Amer Zeidan:

Welcome everybody. Thank you so much for joining us in another session, MDS Sessions from VJHemOnc, focusing on all the new and exciting developments in lower-risk MDS. My name is Amer Zeidan, and I’m joined today by three top experts in the field, Dr. Garcia-Manero comes from the MD Anderson, as well as Dr. Rena Buckstein from Canada, and Dr. Andrew Brunner from MGH.

So what we are going to be talking about today is focusing on all the new developments that have been happening, in particular over the last couple of years with new drugs and new therapies. But we will also focus on some of the practical aspects in the day-to-day management of lower-risk MDS patients, especially some of the common pitfalls that we commonly see in the practice, which might lead to sub-optimal outcomes in some patients. So, thank you so much for joining me today. Maybe I can start with you Guillermo. What’s your current standard approach for patients with lower-risk MDS when they come to your clinic?

Guillermo Garcia-Manero:

I don’t think it probably is very different from what you guys do. So we will perform a bone marrow examination. This is actually something that I always tell my fellows here. Like I see a patient referred by Dr. Zeidan from Yale or Dr. Brunner from Mass General, the top hospital in the country; why should I repeat the bone marrow test? Well, because there’s a 15 to 20% discrepancy rate between one center and the other.

Indeed, actually I can tell you that yesterday I saw a very nice retired cardiovascular surgeon from some place in Pensacola, lower-risk MDS and he had 63% blast in the bone marrow. So the first step is you need to really, when you’re evaluating these patients, confirm the diagnosis. Then of course you’re going to use probably some type of prognostic tool, let’s say IPSS-R, that is what we should all use. And now you’re going to implement the genomic test with the IPSS-M.

And I think that’s the question, right? Now, I think we’ll be discussing this, you get this molecular data and all of a sudden this patient has multiple mutations in the bone marrow and we now think, okay, actually the risk is upstaged by this molecular information even if the features are low risk in terms of blasts and cytogenetics. So I think that’s very important because once you confirm diagnosis, predict risk by IPSS-R & IPSS-M, you look at the age of the patient and the degree of cytopenia and the degree of transfusion dependency. And I guess we will talk at some point about CHIP/CCUS.

And you start putting this all together and you say, is this person someone that needs to be observed? Or, is this someone that is a candidate for let’s say luspatercept or growth factor upfront or lenalidomide, or is it a younger patient where of course there is no indication for early transplant, but something that we need to start thinking about. So this disease is very heterogeneous. That first visit, I think, is critical, and you really need to think about a map that is going to be what guides you over the next few months, few years, hopefully on this patient.

Amer Zeidan:

Andy, what’s your current approach in terms of your first-line treatment for anemic lower-risk MDS patients? And maybe actually I can do a quick poll. Is there an EPO level at which you would not use ESA? What’s your EPO level? Maybe I can start with you and then get an opinion from Guillermo and Rena.

Andrew Brunner:

Sure. I mean I think that that has become more clear. Even just a few years ago when there were fewer therapeutic options, you might try EPO even in patients with moderately high serum EPO levels, just because there are those occasional patients where it might work and there weren’t other options that were really palatable for many, especially older patients. I think, I’m pretty consistent above 500, that I don’t really feel like we have better options and we have newer therapies. Luspatercept has really changed how we approach people with high baseline EPO levels. There’s also a smaller subset, but in del(5q) disease they usually will have a high EPO level, and so it’s just not as much of a debate as to whether to give them a challenge or not.

I think between 200 and 500, I tend to see as a little bit of a gray zone, depends on how quickly they need a response and other features of their disease. But below 200 I’m still generally considering whether we should give them a trial of ESA. And then that gets into a little bit of a nuanced discussion about likelihood of benefit, deciding between ESA and luspatercept, what will give me the longest duration of therapy overall in the lifetime of this patient, and how other disease risk factors kind of impact that decision.

So I guess those are kind of my general cutoffs, that over 500 seems pretty clear, and below 200 I think the chances of response are reasonable whatever agent you use, whether it’s luspatercept or ESA. And then there’s a little bit of a gray zone between whether ESA matters, or has a role in the 200 to 500 upfront setting, I think.

Amer Zeidan:

And Rena, for Canada, I don’t know if luspatercept… I don’t think it’s approved in the front line, right? But what’s your kind of conceptual approach should you, I guess, be able to use it in the front-line setting?

Rena Buckstein:

Yeah, I think I would agree with Andy. I think responses above 200 are uncommon, but we would probably try the ESA. I think if their level was above 200 and they were transfusion-dependent, I think that even reduces the chance of response even lower. So if I had luspa available, my go-to would be luspa for sure, but I don’t have that available yet.

So up to 500, I would try ESA, I’d probably move the dose up quickly. I wouldn’t keep them for three months at 40, I’d move them up quickly. I’d go even as high as 80,000 units to decide if they’re going to be responders within three months. I make sure that their iron stores are replete, and that their B12 is replete and all that stuff because sometimes that is overlooked.

And then my next step would be, if they don’t respond to ESA, would be luspa if they have SF3B1, or they have ring sideroblasts, that’s what’s approved for us, we don’t have it approved for non-ring sideroblasts or SF3B1 in the second-line setting. So in those situations, again, building on what Guillermo said is, if they were younger and their IPSS-M score kind of upstaged them, I would be typing them and thinking about allo transplant. Since we know that somebody who’s transfusion-dependent is basically effectively upstaged already, and then you add the IPSS-M, I’d be thinking about transplant. And maybe as a bridge to there to try to get them off of transfusions. I would think about a hypomethylating agent like decitabine/cedazuridine. Yeah.

Amer Zeidan:

Okay. That’s great. And I think this has been a moving target, like all of you, I used to actually use ESA even above 500 because it’s 7% chance of response, but when you have someone who’s 75 or 76 and you’re not too excited to get an HMA or Lenalidomide from the get-go, there isn’t much kind of harm, I guess, to trying it. And then we went down to 200, and I think now, I think there’s a lot of questions about using 100 actually as a cutoff because in some studies it has shown better discrimination.

Guillermo, do you have an EPO level in mind? And, of course, all of us will account for also transfusions and RS status and potentially number of mutations, but I’m not sure, in your thinking, are there patients in which you would still use EPO in the frontline, or you are using luspa across the board in the frontline management?

Guillermo Garcia-Manero:

No, I think I agree with Andy and Rena, that it is true that here we have moved to luspatercept as a frontline approach based on the COMMANDS data, but it’s possible that you see a patient with minimal transmission dependency, a low EPO level below 200, that patient probably are the ones that benefited in COMMANDS from this kind of approach. Otherwise, we probably will move to luspatercept. So maybe a very low transfusion burden, a very low EPO level with anemia. If you go back actually to the historical data from the Nordic group, if I remember these papers by Dr. Jadderstern, Eva Helmstrom, et cetera. The group of patients actually that had any kind of benefit in terms of natural history with traditional ESAs, were those patients with a very minimal transfusion burden, almost like if you were giving this to CCUS kind of patient actually. So that’s interesting. So I think beyond that, most patients, if you have access to luspatercept, probably will benefit from the luspatercept much better than an ESA.

Amer Zeidan:

Yeah. Andy, do you ever use luspatercept at the highest dose from the get-go, or do you always go through this dose escalation? I was having some discussions actually a couple of days ago at ASCO with some of my colleagues. And in the presentations of updates from both the imetelstat trial and luspatercept, the approach has been interesting, right? With imetelstat you start with the highest dose and you go down, although it’s a drug that probably has more cytopenias, while with luspatercept, we are doing it the other way around, where you’re starting with the lowest dose and then go up. So many people have subscribed to the idea of trying to start higher. And of course, we have an ongoing trial called MAXILUS, tying to look at that question, but what’s your current approach with the dosing?

Andrew Brunner:

Yeah, I mean that’s a great question, and it gets into this idea of what would I like to do versus how have things unraveled. For instance, still, we need transfusion dependence at our institution to get approval to use luspatercept, which is, even with the COMMANDS study, it’s not quite what that label has evolved into becoming. And so I think that there are some moving targets for, what can you do and what do you think is likely?

So if a patient has moderate to high transfusion needs, you know when you’re starting luspatercept that it’s unlikely to get transfusion independence, and it may not even get benefit until you get all the way up to the top dose. So conceptually, I would like to be able to start more patients at a top dose, that’s what I tend to do in EPO. So I tend to do darbepoetin alfa (Aranesp ®) at about 500 mg as an initiation dose when patients have MDS with associated anemia that starts to need transfusions, if I’m going to use it.

And so I do a drop-down approach for EPO, and I think luspatercept, conceptually makes the same rationale. The way that our treatment builds our set, it’s such that we ramp up patients. I think that we are good at remembering to ramp up patients because we’ve grown up with it. But that is a problem globally that you see that most patients in the population that use luspatercept do not go to higher doses. And so you can argue that if we did more of a drop-down, start at top dose and drop down perspective, we’d get more benefit across patients, and you’d probably see better utilization for clinical benefit in a broader scope if you did that. So yeah, we’re interested in that trial data and whether that will impact label because that is a little bit of a challenge for how we can use it so far in practice.

Amer Zeidan:

So Rena, on my flight back from ASCO, I was actually reading a paper, a nice ‘How do I treat?’ from Eva Hellström-Lindberg recently published in Blood about the management of MDS in general. But it was interesting to me when they talked about the lower-risk MDS and the management of anemia, they talked about potentially doing venesection of the hemoglobin overshoots with the EPOs and why you start with a lower dose. And I was like, I’ve been treating MDS for more than 10 years now, I’ve never had a situation where I had a hemoglobin overshoot, and in my mind it has been always suspect, does that really happen in practice?

And I was wondering whether some of this, I think in Europe they tend to treat patients a little bit earlier than in the US, even with hemoglobins of 10 and 11. While I think in the US, we tend to be more restrictive. Most places will not treat until you are less than eight or nine or transfusion dependent or very symptomatic. And you mentioned the same kind of approach about starting with 40 thousand, 60, 80 with the EPO, rather than starting high and going low. So what’s your sense of it? Is this because this is the general practice, or have you seen situations where the hemoglobin did overshoot?

Rena Buckstein:

The truth is it’s not really clear that… I do think there’s probably an additional benefit to higher doses of EPO over 40,000 weekly. I don’t know, Andy, if you’re giving darbapoetin like every two weeks or three weeks or something like that? But I think the incremental improvement in higher doses for ESA is not as clear as it is with luspatercept, and I definitely ramp up quickly, but it’s not the overshoot purpose, it’s just that I get decent responses at even 40,000 units weekly. Which is still quite high doses if you think about it.

It’s interesting that you asked that question about the concern of overshoot. So first of all, in terms of our approach here, we don’t wait until they are transfusion-dependent or severely anemic. We wait until they’re symptomatic from their anemia, which is typically below 10. Most patients are endorsing that they’re more fatigued below 10. If they’re asymptomatic completely, then we will hold off, but most patients are endorsing symptoms between 9.5 and 10. So that’s when we’re starting, and not when they’re close to becoming transfusion dependent. And I think Sophie Park has an old paper from GFM that shows that starting it before their transfusion dependent actually delays time to transfusion dependence. But I’m not concerned about the overshoot, and in fact, regularly I have patients that are getting into the low 120s or even 130 on ESA. I do have to titrate down their ESA dose because when I go for renewal from the government for their drug, they’re unhappy if I let their hemoglobin go too high. But regularly I’m keeping them in the 1.27, 1.28, even sometimes 1.3 level. And we’re not appreciating any increased arterial or venous thrombotic complications.

And we’re looking at that right now in our registry because about 80 of our patients have overshot, and we’re comparing them to the people that didn’t overshoot to see if there’s any difference in venous and arterial thrombotic events for them. And so far, from our initial look there is not, and there’s no correlation between any arterial event and hemoglobin.

So I think, as a community, we need to kind of push the regulators to allow for us to be a little bit more liberal with their hemoglobins and hematocrits, because I do believe that people feel better at higher hemoglobins. It’s my observation.

Amer Zeidan:

No, I think that’s a very good point because you are completely right. I mean, I see this theoretical concern being brought up with every single drug, and I’ve never actually seen a real paper or a real analysis that shows that there is a risk of increased thrombosis. And I think the bigger problem that comes from this is that we are being stuck with keeping the patients on the lower side, because we cannot even normalize the hemoglobin. And this has been always an open question in my mind is like, do you just fix the anemia a little bit? Or, why can’t we normalize the hemoglobin if we can? There’s a reason why normally hemoglobin is 13 in people, why should we stop at 11 or 12? Guillermo, what’s your sense about this issue of the dosing, and concern about this whole thrombosis and how high can you go with the hemoglobin?

Guillermo Garcia-Manero:

Yeah, I think this is an interesting conversation and I have to be honest, I’m not sure I agree with you guys. So first of all, so we were part of the original development of sotatercept and luspatercept with the FDA when actually they were ISTs, so many, many years ago. And it’s correct that the FDA had concerns that if you drove hemoglobin to 20 grams or something like this, people will stroke. Actually this comes back from very old data when they were developing ESAs where apparently this happened and there were some cerebrovascular events, God knows how many years ago. So the FDA had this. So although I agree with you that we don’t know actually what the top dose of luspatercept is, I think that’s the question actually. So when we did those Phase I/II trials of these compounds, we probably never pushed the dose of this drug to let’s say two or three. I mean God knows, right? So they came with this kind of, we found this dose where there was activity, and the FDA, as you guys are saying from safety reasons came with this kind of strategy of 1, 1.33, 1.75, et cetera.

So I totally agree with you that we need to investigate this. Indeed, actually this went for 20-30 years with the ESAs, right? If you remember it was three times a week, then once a week, then the long-acting. So there was a lot of work on this, the EPO level, et cetera. So I think this needs to be studied actually. So is 1.75 mg per kilo, the top dose of luspatercept? I don’t know, can this be pushed safely? Probably. I agree actually that when you give this drug in the right context, what you see actually, early on in first-line, is sometimes actually you have to skip doses because the patients go over whatever the dose is, 11 grams of hemoglobin, I don’t remember. But basically you’ll have to skip multiple doses. So this is not uncommon when you use this drug at a very early stage, which is actually very satisfactory. So I agree with all this, but the question is today, do we have enough data to say, okay, let’s go to 1.75? I know the Germans are doing the study that you mentioned earlier, that’s great. But to me, the question is a little bit more fundamental that is, is that the right dose? Actually could we even look at higher doses?

So someone at some point, maybe, needs to start thinking about increased doses of this drug. So I don’t see it from a safety issue. This is kind of like an FDA guideline. I have to be honest that the kind of like a step-by-step increment, I kind of like it actually because my question is, I have no experience with this, I don’t think anybody does. You start at 1.75, what happens next?

Here you have patients, if you start using this drug, not like in MEDALIST, like in COMMANDS, you start at one, this means can have response for many months, and then they respond to 1.33, then respond to 1.75. So I don’t know, can you exhaust response if you go to the top dose? These things have not really been evaluated. And to be honest, you can go very fast up, right? It’s like two doses you go up, two doses you go up. So I mean you’re delaying it like four times three weeks, whatever that is. It’s a little bit slower than what you would like. Yes. But I think we need to do more work actually on the dosing schedule.

So I agree that probably a higher dose will be better to start with, but my question is, is there even actually even a higher dose, the top ceiling of this drug? It would be a nice study at some point, a little bit different than what the Germans are doing, I think.

Amer Zeidan:

No, I think all of those are great comments and I want to get your thoughts on this, Andy. I just wanted to raise two quick points. One is, I do think a lot of the literature, I think about the initial kind of thrombosis risk and survival kind of concerns or detriment with ESAs have come from solid tumors when they were doing trials, especially in early potentially trouble patients. And there was concern about augmenting tumor growth and there was some concern again about some thrombotic events, but I don’t think in the context of MDS there has been any clear signal for that. But in my mind, what happened prompted the FDA to kind of make this wholesale change in how they approach all of these drugs, which somewhat I think is affecting MDS in particular, because again, we are in a situation where we could probably completely resolve the anemia in some patients, but we are not able to because as you are saying, we have to stop at 11 or 11 and a half rather than get to 13.

And in my mind, the question is, maybe this is why we don’t improve survival in patients with MDS because we are not completely resolving the anemia, and we keep saying, “Oh, our drugs don’t improve survival. We have no drug that improve survival.” Maybe we’re taking the wrong approach of just fixing the anemia rather than completely normalizing the hemoglobin. And I think the second point in my mind is, in terms of, so most of the luspatercept and the imetelstat, most patients actually ended up needing dose changes. So most patients needed higher doses of luspa and imetelstat, most patients needed lower doses with the drug.

Which again brings the question is, did we use the right approach from the get-go in figuring out the right dose? But the practical concern, and this is why I think I want your opinion, Andy, on this is, the biggest concern in my mind about these dose escalations is that many times in the community people forget about them altogether. So while we are good, we have NPs, we have pharmacists, we have other people who will call you and say, “Oh, the patient hemoglobin is this, do you want to change the dose?” I have seen patients with ESAs who are two years and transfusion dependent and they are still getting 40,000, nobody has escalated their dose. Already seeing the same thing with the luspatercept, being discontinued without dose escalation and going to HMAs or whatever.

And I think this is where the practical concern about starting with the best dose is, because sometimes, when it goes to the community, people forget about all of this. So what’s your sense about all of that?

Andrew Brunner:

No, I mean it is a great point and it gets into this concept of, how do you take best practice and extend it to larger populations? And it is interesting, we’re talking about this, but when I treat patients with lenalidomide, they get a normal hemoglobin and I never stop drug or give them holidays. We have different goals depending on what drug we use. And I agree we’ve extended this mostly from like CKD patients and solid tumors where there’s a concern, and they probably had very different risk factors for thrombotic events in the first place, and we’ve carried it over.

I think that practically speaking, thinking about clinical practice, the challenge with luspatercept escalation is that most people are used to, and it’s a similar challenge that we still see with ESAs, is that the dose escalation is less likely to happen even in ESAs, right? To your point, many people will go up to a certain dose but never go to full dose that we often use and need in MDS.

A little bit of my perspective is, why not try higher dose with a different schedule? So say we are still stuck with holding after a hemoglobin of 11.5. Being able to give patients four, five, six weeks between dosing is a big impact on their quality of life and the clinical burden that they have. And I have a number of patients who, because we have this cap, when I have them responding, it means I see them once every two months and they much prefer that and that’s a big benefit for them. And I think we are very good, from ESAs, if you’re above a certain level, we hold and we recheck and we restart at that. And that is really more speaking to facilitating a dose schedule change rather than a dose increase itself.

And so I think that the consensus here is that we really do need A, not only starting at higher dose data, but we really should… This is a safe agent that we have not explored higher doses in an MDS and the rationale for exploring higher doses was not for toxic signals or reasons that we were running into concerns from it, but rather just because we had an efficacious dose. And so I think that there’s a lot of areas to explore in the future, and I do hope that we look, because to me, if we translate it from the EPO experience, there may be different physiology in MDS that a higher dose of luspatercept is really needed for a number of patients.

Amer Zeidan:

Rena, before we start talking about some of the novel approaches, just to conclude this segment on the currently available drugs, you have done a lot of work on real -life analyses and registered studies looking at MDS in particular. What are the most common caveats that you have seen in how people use ESA? We touch on some of them as basically people not dose escalating, or I have seen people using renal doses which are very, very small and they’re not going to do anything in the context of MDS. But, what’s your sense about how people use both drugs, ESAs and luspatercept, potentially lenalidomide, incorrectly.

Rena Buckstein:

So luspatercept’s only been available to us, funded, for about a year, and maybe an extra year under the patient support program. So I still don’t have a great sense of any mistakes or lack of dose escalation with luspatercept. Certainly when people ask me, I am sort of like Andy, and there’s no policing. So I tend to start at the intermediate dose, and then go up or go down according to response after their first three weeks as well as their burden of transfusions.

If they’re heavily transfusion-dependent, you know that their response rates are going to be pretty low, and even at that 1.75, they’re going to be lower, so I tend to escalate quickly. From the registry point of view, I would say people are pretty, don’t forget, these are all teaching hospitals, these are all experts in the field, so the registry patients are being treated appropriately, the length of exposure is appropriate. We’re not seeing a lot of abnormally short exposures. So I would say there’s good adherence to EPRACs and dose escalation and so forth.

But your experience, which is people being inappropriately kept on ESAs, and I think you did some work at Yale using SEER data, right? Showing that people were inappropriately kept on ESAs for years when they were requiring transfusions, and that’s clearly inappropriate. But the things that we did learn from the registry, because we do do quality of life assessments, is that there does seem to be this threshold effect in quality of life. For sure, like a major, major difference at 100, below 100 and above 100. But for some of the symptom and function domains, there’s really only kind of a ceiling effect in the utilities and the scores, sometimes at 120 or 130.

So to your point about, why are we not correcting them to normal levels? I do think we’re probably under treating our patients, we’re keeping them alive or keeping them off of transfusions, but we’re not maybe optimizing their symptom and function. And that may be why luspatercept didn’t show an improvement in quality of life. Because if you think about it, the median improvement was only about 1.5 grams, right? So they did improve their hemoglobins, many of them substantially, got off of transfusions, half of them did, but we still didn’t really increase their hemoglobin substantially. Which is why I’m really excited about at least imetelstat, despite the inconvenience of it being IV, is that the hemoglobin increase was 3.5, not 1.5, and so you’re seeing much more dramatic improvements in their blood counts.

Amer Zeidan:

No, all of these are great points, and I think that ODAC meeting was very interesting. And when you take the view of the solid tumor docs on many of our lower-risk MDS drugs, people always focus on overall survival, on quality of life improvement, progression-free survival. And I think this transfusion independence, and how the quality of life is significantly impacted by transfusion dependency is not fully apparent I think many times outside of the doctors who see these patients and the patients themselves. So it has been I think a big, big challenge conceptually to understand this endpoint of transfusion independence.

Moving into the last 15 minutes or so to talk about some of the novel drugs, and maybe I’ll start with you Guillermo. If you asked me five/six years ago where the MDS field would be, I would be telling you we would probably have three approved high-risk MDS drugs. We are going to have aza combinations, lower-risk MDS probably going to be on the back burner, ESAs, and here we go, great development in lower-risk MDS, one approved luspatercept second line, now first line imetelstat potentially this week or next week. And I think it has been a rapidly moving field. So out of all the agents that are being studied, what’s your overview of the lower-risk MDS space in general?

Guillermo Garcia-Manero:

I agree with you. I think that maybe we were not very explicit or planning, but all of a sudden we are doing good for these patients. Actually I have no experience with the telomerase inhibitors. But if we put all this together, you have now ESAs, luspatercept, maybe imetelstat, as Rena was saying, the oral hypomethylating agents, and let’s not forget about the new data with the low-dose lenalidomide also.

So all of a sudden I think we cover a lot of the needs of our patients, which is really great. And I think the earlier discussion was really interesting to me because I think we were going from what we would like to do in practice to maybe a research agenda, like exploring these drugs in different doses and schedules. Absolutely. So I would like to have 14 grams of hemoglobin if I was a patient with MDS, why we cannot do that with any of these drugs?

So it’s really fascinating, and some of these are less frequent, but IDH1/IDH2 mutations, we have an indication second line IDH1-mutated myelodysplastic syndrome that I believe covers a very small group, but it could be very meaningful. So the bottom line is that we are really starting to really do well on these patients. And remember, patients with MDS die from MDS. They do not die from transformation. Actually, my very first paper on MDS many years ago was, what is the cause of death? Infection, bleed. And these issues that Rena has investigated in terms of quality of life, et cetera. They’re really fundamental. So I think we are going into a very good situation, and maybe moving to the left to high-risk CCUS where maybe one can start making some of these points of very early intervention. So I think between all these drugs that I mentioned earlier, we are in a position to help a significant fraction of our patients with lower-risk MDS.

And I was happy that Rena actually was supportive of this idea of thinking in a more aggressive way about transplanting some patients with “poor prognosis, low-risk MDS.” I’m going very long, but give me two more seconds here. We had defined this many years ago, when we did that low-risk MD Anderson model, we did not understand it, we had no molecular data. We just identified people with low-risk disease with a more aggressive behavior.

So if you put all this together, I think we’re good actually. And I see this in my clinic, we are starting to see people that are now years and years and years on multiple therapy. So very exciting, but we need to do something for high-risk and we need to do something for second-line HMA failure, and TP53.

Amer Zeidan:

Yeah, no, I think all of these are great points. Andy, and it’s actually an interesting timeline in my mind, because last June when both in ASCO actually, the first data were revealed from the COMMANDS and the IMerge in the same session, it was very interesting to me that many people did not realize how unusual it is to have two positive Phase III trials in lower-risk MDS in the same year, not even in one meeting. And this ASCO, we are back to where we are normally because you have a million multiple myeloma positive trials and New England papers. And I feel like it’s just amazing how the field has moved. When I was in fellowship in multiple myeloma, they were still giving chemo, just like there was nothing that works. And now we have, I cannot even keep track of all the drugs that they have in multiple myeloma and the sequencing, and they are moving on the end points as well. All this discussion about using MRD negativity as a surrogate endpoint. So is this were lower-risk MDS is going? Do you think it’s going to be combination sequencing, novel endpoints, more ambitious goals? And how do you think we can do that?

Andrew Brunner:

Yeah, absolutely. I think that it is a great point. It was an amazing year for MDS last year, and I mean I think we’re still seeing a lot of excitement in the field about learning new data and further interpreting studies that we’ve done. I think we are at a point, to what you discussed, where we really need to be vocal about what matters to patients with MDS. And we’ve been stuck with a few endpoints for trials that, yes matter, we want to make people live longer, we want overall survival benefit.

In many types of MDS, in the majority of patients with MDS, the timeline of their disease is years. And it’s a great point. If you look at leukemic progression, even in the IPSS-M, even in the very highest risk group, the leukemic progression is the minority of people. Their survival is all poor, but they’re dying from cytopenias. And we restrict therapies that have activity in cytopenias, for instance, that we’ve been discussing right now. We restrict them to, so-called low-risk disease, where we probably need to have a stronger voice about what burden cytopenias have on patients, and what impact those are. And how can we make… You talked about the ODAC, and saying transfusion dependence is a dismal life. It takes over somebody’s life. They live in our clinics, they can’t go on trips, they’re stuck finding ways to get blood, they can’t do things that they wanted to do. And how do we as a community make it apparent that these are the metrics that we need to move? And pancytopenia, the burden of poor hematopoiesis, it extends across the MDS spectrum from low risk to high risk. It is a universal problem.

And so I do hope that we see, with the number of agents that we have, more and more combinations, sequencing, studies looking at different sequences and using them for novel backbones. Now that we have a lot of things approved, can we try to explore targeting a clone, or adding therapies based on dynamic changes like myeloma has been able to do over years? But I really do think that that is a model that we can try to emulate a little bit in MDS.

Amer Zeidan:

So maybe in the last few minutes talking about some of the specific agents, and Rena, maybe I can start with you with this roxadustat, which was a disappointing Phase III trial for many of us. Because I think, I certainly believe the drug is active, and I think the issue of the design of the trial was quite problematic. And this has been somewhat already addressed in the IWG 2019 or 18 in terms of using 16 weeks, but actually based on the COMMANDS trial, and based on my overview of where the field is, I’m becoming more convinced that you have to have a dual endpoint of an objective hemoglobin rise with transition independence.

Because this whole issue, especially in early development, I feel like when you have an open phase or a single-arm study without a control arm and, “Oh, you have 20% transition dependence”, when we know that the behavior of the physicians and the patients might be just changed because they are on a trial without an objective rise of hemoglobin. And certainly that could lead to failure of Phase IIIs, which we want to try to avoid. So is your sense that, what is the best endpoint, I guess, for lower-risk MDS development for early phase and late phase trials in your opinion?

Rena Buckstein:

Look, I totally agree that transfusion independence… So I think there’s several things. So first of all, there are many factors that contribute to quality of life. There’s the hemoglobin, of course, there’s the fact that you’re coming back and forth for transfusions. And they’re tightly correlated, but they’re also independent too. So getting somebody from eight to 8.7, and they’re no longer needing transfusions, but they’re still anemic, their symptom and functions may not improve significantly. So it may not be reflected in your quality of life scores. So I do think they have to go hand in hand.

I am concerned that some of our agents aren’t hitting the mark completely. For example, I see this with my luspatercept patients, that they are getting off of transfusions or they’re getting very intermittent transfusions, but they’re again running hemoglobins around nine, 8.9, 8.8, 9.2. And I do think we could do better with those patients. So speaking to your idea of combination therapy, and of course I’m very intrigued by the combination of ESA with luspatercept, or who knows, maybe luspatercept plus imetelstat or roxadustat or so forth.

I do think that we are going to probably do better in combination therapies in people that are suboptimally responding to monotherapy. At least it needs to be tested. So to your point, I do think there should be a minimal hemoglobin rise. I don’t know what that value is, I think it also depends on what your starting hemoglobin is, and everyone has a different hemoglobin threshold for transfusions. Some people are being transfused at seven, so from going from seven to 8.5. versus someone being transfused at eight, goes from eight to 9.5, maybe that magnitude of improvement is probably more important between… That 1.5 is more relevant in someone who started their transfusions at eight, now got off of transfusions and now their hemoglobin is 9.5, versus someone who was getting transfused at seven, they stopped needing transfusions and they’re now at 8.5, but they’re still probably symptomatic in my opinion. So I think the starting hemoglobin probably plays a role as well.

Amer Zeidan:

No, that’s fantastic. Guillermo, I want to ask you about an area that you’ve done a lot of work in, which is targeting the innate immunity dysregulation and inflammasome and [unintelligible]; all of these have very nice science behind them and some interesting agents between the IRAK inhibitors and canakinumab, and inflammasome inhibitors, et cetera. But so far we have not seen the kind of clinical data that we were hoping for. Of course, many of those trials are still early, the results are still not mature. But what’s your sense in targeting the innate immunity in terms of whether it’s going to lead to meaningful clinical impact in lower-risk MDS?

Guillermo Garcia-Manero:

This is a fantastic question. It brings actually two issues. One is actually regulatory and one is kind of like translational. So let’s start with the scientific aspect of this. So if you interrogate these pathways, actually they’re extremely redundant. So you block, let’s say IL1 with canakinumab, that’s great, but it happens that you have other cytokines. And so I actually think that it will be very unlikely that a single molecule in one of these pathways will really have enough activity to get you to the next step.

And that’s where actually now we are going back to the question like the great context that we’re in low risk MDS, but another question is, actually how do you move a drug forward in this disease? So I think these innate immunity targets are great, but they probably will require some type of combination. And we can spend an hour talking about rationale of IL-1 with IL-6 or MP3 inhibitors or TolA receptor inhibitors, IRAK4 inhibitors, but they all actually converge.

And the question is, you block one, maybe there is another aspect of this that is activated. But the reality is that now you are a drug company, and you know what’s happening with some of other drugs. And these drug companies, they want to see X amount of response the way you define it, increasing hemoglobin, transfusion dependency, but now these patients are exposed to ESA, luspatercept this, that and the other. So how do you develop now a drug in lower-risk disease like this?

So this is something that I’m starting to think a little bit because I think that the path forward for monotherapy, it’s going to be complex unless you come with some super drug that all of a sudden is like the master drug. But it’s going to be interesting because these criteria that you are talking are now tough, and the companies seem to be very shy about spending time and doing the combination studies. And we talked for 30 minutes about, we don’t know the dose and the schedule of luspatercept, and that took so many years. And now you have a small company that is very anxious to get this, not to lose money, whatever it is, and you’re telling them, “We don’t know.” It is probably unlikely that you’re going to see anything with your Phase I/II trial. Actually, I was part of a study just to finish, and I didn’t realize that the protocol said any drug… So basically they wanted you to expose the patient to any potential drug in lower-risk MDS, meaning ESA, luspatercept, lenalidomide, HMA. I said, “Wait a minute, who is going to respond? What type of hematological response you’re going to see?” Oh, the FDA mandated that actually it was not correct.

So we are now in a very interesting area in lower-risk MDS. The theme was combination and doses. So that’s very important. How do we do this from a clinical trial perspective? Maybe what Andy was saying, following what you were saying, Andy, that’s really important, is that maybe we should design some kind of early safety studies, make sure that we don’t do damage with these compounds. And we need to start moving very quickly in terms of actually combining or something like this. Because traditional criteria that we use right now are going to be very tough to get these into these kind of responses. For instance, to finish what is the natural history of a luspatercept failure? Or, imetelstat, what happens when you fail that? I don’t know. So what’s going to happen?

Amer Zeidan:

That’s a fantastic perspective, and I feel like many industry and pharma companies have figured out the myeloma situation very well in terms of triplets and now quadruplets, and so I’m hopeful that the same will happen with lower-risk MDS. Because I get the same sense that many people don’t fully understand lower-risk MDS on the industry side, and they need a lot of help from us. So hopefully those protocols are going to be designed in the way that makes more sense and lead to approve of drugs.

Andy, the PDUFA data for imetelstat is June 12, and many of us have been waiting to see what’s going to happen. I guess it’s going to come down to the last minute with this, but what’s your sense if imetelstat gets approved, how do you view that you’re going to use it in your clinic?

Andrew Brunner:

It is really exciting to have a lot of agents in MDS, and I think especially as we’ve learned the molecular landscape of MDS, we now really know patients who are just going to live with their disease for years and years. And so having multiple lines of therapy makes such a big impact. It is clear that it has more activity than other agents in high transfusion burden, kind of later disease. And I think that is the most obvious initial point where that’s going to be the heavy use.

In my clinic actually, I have a bunch of patients lined up where we’ve kind of petered out what they have. They’ve got MDS, it’s still there. To the points mentioned before, it’s not progressing, but we’re stuck doing heavy transfusions. And so I think the heavy transfusion burden patients who have been through a couple of lines of therapy, I mean this really offers hope that they get off of transfusions, that they have a high hemoglobin improvement, that they might make some of these quality of life metric improvements that we have been discussing.

And so I think that that is the first step, if approved, that it is going to have a big impact. Future areas of interest in it, I think we’re all curious about how it might impact the overall landscape of MDS. Where to place it, how would it do, what is a luspatercept failure? Where do we put it into play? But I think, at least in our hands and in our clinic, what we’re most excited to use is for these heavy transfusion-dependent patients that really need something.

Amer Zeidan:

Yeah, this is going to be very exciting, I think, to see how the field evolves. Rena, we are going to close with you, we’re coming to the end of the hour. But clearly a lot of this progress has been made by industry trials and small IITs, but the cooperative groups have been active in this space. But we certainly need, I think… In my mind there are questions that are very tough to be done by pharma, but they are the most probably important questions.

One question in my mind aways is that the ideal study in lower-risk MDS in my mind today would be luspa followed by ESA, versus ESA followed by luspa. But who’s going to do that? I think it’s going to be very tough, maybe in Europe, maybe somewhere else, but you’ve been in the cooperative group mechanism. How do you think this can help in moving the field forward with lower-risk MDS?

Rena Buckstein:

Yes. I mean, certainly if you’re alluding to something that’s being considered by the myeloMATCH program, there is a randomized Phase II study that is going to maybe ask the questions that pharma is not going to ask. Which is that, does the addition of other agents to luspa backbone improve ESA responsiveness and duration and durability, depth of response, and what are the predictors of that?

And to your point, Guillermo, one of the arms is going to be involving an IRAK4 inhibitor. But I think another study design, although it might be harder to do, would be to start everyone with monotherapy and then randomize in non-responders to the addition of something else, versus switching to something else. Or if you don’t have anything else, just standard of care, because then we may be not over treating some patients who don’t need doublet therapy, that could get away with just monotherapy and not incur the expense.

I mean, luspa is extremely expensive, and I’m sure imetelstat is going to be pretty expensive, and ESAs are not inexpensive either. So it may be that that is also a study design to pursue if it could be done properly in the frontline setting, to, again, with a lot of annotated molecular and cytogenetic data, serially done to better understand who’s more likely to respond, who’s less likely to respond, and so forth. Yeah.

Amer Zeidan:

No, I think that’s a great summary, and we’re coming to the top of the hour. If you asked me five years ago, can you spend a whole hour talking about lower-risk MDS? I would be like, whoa, there is no way. But we probably could go for another hour. Very exciting discussion. A lot of, I think, exciting studies and developments in the next year. Thank you so much for providing your perspective, and hopefully we’ll have you join us soon in another VJHemOnc MDS sessions in the near future. Thank you so much.

Guillermo Garcia-Manero:

Thank you.

Andrew Brunner:

Thank you.

Rena Buckstein:

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.

Rena Buckstein: Honoraria: Abbvie, Taiho, BMS; Research Funding: Taiho, BMS.

Andrew Brunner: Consultancy: Agios, BMS, iMab biopharma, Keros therapeutics, Lava therapeutics, Novartis, Rigel, and Takeda.