there’s neutropenia, but yet there’s often excess blasts, sustained platelets. And so that IDH2 happens more often, but there are IDH1 mutations rarely in patients with MDS.

But there is also an association of IDH1 and IDH2 in clonal hematopoiesis and CCUS. And you can see these lower-risk MDS patients as well. And so I do think it’s one of those discussions where it’s certainly not approved to be using the IDH inhibitors in kind of the lower-risk frontline setting. But for all the things that we’ve been talking about where initiating treatment early and improving cytopenias and impacting the disease course is relevant, I think it makes perfect scientific sense to me that this would be an appropriate treatment to consider.

And so anecdotally, yes, we have done this in the clinic here where we’ve had patients who have cytopenias, relatively mild sometimes, but where there is a motivation and desire on behalf of the patient to try to improve those with an IDH inhibitor when they have either an IDH1 or an IDH2 mutation. And again, this is anecdotal, no published literature, but we have seen patients respond quite well to that approach. And there is, I will say, not to IDH1, but to IDH2, Kelly Bolton at Wash U is kind of running quite an interesting clinical trial of enasidenib, the IDH2 inhibitor, where it’s kind of a virtual trial only.
So it’s I think one of the first precedents in the United States at least, where kind of patients can be treated and enrolled in their home city. And I believe LabCorp or Quest comes to them to draw blood and deliver medication, and so I think it’s worth highlighting. I know it’s a little bit out of scope of this talk, but I just think it’s a really interesting format to be moving towards kind of these rare genomically molecularly defined subsets of myeloid diseases where we could potentially identify a benefit.

Amer Zeidan:

Yeah. And certainly the area of precision medicine has been a bit of a challenge in MDS because, as you mentioned, the rarity of these mutations, IDH, FLT3 is even way more uncommon, and I guess with the new classification, some of the patients who have NPM1 or other things could now be moved, I guess, to the AML field. So I think it’s a moving target, but still getting those next-gen sequencing results will help with some of the decisions about treatments.But certainly the presence of SF3B1, and the decision about use of luspatercept.

Valeria, I guess now moving to the second-line treatment, and I think this is one of the biggest kind of diversions between the U.S. and Europe because we have readily access to hypomethylating agents, which I think continues to be challenging in Europe for lower-risk MDS patients even after failure of other drugs. So what’s your perspective? Once you have tried ESA, luspatercept, potentially lenalidomide, and the patient is still anemic and transfusion-dependent, are there situations where you’re able to access hypomethylating agents, and how do you view the data in that setting?

Valeria Santini:

Yeah, indeed, we can, with enough labor requests, we can access hypomethylating agents. I actually worked on these many years ago and we showed that patients who lost response to ESA could respond in more than 50% of cases to hypomethylating agents. But then, in 2017, we published a very interesting paper together with the French group and Sophie Park led the study, in which we showed that actually hypomethylating agents or lenalidomide, mainly hypomethylating agents, were affected in inducing response in patient refractory/relapsed after ESA.

But in fact, the overall survival didn’t seem to be prolonged significantly more than the one we saw for patients who received only supportive care. Now, this is an old study, of course, and there were more than a thousand cases treated with supportive care and very few with the hypomethylating agents. So I think that we should indeed evaluate better the overall survival in this setting because sometimes these patients do progress not to higher-risk, but they have additional cytopenias.

And as I mentioned before, I think in these cases it should be one of the alternatives. They work, they work very well. Again, going back to the mechanism of action, I’m not so sure that the hypomethylating effect is the only effect to which we owe the efficacy, but I think that it’s indeed a tool that we should use more often in Europe as well. Keeping in mind again that they are mildly myelotoxic and we have to manage this, but I think we may access them. It’s a limited access, but still possible. So it’s not a widespread use.

Amer Zeidan:

Yeah. Courtney, your colleagues at MD Anderson have been near some of the, I think, bigger studies looking at the earlier use of hypomethylating agents in lower-risk MDS and continuous, I think, significant debate in the field about whether using these drugs very early in the disease is a good or a bad thing. I think some people say it’s disease-modifying, it might work on the disease in a more meaningful way if you do it early, while there has been some kind of theoretical concerns that you might induce some kind of concerning changes in the disease if you pull the plug on hypomethylating agents very quickly. So I’m not sure, where do you stand on this? How quickly do you tend to do a hypomethylating agent in a lower-risk MDS patient?

Courtney DiNardo:

Well, I think it really depends on the specifics of the patient because we will have some lower-risk MDS patients who have that isolated anemia and maybe have lost response or never responded to an ESA and luspatercept and they’re doing okay, they get maybe a red cell transfusion once a month and otherwise are not particularly impacted. And so that’s not a patient that I think you would want to start a kind of an early intervention hypomethylating agent for. But there are a number of patients that we’ll see in the clinic who just, like we were talking about earlier, that just feel horrible, that are getting frequent transfusions and have lower-risk MDS, but they have a really awful quality of life, and they say, I’m willing to try something to try to improve this. And so those are the patients that these kind of early intervention hypomethylating agent trials are appropriate for.

And I will say that you’re right, sometimes we will start a hypomethylating agent in a lower-risk patient and actually the other counts, the white count, the platelet count gets lower and it’s not clear that we’ve helped that patient feel better or do better. But conversely, we will see patients where they do, counts improve after a few cycles and they feel better, and that’s clear evidence to me that this is a reasonable strategy. We often do, I keep saying early intervention, lower-intensity HMAs because we’re often doing three or five days of azacitidine or three days of decitabine. So it’s not usually the full hypomethylating agent dose and exposure that a high-risk MDS patient gets.

Amer Zeidan:

Yeah. So in the last 10 minutes or so, I want to shift gears to some of the investigational drugs. Two areas I think would be worth covering. One is some of the novel drugs, which Valeria touched on at the beginning, such as imetelstat and oral hypomethylating agents, but also try to talk about some of the newer trends in the field, which are combination therapies and going to transfusion-independent patients very early on with some of, I think, the big even randomized trials right now. So Valeria, maybe we can start with you. Can you overview some of the most promising new agents, some of them, I guess, have been successful, such as imetelstat, others such as roxadustat have not been unfortunately that successful.

Valeria Santini:

Yeah, just to start, I just want to add one thing to what Courtney has said, and I agree with her. I just want to point out that hypomethylating agents are really useful when you have other cytopenias besides anemia, and that is something very important to keep in mind, also for the oral drug that we will touch upon later. Now, what about roxadustat? Roxadustat has been used in MDS after the evidence that this HIFalpha hydroxylase inhibitor was working so well in anemia of chronic kidney disease. So the chronic kidney insufficiency leading to anemia was very well treated with roxadustat, that was for that approved in China and also in Europe. Unfortunately, the design of the study in MDS, lower-risk MDS, was a little bit non-linear I would say so that the results led to a very high proportion of patient, 33%, responsive to placebo. So that cannot be what we should see. So there must be some bias in the design of the study. But beyond that, the efficacy of roxadustat didn’t seem to be extreme. I think that this is also an important warning to design very clean and very clear studies, because otherwise we lose the possibility to have an extra drug for our patients. I’m not sure what would be the result of roxadustat in a better setting, but it was an interesting drug that we will not see developed in this setting of patients. And it’s a pity.
Other drugs, like imetelstat, as you mentioned, have shown activity. Also partially on neutrophil and platelet counts, s,o meaning that there is the possibility of having a disease-modifying effect, which is very important and should be confirmed and explored further. And then I think you want to touch later on the hypometylating agents, oral hypometylating agents, maybe some other drugs are coming, like very early data with canakinumab, interleukin-1alpha inhibitor, that could be very interesting in some cases of lower-risk MDS where the prevalent alteration is an increase in inflammation, and other drug source like the IRAK-4 inhibitor that Courtney mentioned before.

Amer Zeidan:

Yeah. So I think all of these are potentially exciting drugs. I think in my mind I agree with you, the design of the trials in lower-risk MDS can be problematic. And I do share your concerns about the roxadustat Phase III design. I do think the drug seems to have clinical activity based on early phase trials, but imetelstat as you mentioned, I think the activities there is clear and it sounds like the drug should be approved, at least in the U.S., and I guess we’ll see what happens in Europe. Courtney, in addition to the drugs that Valeria mentioned, anything that catches your attention from what you have seen in the field in terms of lower-risk MDS?

Courtney DiNardo:

Just to highlight, I think that the IRAK inhibitors are something that we are paying attention to and have trials open here. Because these MDS patients, especially the lower-risk MDS patients, there is this kind of heightened inflammatory signature. And I think there’s a rationale where inhibiting the IRAK inhibitors and leading to downregulation of the inflammasome pathway could potentially be beneficial for these patients even who don’t have excess blasts and all the things that make it harder to do the MDS trials in terms of response criteria. So I think that is a major concern and challenge with low-risk clinical trials.
We haven’t talked as much about imetelstat, but I think it’s a really interesting new therapy regardless of whatever the mechanism of action is, if it is really related to telomerase inhibition or not. I think the fact that 40% or so of patients become red cell transfusion-independent is good, and it is kind of in line with some of the other therapies we’ve been talking about. But what’s really impressive is just the duration in those patients who do experience that transfusion independence, just how sustained it is for many months and even upwards of a year in the follow-up. So I think that’s really interesting.

I’m a little bit nervous, that wasn’t a study that I participated in, so when I look at the neutropenia and thrombocytopenia, that is a side effect of the imetelstat, I think that’s something to be paying attention to. But from what I can tell, and I would be interested if either of you have more insight, is it seems to be relatively short-lived, a thrombocytopenia and neutropenia that is really only present during the first few cycles and seems to improve over time. So I think it’s definitely something that, if it is FDA-approved in the coming weeks or months, will be interesting to get some clinical experience with.

Valeria Santini:

Yeah, you are perfectly right and I agree with you. Imetelstat is very interesting drug, and as you mentioned, sometimes you have thrombocytopenia. Actually, I have quite a large experience with the drug and I can tell you that patients who respond can still have a mild thrombocytopenia, but they recover and it’s transient before the following administration of the drug. At present, I treat one patient who has been responsive for four years and still has a very mild decrease in platelets in between cycles, but he’s doing fine. Normal hemoglobin, he was very severely transfusion-dependent, and I think that the maintenance of the response is really impressive. It’s something that we should keep in mind for our patients.

What I think we should touch upon shortly is the fact that we don’t have only anemia, but in some patients, we have severe thrombocytopenia. And unfortunately, we have very small choice here and very little options of therapy because no therapy has been approved specifically for thrombocytopenia, nor romiplostim, nor eltrombopag, although they showed activity. And then that’s a point of research and reflection we have to do. And then, there, I think oral hypometylating agents that you mentioned are really active and should be considered. Although, again, I use off-label eltrombopag with some success in patients with low-risk MDS and severe thrombocytopenia.

Amer Zeidan:

And I agree with this as well. I do think imetelstat, I think is very valuable in terms of transfusion independence that’s durable. The cytopenias are certainly there, but they are manageable generally. For those who are actually interested in more details, I encourage them to go to the recording of the ODAC meeting that took place a few weeks ago in which I think there was a very intense discussion about the benefits and the risks. But I was happy to see that the Oncologic Drug Advisory Board came up with the same conclusion that many of us who worked with the drug did, is that the risk-benefit profile is significantly in favor of the drug and I anticipate the drug should be approved in the U.S.

So in the last few minutes, I think one subject I wanted to touch on is the concept of combinations. This is something that is used really in all oncology, in AML, and starting to be used in MPN. It’s not something that we historically have used much in lower-risk MDS. We tried a lot in higher-risk MDS without success, but in lower-risk MDS in particular, some centers are looking at combining ESAs with luspatercept such as Lionel Edes in the French group, and Mikkael Sekeres is looking at combining luspatercept with lenalidomide. I think there’s a number of combinations that also have been tested that did not go very well, such as ESA with aza, and TPO with aza in the higher-risk disease.

But conceptually, maybe I can start with you, Valeria, and then go to Courtney. Do you view lower-risk MDS as something like multiple myeloma and others where we should try to combine and hit very early on rather than think about sequential monotherapy with the idea of minimizing symptoms and prolonging control versus going after the clones from the get-go with the best combinations that we have?

Valeria Santini:

Going after the clone is difficult still for lower-risk MDS, unless you consider the fact that, for instance, imetelstat seemed to have a disease-modifying effect with the lowering of variant allele frequency correlated with response. So in that case, yes, I would think that combining this agent with, for instance, ESA could be a good idea because you’re lowering the clone, the dysplastic clone, and at the same time stimulating the normal, hopefully, the normal erythropoiesis.

On the other hand, there have been data published, especially by Rami Komrokji and the Tampa Group of the association of luspatercept and ESA and, previously, lenalidomide and ESA with quite interesting results. Lenalidomide seems to re-induce a response to ESAs, even in patients who have lost this response. So I think that, as you pointed out, not sequentially, but in combination, these drugs could be synergistic, so induce more response and possibly with a longer duration. We have no data, unfortunately, in this sense. So, I suppose that a good and extremely fruitful idea would be to combine our efforts and design randomized combination studies to see whether we can prolong these responses, increase and prolong these responses.

Amer Zeidan:

Courtney, I don’t know if you have any thoughts on this. Clearly combinations in AML has been, I think, a mainstay of treatment. And I don’t know, conceptually do you view that this is an approach that makes sense in lower-risk MDS?

Courtney DiNardo:

I think it makes sense. I think there are very few, if any, kind of experiences in all of cancer oncology where sequencing one drug after another is the best approach as opposed to putting things together to make synergistic combinations. And these have different mechanisms of action and really should be complementary and potentially synergistic. The main challenge, of course, with the low-risk MDS is you don’t want to be compounding toxicity, right? These are patients that… you want to make sure that there is good tolerability to the things that you are combining together, but that’s the whole point of the clinical trials that need to be done to see if this is a valid strategy, which I suspect will be.

Amer Zeidan:

Thank you so much. So this was a great discussion. I think we’ll conclude by any final thoughts from both of you about anything that is particularly exciting for you in terms of lower-risk MDS development or any particular data sets that you look forward to in the next couple of years? Maybe we’ll start with Valeria.

Valeria Santini:

It is difficult to see the future, but I suppose that selecting patients, so characterizing patients in the optimal way, would help us to choose therapy. So, I think that both molecular phenotyping and flow cytometry phenotyping will be incredibly important to choose therapies in the future. So it’s something that is not available widely today, but putting more attention into this characterization and stratification of lower-risk MDS patients is going to lead to very important results, in my opinion.

Amer Zeidan:

Courtney?

Courtney DiNardo:

Yeah, I completely agree. I think our improved scientific understanding and molecular and genomic classifications really have helped us to better understand the different biology of myeloid diseases. And so now I think building off of that, identifying subsets, and then creating therapies that are beneficial for certain subsets are going to be really important. We haven’t talked about the splicing factor inhibitors because that was a story that kind of came and went, but potentially in the future, I think there’s so many subsets of patients with MDS that could potentially be benefited by novel therapeutics coming down, hopefully, the pike soon. So thank you.

Amer Zeidan:

Yeah, and thank you so much to both of our experts, Dr. Valeria Santini and Dr. Courtney DiNardo, and we look forward to having a subsequent discussion with both of you once we have additional data in the future on lower-risk MDS in these MDS sessions for VJHemOnc. Thank you so much everybody.

Valeria Santini:

Thank you.

Courtney DiNardo:

Thank you.

Amer Zeidan: Consultancy: Schrödinger, Notable, Chiesi, Mendus, Otsuka, Foran, Syros, ALX Oncology, Kura, Seattle Genetics, Servier, Boehringer-Ingelheim, Jazz, Orum, Geron, Syndax, Gilead, Zentalis, BeyondSpring, Incyte, Pfizer, Celgene/BMS, Janssen, Amgen, Agios, Daiichi Sankyo, Tyme, Taiho, AbbVie, Ionis, Takeda, Genentech, Epizyme, Lox Oncology, Novartis, Astellas, BioCryst, Regeneron; Honoraria: Schrödinger, Notable, Chiesi, Mendus, Otsuka, Foran, Syros, ALX Oncology, Kura, Seattle Genetics, Servier, Boehringer-Ingelheim, Jazz, Orum, Geron, Syndax, Gilead, Zentalis, BeyondSpring, Incyte, Pfizer, Celgene/BMS, Janssen, Amgen, Agios, Daiichi Sankyo, Tyme, Taiho, AbbVie, Ionis, Takeda, Genentech, Epizyme, Lox Oncology, Novartis, Astellas, BioCryst, Regeneron; Research Funding: Foran, Shattuck Labs, Astex.

Valeria Santini: Advisory board: AbbVie, CTI, BMS, Curis, Geron, Gilead, Keros, Novartis, Servier, Syros.

Courtney DiNardo: Research Funding: Abbvie, Astex, Beigene, BMS, Foghorn, ImmuneOnc, Jazz, Rigel, Schrodinger, Servier; Consultancy/Advisory Board: Abbvie, AstraZeneca, BMS, Genentech, GenMab, GSK, Immunogen, Notable Labs, Rigel, Schrodinger, Servier; CDD is supported by the LLS Scholar in Clinical Research Award.