A session with experts Amer Zeidan, Uwe Platzbecker, Andrew Brunner and Jacqueline Garcia, who discuss the latest myelodysplastic syndromes (MDS) updates from ASH 2020.

Welcome to The MDS Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Amer Zeidan, Uwe Platzbecker, Andrew Brunner & Jacqueline Garcia, who debate key topics in the treatment and management of MDS from the ASH 2020 virtual Annual Meeting.

The topics of discussion include the evolving MDS strategy, immune checkpoint inhibition as well as higher-risk and lower-risk MDS.

 

Thoughts on a virtual ASH

 

“I think this kind of format is, especially if performed in a hybrid way, is the future. . . .I think this will allow us to be more interactive, also to exchange more data, present more data in a different way, but be at different places and still can do the work at home.”

– Uwe Platzbecker

The evolving MDS strategy

“We have three different or at least actually five phase three trials that are ongoing with pevonedistat, magrolimab, APR-246, sabatolimab and venetoclax. It’s just an unprecedented time in MDS, with the number of the phase three trials that are ongoing.”

– Amer Zeidan

“I think that the pandemic has really brought up a lot of real life issues to us that treat patients in the academic center. Most patients with MDS are out in the community and a lot of patients are treated by local providers. . . .I’m looking to see that these phase three studies offer flexibility for local administration. I think that brings in a more of a reality as opposed to having a biased population, like who could get to the academic center and be treated there. I think that the data that comes out of these phase three studies given the pandemic, might be more realistic.”

– Jacqueline Garcia

 

 

Higher-risk MDS at ASH

 

“Well, I think every patient, at least this is my impression, in general, prefers tablets, prefers an oral formulation. . . .I think we sometimes overemphasize this kind of oral and IV debate. The major driver of a decision is what we recommend as doctors and what’s basically the most efficacious combination or whatever treatment. And even patients would tolerate three weeks of IV decitabine if it does prolong survival by 12 months, this is quite clear. I think patients would take every burden which comes with a treatment.”

– Uwe Platzbecker

Immune checkpoint inhibition

 

“So can we use advances in MRD and disease monitoring and having now new agents, new backbone combinations, should we be sequencing therapies? I think that that’s a big area of exploration that we have on the horizon. And if we had five new drugs to combine, all of a sudden it might look very different how we approach someone and when we decide to change therapies versus, historically, just having one drug where you have to stay on it until the wheels fall off the car, so to speak.”

– Andrew Brunner

 

 

 

Lower-risk MDS & more ASH highlights

 

“And I think the diversity of the disease and the biology is immense, is I think much more than in the higher-risk segment, also from a driver mutation perspective and from the pathways involved. You also already mentioned inflammation, but again, I think the inflammation story seems super simple and super straightforward, but honestly, I don’t think it is the case. I think it’s not like you just, give X, Y, Z anti-inflammatory treatment, and then everything is resolved. I think it’s much more complex and we will delineate, and we will identify super small subsets of patients where a given treatment, a targeted therapy may work.”

– Uwe Platzbecker

“So overall, a lot of great exciting therapy studies, there was a bit more emphasis on machine learning, trying to find more tools to help us potentially once we get all this data from the randomized phase three and phase two studies, maybe the machine learning models that were presented can then be adapted to help us select proper therapies for patients based on either frailty, presenting characteristics or even mutational subsets.”

– Jacqueline Garcia

Full Transcript

Amer Zeidan:
Hi everyone. Thanks for joining us. It’s a pleasure to have you in another episode of our MDS sessions at VJHemOnc and today we’ll be talking about highlights of the American Society of Hematology meeting, the 62nd meeting that was just held virtually a few days ago. And it’s a pleasure to be discussing a lot of important abstracts and new developments. I have a highly esteemed panel with me, including investigators who presented some of the most important data in the meeting, and we’ll be discussing all of that. So I have Dr. Jacqueline Garcia who is an Assistant Professor of Medicine at the Harvard School of Medicine. And she focuses on understanding and studying the apoptosis pathways in myeloid malignancies. I have Dr. Uwe Platzbecker, who is a Director of Hematology and Cell Therapy section in the University Hospital of Leipzig and a very known investigator leading a lot of trials in myelodysplastic syndrome space.

Amer Zeidan:
And last but not least, I have Dr. Andrew Brunner, who is also an Assistant Professor of Medicine at the Harvard Medical School. And he leads MDS clinical research within the Mass General Hospital program. Thank you all for joining me. And I would probably start by getting your impressions of the virtual experience. This is a first time for ASH of course. We’ve been having a multiple number of meetings throughout looking at different presentations virtually, but for ASH for such a large meeting, I think this was the first experience. So maybe we can start with Jacqueline and go around in terms of your impressions.

Jacqueline Garcia:
Yes. Thanks so much for having me. Again, my name’s Jacqueline Garcia. I’m one of the adult leukemia investigators at Dana-Farber Cancer Institute. I’m an Instructor of Medicine, but thanks for the virtual promotion. I appreciate that. This was a really interesting ASH year. I would say one of the benefits that I think that a lot of us appreciated is that we were able to go to more abstracts and see them firsthand, hear the Q&A, more abstracts than usual. I probably saw two and a half times as more abstracts because I was able to see them, I could rewind, re-watch, and not have missed any of the abstracts that were occurring in parallel or on opposite sides of the building. I really appreciated that aspect that also made it a bit overwhelming with the information overload. And so a lot of pluses and minuses. And I think it was a little bit more mentally exhausting because we were able to take in more data.

Jacqueline Garcia:
I would say definitely one of the best aspects of ASH that we all appreciate is the ability to network in person and collaborate. And that part is definitely missed by not having the face-to-face contact. So I know a lot of us are looking forward to being able to be in person, potentially in the next year, but the ability to see these abstracts at such a big forum, to answer questions live, I think was really wonderful. And the only thing I just wanted to pipe in there, I completely agree with you Dr. Zeidan and it’s been so exciting in the MDS field much like, with acute myeloid leukemia and MDS, we have essentially been those left on the bench for the last several years waiting for our turn to have some exciting therapies.

Jacqueline Garcia:
And the AML has certainly had a few exciting plays in the last couple of years. And now I think it’s MDS’ turn where we finally have some really exciting treatments that are available and there’s a lot of heated discussion on which one is really going to be the home run for patients. And it’s just nice to hear that there are options. It’s great to see some exciting safety data, is good to see really incredible responses that are meaningful to patients. So it’s been really great over the last couple of years to see what’s been playing out.

Amer Zeidan:
Yeah, thanks Jacqueline. And I’m pretty sure the promotion is going to be coming soon considering all the great work you’ve been doing. Uwe anything you want to add, this was a pretty comprehensive answer from Jacqueline.

Uwe Platzbecker:
Yeah. Let’s say it this way. I think this kind of ASH meeting has pros and cons. And of course, if the meeting would have been scheduled for Atlanta, I would have been preferred to have it as a complete virtual meeting, but this time it was scheduled to be in San Diego. Again, apart from making jokes, I think this kind of event, also the EHA before showed us that virtual meetings are possible and they have I think the access to data and the access to also a lot of presentations, but the rewind function is a tremendous, and I think selection, therefore and preferences are very important to make already in advance. What I really liked with the ASH meeting this time was the way the posters were presented because this poster walk at ASH is like 4,000 posters and in one hand, you have to be on the other hand, you have to pretzel. And actually after like 200 posters, you have another pretzel and another beer.

Uwe Platzbecker:
All I want to say is that the granularity of the poster is not very easy to get with the poster walk. And you also sometimes connected to people you are involved in to talk. So I think the way the posters were introduced this time with the five or six slides, five minute presentation, I think is a very interesting format. And this, I think, needs to be kept also for future meetings because you have also access to the entire poster because it’s also individual format. But to summarize what is presented at the poster in a little presentation, I think makes it also more haptic, you really get access to the PI, to the person who basically generated the data. And it’s not slash only a poster presentation.

Uwe Platzbecker:
So let’s say to summarize, I would really love to shake your hand Amer at the next ASH meeting, I would really like to have a glass of beer with you at the next meeting, whatever, but I think this kind of format is, especially if performed in a hybrid way, is the future. I’m pretty sure about it. Because the plethora of meetings we are involved in and the plethora of meetings which require presence before is no longer possible for us also because, I always make the joke, sometimes I have to work, and can’t travel. So I think this will allow us to be more interactive, also to exchange more data, present more data in a different way, but be at different places and still can do the work at home.

Uwe Platzbecker:
But on the other side, traveling to a certain place, especially for us Europeans going to the U.S., gives you also a real break, you are really out. And now with these virtual Zoom meetings, people think that you are accessible 24/7 because it’s just a Zoom. You can do the Zoom 8:00 PM or 9:00 PM at night. It’s not a problem. So I think this brings us into trouble and we need to be cautious. Sorry, a long statement, but I thought the question was not easy to answer.

Amer Zeidan:
No, I think you bring up the great points beyond just ASH. I guess ASH was based on the Pacific coast timing. So it was starting 10:00 AM for us on the East coast, 7:00 AM on the West coast. But for Europe, it was starting also later. And some of the sessions went later at night. And I think as you mentioned, some of the meetings, the investigator meetings and other meetings we’ve been doing some, I was with Andrew recently on one at five or 6:00 AM in the morning. And it’s definitely has been a little bit challenging. And like you, I do miss that aspect of the break that comes with the actual meetings where you travel to a place and not vacation, but at least having some break from the routine of the work. So that aspect has definitely been missing. Andrew, anything else you’d like to add to all of this?

Andrew Brunner:
What more can I add? I think a lot of points have been said that are true. We all are missing in-person meetings and the chance to connect. I think I might just know that as virtual meetings have gone on, they have become I think better and they’ve learned from the prior experience. I agree with the poster format. And also I think that the way that questions were handled during the oral sessions was really, the curation by the moderators and the ability to answer more questions per session, I thought was really a nice aspect of how the format lent itself to that kind of presentation in interaction with the speakers.

Andrew Brunner:
I wish that that kind of interaction could also be carried into the poster sessions because while the data was much better managed, I think by using these short five minute presentations just made me want to chat with the presenter about it, which is hard to do. I’m sure things will evolve and I’m looking forward to in-person sessions, but I think that they learned a lot from the conferences that come before and I definitely have some aspects that I hope they keep going forward.

Amer Zeidan:
Yeah, very well said. It sounds like there’s a consensus that nobody wants back completely to the old ways, but keeping a hybrid format where you have most of the data available after the meeting for easy access, but maintaining an in-person component for networking and all of that. I guess we’ll delve into the data and I’m going to introduce myself because I always forget to introduce myself in these calls. So my name is Amer Zeidan and I’m Associate Professor of Medicine at Yale University and the Director of Hematology Early Therapeutics Research, focusing on MDS and AML as well.

Amer Zeidan:
So, Andrew, I’d probably start with you since I know again, in these panels, the person who gets to answer after everybody answers always feels left out, not much more to add. So I’ll start with you, I think globally for MDS as a disease, and you’ve been seeing how things are evolving in acute myeloid leukemia, where we are going now into the doublets for older patients with acute leukemia and already starting with triplet trials. And people are making comparisons to multiple myeloma where you are going to the doublets, triplets, even quadruplets and completely oral therapy and outpatient management, all of that.

Amer Zeidan:
And comparisons are being already drawn in the MDS world, where we’ve been using only hypomethylating agents. And now a lot of the development has been focusing on doublets, but people already talking about triplets and potentially complete oral therapies. And so how do you see the field going forward? I guess, keeping in mind that MDS patients on average are around 10 years older than AML patients. Many of them are in seventies, many of them are more frail and more co-morbidities. And do you think this is a realistic view?

Andrew Brunner:
Sure. I think that it’s a great question. And it was exciting meeting for that reason. I think that all of a sudden, where AML and other non-myeloid malignancies have had really a lot of growth in new therapeutics and subgroups with targeted agents and novel ways to incorporate those therapies. MDS has been hard to improve upon azacitidine or decitabine alone. And in some part, you bring up a good point with the patient population. These are older patients by the time, I think the intergroup study showed how it can be challenging to move therapies that are effective in small cohorts of patients into a larger treatment setting.

Andrew Brunner:
Even if you look at how azacitidine or decitabine are used as monotherapy, we know that they’re under utilized in the general population, and we know that the dosing that is typically used is not that, which was studied, often is reduced in dose. And transplant as well is under utilized if you look broadly in MDS, which is notable given some of the studies that were presented at ASH this year as well.

Andrew Brunner:
So I think that we have a gap, both in how effectively we administer the therapies that we already have, but then that has been a limitation to how we move forward with novel therapeutics in this disease. And suddenly there are a number of agents which have novel targets that are slightly different or used in a slightly different way than other myeloid diseases. We’ve learnt a lot from AML previously, but suddenly there are drugs that seem like they may be as, if not more, focused toward an MDS type population. And those studies are moving further into development where you can actually see that perhaps we will have a chance to redesign how we treat patients.

Andrew Brunner:
And I think that the next step, yes, will probably be some form of doublet-based approach that I think it’s an open question, whether that will be continuous throughout the treatment until progression or if we’ll have different phases of treatment, more like myeloma, where we try to obtain a remission and then we do something that’s more of a maintenance type of therapy. And these are studies that we need to be ready to perform.

Andrew Brunner:
But suddenly, there are studies moving into phase three that seem that they might have legs to move to a full, I think that that’s an exciting in the field because MDS as noted by everyone here has not seen the same amount of attention and interest and development, in part because drugs haven’t been able to really change that course of disease. So I think that we are probably looking at, it’s great that we’re looking so far ahead. The practical next steps are identifying doublets that can be used, and that see like they improve upon azacitidine or decitabine alone. And then moving from there, following behind AML and its pathway, perhaps. But also thinking about alternative strategies for managing these patients.

So if we have highly effective agents, maybe rethinking the phases of treatment, and breaking them out a little bit. So I’m excited. I think it was a good ASH to show that there really are a number of agents where in one to two years, we might be talking about MDS in an entirely different fashion.

Amer Zeidan:
What about you Uwe, like globally, if you look at your crystal ball and over the next five years, let’s say for the MDS field, we have three different or at least actually five phase three trials that are ongoing with pevonedistat, magrolimab, APR-246, sabatolimab and venetoclax It’s just an unprecedented time in MDS, with the number of the phase three trials that are ongoing. Do you see us going into doublets and triplets and completely oral therapies, or do you think MDS patients are going to be unable to tolerate these type of intensity that has been seen in other malignant hematologic conditions?

Uwe Platzbecker:
So the question was for me at Amer, right?

Amer Zeidan:
Yes.

Uwe Platzbecker:
Okay. Well, I think there are two ways to see this from a European perspective. Number one, I think we started in hematology with myeloma 10 years ago, the way we are now in AML and I think that the status we may reach an MDS at least in the next two or five years. So doublets, triplets, quadruplets, introduction of maintenance, I think this is the way to go. And of course the question is at the moment, if we talk about high-risk MDS, are we combining targeted treatments like IDH inhibitors, for instance, first-line in patients with this kind of mutation or are we going for a rather debulking strategy with common players like venetoclax, azacitidine, and then add, for instance, MRD-guided, for instance, additional drugs to eliminate what is basically left from this kind of debulking strategy?

Uwe Platzbecker:
I foresee rather the development of, I would say unselected triplets of course selected for then patients with IDH mutations, but the backbone I think will be ASR, Venetoclax, and, but also magrolimab is a very interesting combination partner for azacitidine. What I’m a little bit sad as a European is that the US, or let’s say North America is the driver of this development. I think that’s perfect for you, but it’s a little sad for us. Because you use azacitidine now, I don’t mean personally Amer you personally, but U.S, as researchers in the U.S., you are using it already in combination with gilteritinib and others in FLT3 relapsed/refractory AML and I can give you tons of other examples where studies have been presented. And in the European Union, azacitidine and venetoclax for AML is anticipated to get approved first quarter of 2021.

Uwe Platzbecker:
So we are basically almost two years behind the U.S. and the same is true also for other things. This is a scenario also for CAR-T cells and others. This is something which I really don’t like and, of course not on a personal perspective, primarily because access to treatment also means access to research, translational research, but also for our patients, primarily for our patients, because we cannot offer these novel therapies outside clinical trials. And so I think this development is something which, with my impression, accelerated a little bit in the last couple of years, and we bring it here at a European level. We bring it to the attention, to all the pharmaceutical companies being based or having headquarters also in the European Union.

Uwe Platzbecker:
Of course, this is something, which on a global perspective, we may not completely change in the future because the U.S. market of course is also the driver of research and development. But maybe this is something we, as academic partners, and I count all of us here in the audience as potential collaborators, I think, should take into account when we design clinical trials, when we talk to companies that we, at least at the research level, at the clinical trial level, we should work together and bring these drugs also to other parts of the world where maybe the access is not that easy.

Uwe Platzbecker:
So again, a long answer for a very simple question, but this is my take home message. So I think MDS, a plethora of novel treatments, targeted treatments, triplets, quadruplets, whatever you can imagine happens there. But also there is a shift, and the shift with regards to access to novel drugs is a little bit, I think sometimes which worries me and where we have to at least communicate that this should be changed maybe in the next couple of years.

Amer Zeidan:
I think Uwe you bring a great aspect. And I think beyond only the clinical research component, I think even for the standard of care agents, especially as more drugs get approved, we’re actually planning to have the subsequent session of the MDS Sessions, talking to MDS physicians from developed or developing countries basically, especially. You’d be surprised how many countries don’t even have access to azacitidine or decitabine. I’ve met many of my colleagues, I grew up personally in Jordan, so I know a lot about what’s happening there, but many other countries, they have very limited access to even the basics of azacitidine, the cytidine for MDS patients. Many patients, even with high-risk disease, never get considered for transplant because the age cut off for many of these places or countries is 60 or even 55 and even blood supplies.

Amer Zeidan:
So there are, I think, a lot of challenges and I think it’s going to be important in the context of all these exciting developments of how we can carry, with our pharma partners and regulators, some way of trying to get these benefits to the rest of the world aside from the developed and Western countries, in terms of views of, of these agents, I think is going to be a big challenge financially.

Amer Zeidan:
Jacqueline, you also work across the AML/MDS spectrum. How do you see like MDS… a lot of the developments historically have usually occured first in AML and then move to higher-risk MDs. But we are finally starting to see some efforts that are focusing initially on high-risk MDS, which is somewhat of, I think, a welcome trend because MDS has been historically under researched compared to acute myeloid leukemia. So how do you see that transition going back between the two diseases in terms of how patients respond to therapies and enroll in trials?

Jacqueline Garcia:
That’s a really great point. I agree with my colleagues. So we have been benefiting from what we’ve learned in AML, but we’ve learned so many things. One is MDS patients are still very different from AML, they’re older, they can’t handle the same level of toxicity. We learned that very early on with the azacitidine-venetoclax trial, which was correctly amended to be a shorter schedule to reduce toxicity. And that has led to durable responses that are meaningful. So we are grateful that we can learn from what drugs are active, what diseases that have myeloblasts, but we certainly have to understand the drug toxicity that’s going to be different and in an older patient population.

Jacqueline Garcia:
A few things that I think about when I think about AML versus MDS therapies and the points that you’re mentioning, one there’s toxicity, both financial and drug. Financial toxicity, in that, we now have oral decitabine as an example, which is phenomenal for access to our patients that can get it, but the cost of oral decitabine is not trivial. And if we eventually one day get venetoclax approved for patients in MDS, if it does meet its primary endpoint, that has a lot of financial toxicity to the patient having had experience with getting access to that for patients in AML. If we’re moving towards all oral strategies, the cost to the system might be pretty substantial.

Jacqueline Garcia:
And so I think when we think about what therapies will be best for an older patient population, we have to look at MDS patients slightly differently from AML. We have to think about, given the older patients, what is the quality of life? And I think we’ll have to borrow from patient report outcomes to really understand what meaningful increases they have as opposed to just a few weeks extra of life. Well, how meaningful is it? Is there a decreased transformation to AML, decreased hospitalization, are they feeling better, are they able to have less transfusion burden? I think we’re going to ask more from our MDS data in order to put these in to our older patient population.

Jacqueline Garcia:
So besides financial toxicity, there’s real drug toxicity that we have to look at. Having oral options, I think will be important for this population, but certainly not if they’re sick from oral therapies all the time. So I think we’re going to be scrutinizing the data quite a bit. And because we actually have really exciting drugs out there from pevonedistat, venetoclax, the TIM-3 antibody – I’m sorry, Andrew, I cannot pronounce the antibody yet and magrolimab, we’re going to be asking a lot about it. I do think now that there’s more drugs that are available that, not only are we interested in, is overall survival the most appropriate endpoint for MDS? I think that’s a really good question that’s still out there.

Jacqueline Garcia:
I think that things that we’re going to look at is whether or not we can, for instance, identify subsets within MDS that would benefit from one of these newer therapies or combination therapies compared to others. I think that we’re going to learn a lot about, maybe with magrolimab will be really great for p53-mutated patients. Although I still don’t fully understand the mechanism of why that cohort of patients benefits more than others. And maybe that will be more beneficial compared to venetoclax or the TIM-3 agent. I think that that’s something we’re going to be looking at. The ideal study in my mind, which I know pharma would not be excited about would be a very larger, unbiased study where you get randomized to these novel combinations and not these separate, isolated, large-scale studies that are essentially in competition with one another.

Jacqueline Garcia:
The last thing I do want to mention is I think that the pandemic has really brought up a lot of real life issues to us that treat patients in the academic center. Most patients with MDS are out in the community and a lot of patients are treated by local providers. I think that what we’re seeing now and having seen what’s happened to our patient panel, our referral patterns, clinical trial enrollment, we’re really seeing the reality of what happens to patients that just can’t get to us. And so we’re learning about how can we treat patients locally and safely. So there’s a little bit more added pressure, I think, to these phase three studies, meaning can we get these patients access to drugs? Can they be safely delivered in the outpatient setting? Can they be given locally?

Jacqueline Garcia:
I think there’s a little bit more ask compared to what we’ve done before with the MDS trials. I’m looking to see that these phase three studies offer flexibility for local administration. I think that brings in a more of a reality as opposed to having a biased population, like who could get to the academic center and be treated there. I think that the data that comes out of these phase three studies given the pandemic, might be more realistic. And as an example of that, we always compare our AZA outcome to the AZA-001, but we have often and commonly not seen the survival benefit and the high response rate that was reported in that study and the more modern MDS trials.

Jacqueline Garcia:
So I do think the more updated phase two and three studies that are ongoing might potentially reflect our new reality, where we are really sharing patients with our local physicians as we should be. We’re seeing who can tolerate therapies, how can patients get access to drugs. And I think that as we start to get the data out over the next couple of years, we’re really going to be asking a lot more from the studies. And I think to do that we’re a little bit greedier in our ask, not just looking for higher response rate, maybe a few weeks extra survival. I think we’re going to be asking a lot for them since there’s more competitors.

Amer Zeidan:
Yeah. And I think you mentioned the venetoclax, so maybe now we can go into some of the abstracts I think are most highlighted from ASH. One of them, or two of them, were the venetoclax abstracts. You presented the frontline study update, which is an ongoing phase one, two study, and I think importantly as you mentioned, venetoclax was dosed for 14 days and the overall response rate was in the range of 80%. Around 40% of those were complete responses, but I think the median survival, although the short-term was limited, the median overall survival was impressive at only seven months. So there’s an ongoing phase three trial now. Are you treating patients, if you have a patient who cannot go on a trial or for whatever reason, basically, are you using venetoclax based on the trial data outside of the trial setting basically for patients based on its availability for AML, or are you only using hypomethylating agent monotherapy currently?

Jacqueline Garcia:
I would say I’m doing my very, very best to just treat patients with venetoclax that have higher-risk MDS only on trial, but I definitely have a small panel of patients where I have given it to them because they didn’t quite meet eligibility, but I knew it would be safe if I could manage them, given my experience with it. And it was for patients that I knew I would want to cytoreduce before transplant. And I know the role of cytoreduction still remains under play. Now that we have more active drugs, I think our question of the role of cytoreduction will be more substantial.

Jacqueline Garcia:
So I would say there are definitely patients I have considered for it, but when possible, we actually have the luxury of having several MDS trials open for the upfront setting. So we’ve been able to have options. But certainly even when HMA therapy has failed some of our patients and from the data that you’ve presented from the phase Ib relapsed/refractory MDS hypomethylating failure patients, we have added venetoclax in those settings when insurance has approved delivery of those drugs, because out of pocket, it would be way too expensive, but we have certainly used venetoclax off-label for that.

Jacqueline Garcia:
When possible, always do a trial, of course, but when not possible, which is the reality often, the data has demonstrated at once safely administered at a 14 day dose, a dose of 400 milligrams with proper supervision, proper lab checks, clinical visits and with antibiotic prophylaxis, you can deliver a combination therapy safely to patients that lead to meaningful and durable responses.

Amer Zeidan:
So Uwe, we’ll be talking about lower-risk a little bit later in the chat, but for higher-risk MDS anything in particular has struck your attention from this ASH? We had the venetoclax data. We had updates from pevonedistat and sabatolimab and the magrolimab, I guess, some updates and a number of agents who are in earlier phase trials. What caught your attention from what’s going on in the high-risk MDS from this ASH?

Uwe Platzbecker:
I think you just named the major players in clinical trials at the moment. And I think the major question is also, given the advantage with regards to the phase three development of pevonedistat and also venetoclax, is this driving the decisions and is this driving also clinical practice in the future? Honestly, I don’t know. We know that the pivotal trial readout I think will be 2021, aza-ven phase three is running at the moment already. So I think both drugs are rather drugs for all-comers. So the combination is rather than all-comers combination, the same appears to be true for sabatolimab and also for magrolimab, although magrolimab seems to have an advantage in the TP53 segment, therefore I think a trial in AML has been started.

Uwe Platzbecker:
But I think the major question is, which combination will be our preference for an unselected cohort of patients if the availability of either one is an option and also reimbursement is an option? Honestly, I don’t know. But I think the good news is at the moment that we have competition, competition’s always good. And we have also drugs, like pevonedistat, I just want to highlight this because it’s already pretty advanced with regards to the clinical development, which does not seem to add a lot of toxicity on top of the, let’s say not noise toxicity which is seen with azacitidine alone.

Uwe Platzbecker:
So I think it’s a safe add-on drug with a significant addition of efficacy with regards to CR rate. And the phase three, I think will show us whether there’s also improvement in survival and other end points. So the jury is out, I don’t have an answer to this, but I think we have several combination partners and one could imagine of course, switch from one to the other, if there’s no response or loss of response. I think that’s my picture or my take home message from the non-transplant segment in high-risk MDS.

Amer Zeidan:
So Uwe, just to follow up on what you mentioned, so some of those drugs are IV and venetoclax, for example, oral, pevonedistat is IV. Some are given every two weeks, some are given every four weeks. And do you think, in the U.S. some of the co-pay issues, if some of these drugs get approved, this sometimes determine for many patients what they can go on and what they cannot go on? Because there’s a significant cost sharing component that comes with some of the oral agents that might not necessarily be there with the IV drugs, especially for Medicare patients, which the vast majority of MDS patients in the U.S. are under Medicare. So is that in play in Europe, or do you view this as a discussion basically, if you have multiple IVs and oral options, in terms of just looking at safety and efficacy and deciding with your patient, what would they like?

Uwe Platzbecker:
Well, I think every patient, at least this is my impression, in general, prefers tablets, prefers an oral formulation. However, the median age of our patients is 72 at diagnosis. They have hypertension, they have diabetes, they have, they have, they have, so they have many, many other diseases which requires quite often also the treatment and the intake of several tablets a day for the treatment of other concomitant diseases. So therefore I would say that’s the preference, yes. But I think if, let’s say a drug is given every four weeks IV and that’s the substitute for instance, five days of azacitidine subcutaneously in a row, I think every patient would go for the IV. And every patient also would prefer this if this is a substitute for an oral decitabine or whatever because sometimes you have GI toxicity, you sometimes forget to take the drug.

Uwe Platzbecker:
So I think we sometimes overemphasize this kind of oral and IV. The major driver of a decision is what we recommend as doctors and what’s basically the most efficacious combination or whatever treatment. And even patients would tolerate three weeks of IV decitabine if it does prolong survival by 12 months, this is quite clear. I think patients would take every burden which comes with a treatment. I’m not talking about bone marrow transplantation now, but burden with regards to quality of life, coming to the doctor, getting an IV, getting a needle, getting whatever you may need for IV, if the drug is really superior or if the combination is really superior of what you have. So this I think is something which many patients do recognize.

Uwe Platzbecker:
And last but not least, I think we talk about the different situation at different sides of the planet. Decitabine for instance, is approved for AML in the European Union, it’s not approved in your country for AML. Other combinations may be approved or reimbursed in the U.S. and not in the European Union. So I think also the approval and the nature of the data and how they are interpreted by the authorities, I think also drives our decisions nowadays, maybe much more than we did 10 years ago.

Amer Zeidan:
Yeah. So Andrew, immune checkpoint inhibition has been a major advance in solid tumors. And several of us, basically, have been working on getting, what I would call the traditional immune inhibition approaches, you know, PD-1, PD-L1, CTLA-4. And so far the results have been somewhat mixed, and it’s not clear whether we are not able to identify patients subsets who benefit from these agents, but generally we have not seen overwhelming responses so far. And then we start to see these, what I would call novel immune checkpoint inhibitors, like the TIM-3 and the magrolimab. And there is more excitement with the early data. You presented an update on the sabatolimab phase one/two study on this ASH meeting.

Amer Zeidan:
So what’s your sense in terms of the use of these drugs? And I think Uwe brought up the point of some of the drugs adding additional myelosuppression that MDS patients might not tolerate and some other agents like potentially sabatolimab or pevonedistat, I’m not sure about magrolimab, but I guess it could be along those lines, might not be especially for our frail MDS patients. So maybe you can walk us through some of the data and your sense on where immune checkpoint inhibition is going forward in MDS.

Andrew Brunner:
Absolutely. Yeah. And I think it’s interesting to a few points that were mentioned earlier, for a long time MDS has been a late studied disease. So therapies are evaluated in other diseases, are evaluated in AML and then come to MDS and are tried largely in the same basis that they were used in other diseases. But suddenly I think at ASH this year, we did start to see more emphasis on MDS as a testing ground for treatments. And I think that’s an exciting development because it means we might really get some changes in the treatment of this disease.

Andrew Brunner:
I think that historically, we’ve had some challenge with toxicity in these patients. These are older patients. I think the inter-group study showed the challenges that can be when you expand therapy to more sites and especially when you have a therapy where responses are dose-dependent. And so I think that we may have some changes in how we approach patients. Speaking of like debulking certain patients versus focusing on survival or tolerability for other subsets of patients, we might have a transplant-eligible versus transplant-ineligible type of segregation of patients in the future. But I think that one area where we don’t know a lot yet, we think that there’s great potential, particularly out of the experience with transplant and the idea of being able to stimulate some sort of graft versus leukemia effect.

Andrew Brunner:
There’s been a lot of interest in myeloid disease to somehow use the immune system to moderate and maintain responses. And I think that you showed very nicely the importance of randomized trials in that setting and the challenges that we can see with some of the traditional PD-1, PD-L1, CTLA-4 axis of therapies. We all I think, have seen some experience where there can be really impressive responses with those agents, but I don’t think we know well enough how to select patients for those treatments. And we have run into certain toxicities that are more challenging when combined with HMA, for instance.

Andrew Brunner:
And so I think that it’s welcoming to see a few newer agents that may have different ways in which they add to the therapy of patients, especially frail patients with MDS. I think the data seen from pevonedistat does seem to suggest that it can be easily added to standard HMA without adding marked toxicity, at least in early phase studies. The phase three will really tell us whether that’s true and see if we can see these same high response rates. And so for frail patients, for instance, where you want a quick response, that may be a route that we pursue if it ends up being approved. I think that the magrolimab data is also very interesting. I’d like to see more and in a comparative fashion, because so far we’ve had one large series of patients that continue to enroll and show the same responses, but it’s harder to know until we’ve gone into bigger populations or more sites.

Andrew Brunner:
But I think that from what I can tell of the data, once you get past an initial hemolytic monitoring component, transfusion-dependent element, then subsequent treatment with that seems similarly something that we can do for our more frail older patients. And I think that sabatolimab or targeting TIM-3 falls into this realm of treatment as well. TIM-3 is a less well, studied immune checkpoint or has been classified as an immune checkpoint blocker. I think we’re still learning what TIM-3 signaling does. It was also early on identified as a way really to sort leukemic progenitors from hematopoietic progenitors. A lot of the work that came out of Ravi Majeti’s lab at Stanford, looking at it as a possible marker along with other markers that we’re also exploring in AML, for instance, like CLL-1 and other such markers to distinguish healthy versus leukemic progenitors.

Andrew Brunner:
And in the study that we were involved in, we had interest in it for both of those reasons. Both, we don’t know what it might do to these progenitors, but also because I think there is a lot of hope that we can use the immune system to maintain responses for more durable periods. And so our data has been updated now several times. I think that the ongoing long responses for some of these very high-risk patients that are more frail and where having an alarm response probably matters a lot for 80/85 year olds who you’re not really planning to transplant them. You’re just trying to extend their lives as long as possible. I think that will be a really meaningful outcome.

Andrew Brunner:
The question that needs to be addressed, and what I think all of these studies are moving too quickly is how does that compare azacitidine alone first? A question that’s on horizon is how does that compared to some of these other combination agents? But I am really encouraged that all of these studies have moved fairly quickly to randomize comparisons because I think we need to know how patients do when they have a placebo arm. And I think that even azacitidine in TP53 patients has been a vexing question of, just what should we expect from TP53 mutated disease with HMA. It’s a lot of retrospective series of few comparators in small numbers and so even these studies looking specifically at the TP53 population, I think it will be really important to better define and I’m glad they’re all using a randomized comparator.

Andrew Brunner:
But so to the points that have been brought up, I think what we’ll see emerge to a degree from these studies is that we will be dividing how we care for patients a little, perhaps like AML, where for some patients where we find them more fit, or they have a more urgent need for debulking, we’ll choose certain treatment strategies. And for other patients where, maybe we’re worried about treatment intensity or our goal is really prolongation of life but in a palliative setting, knowing that they may not have more robust future treatment options like transplant, we may approach them from a different strategy. So I think that the three agents you worked with and we’ve had you mentioned and we’ve had the most experience here with sabatolimab, but all of them seem to be the agents that will add to this population that may not be able to receive more intensive treatments.

Andrew Brunner:
At the same time, I think a big area that we’re going to need to look at next is, and I’m speaking to a point also brought up earlier, is perhaps sequential therapy intervening sooner than by the time patients have progressed completely off of one therapy, it’s very hard to salvage them. And our outcomes post once patients have progressed on hyper methylene therapy are still pretty dismal. And so can we use advances in MRD and disease monitoring and having now new agents, new backbone combinations, should we be sequencing therapies? I think that that’s a big area of exploration that we have on the horizon. And if we had five new drugs to combine, all of a sudden it might look very different how we approach someone and when we decide to change therapies versus, historically, just having one drug where you have to stay on it until the wheels fall off the car, so to speak.

Amer Zeidan:
Yeah, so those are all great points Andrew you bring up. I think in terms of sequencing of therapies and total therapy type of approaches, and especially in the HMA failure setting, which is very challenging so far and how we delay or prevent that. We are unfortunately running out of time to discuss a lot of this, but I want to talk in the last few minutes about lower-risk MDS, because also, there have been some, I think, exciting developments there. Maybe I can ask Uwe to talk to us about his view in management of the lower-risk MDS after ESA failure. So now we have imetelstat which Uwe has updated in the meeting, but we recently had luspatercept approved in the U.S., I’m not sure if it’s approved yet in Europe or not. And then we have roxadustat and we have a number of other inflammatory targeting type of agents as well in the pipeline. So where do you see the space heading Uwe?

Uwe Platzbecker:
I think lower-risk MDS is an unrecognized target for development of drugs. And I think also many pharmaceutical companies, now with the development of luspatercept, I think have basically witnessed that the treatments to develop treatments for this large group of lower-risk MDS patients in need of therapy with cytopenia, as you mentioned and sometimes also failing ESA treatment, I think is really worth. Also from an economic perspective, which of course, is not our driver here and should not be driving our discussion. But I think everybody talked about high-risk MDS and AML also from an end point perspective and that this appeared to be more appealing as a subgroup of patients with mild neoplasm. But I think the story of luspatercept was therefore very important.

Uwe Platzbecker:
So yes, luspatercept you just mentioned is an interesting drug also with regards to the way it is administered to our lower-risk MDS patients, where quality of life, as we know, is very important, less visits at the doctor, less transfusions. This drug is given IV every four weeks in a very easy way, two hours infusion and apart from heme toxicity the drug is very well tolerated. And I think I was also impressed by the data and by seeing also a couple of my own patients being transfusion independent for sometimes years. And this is with the single agent I think is quite impressive. So let’s see how the phase three works out. I think we all hope that we get maybe another drug in our hand for our patients, but again, we are just about to start to understand the biology of lower-risk MDS, and maybe also the way we can combine the drugs currently in development or already in place.

Uwe Platzbecker:
And I think the diversity of the disease and the biology is immense, is I think much more than in the higher-risk segment, also from a driver mutation perspective and from the pathways involved. You also already mentioned inflammation, but again, I think the inflammation story seems super simple and super straightforward, but honestly, I don’t think it is the case. I think it’s not like you just, give X, Y, Z anti-inflammatory treatment, and then everything is resolved. I think it’s much more complex and we will delineate, and we will identify super small subsets of patients where a given treatment, a targeted therapy may work.

Amer Zeidan:
Yeah, certainly a lot of exciting developments in lower-risk MDS. So in the final couple of minutes, if each one of you has any final thoughts, basically any quick abstracts they’d like to highlight, or any concluding remarks, maybe in one minute or less for each. I’ll start with Jacqueline.

Jacqueline Garcia:
Yeah. Again, I was very happy to present the updated aza-ven data that showed the prolonged overall survival, which was highly encouraging. I think, it leads a lot of enthusiasm for what might happen with the phase three. And of course you already mentioned Andy’s TIM-3 trial, which was really exciting to see broad responses, tolerability and with the pevonedistat, the decreased AE profile, oh not decreased, sorry, the relative tolerability of the addition of [add-on] compared to azacitidine alone.

Jacqueline Garcia:
A couple of other abstracts that I thought were interesting at the study was the presentation decitabine versus hydrea for the patients with CMML and how it looked like hydrea still remains a solid frontline therapy disappointingly, and a lot of us, at least me, I give decitabine until I have patients who are highly proliferative, thinking that will be the answer. And that it seems like I’m treating myself and then escalate a patient based on how this data is coming out. It also highlights the point that it remains a camp of an underserved population where we really need to do more. So I am hopeful that CMML will be our new ‘MDS’ and a couple of years where we’ll offer and see more abstracts and data that’s exciting for those groups that are often ridiculously excluded from trials at home. And so that would be something I look forward to.

Jacqueline Garcia:
Similarly, how there’s a lot of enthusiasm for treating lower-risk MDS, the phase three Len versus placebo for the non-transfusion dependent patients. Can we treat them very early? If so, how early? And is that safe? I thought that data was really interesting. I’m using Len five milligrams daily versus pre-set prevention, transfusion dependence. I thought that was really important, especially because transfusion burden is a huge problem for lower-risk MDS patients. Lenalidomide is a really great drug, interesting drug for those that are 5q del, but long-term toxicity is something I’d like to see from that readout. We know when we start to try to treat patients and intervene early, we then want to know what type of trouble might we be causing. I think there was a little bit of an early signal of secondary malignancies. So I’d like to see how that pans out. We have certainly seen that when we’ve done that to patients with lymphoid conditions.

Jacqueline Garcia:
So overall, a lot of great exciting therapy studies, there was a bit more emphasis on machine learning, trying to find more tools to help us potentially once we get all this data from the randomized phase three and phase two studies, maybe the machine learning models that were presented can then be adapted to help us select proper therapies for patients based on either frailty, presenting characteristics or even mutational subsets.

Amer Zeidan:
No, that’s fantastic summary, Jackie. Uwe any final remarks?

Uwe Platzbecker:
No. I think we covered everything and we would require another four hours to get into detail, but I very much enjoyed the discussion.

Amer Zeidan:
Thank you. Andrew?

Andrew Brunner:
Yeah, no, I think Jacqueline provided an excellent overview of a lot of the highlights of the meeting. I would be remised, even though our work is really to try to replace the need for transplant, the BMT CTN 1102 study. And besides what we had long suspected out of retrospective or smaller series of patients. But I think the reality is early transplant for our high-risk patients remains a cornerstone of care, it is under-utilized and I think that it was a very important study to be presented.

Andrew Brunner:
In particular, I think the biggest takeaway for me was that the survival curves split towards transplant from the very beginning. And I think we’re often struggling with patients about counseling, who might be on the fence based on the toxicity or the risk of transplant and the reality is high-risk MDS has a lot of risk itself. And so, while I hope we continue to find new therapies that maybe someday will negate the need to transplant patients, it is really important that we design trials that incorporate transplant as an option and we continue to emphasize that to our patients who might be eligible.

Amer Zeidan:
Very well said. And thank you so much. As Uwe said, we probably can go into hours to try to cover everything in ASH. 2020 was a very difficult year for everybody especially with the COVID situation. And I’m glad to see a lot of still clinical research going on and a lot of exciting drugs moving forward. So thank you so much again for this discussion and happy holidays and happy New Year, and look forward to talking to you soon after the next meetings about additional updates. Thank you so much.

Jacqueline Garcia:
Thank you. Happy holidays.

The MDS Channel

 

Explore the latest updates in MDS, including expert interviews from major international congresses, podcasts and e-learning.

Disclosures

Andrew Brunner – Research funding to my institution from: Novartis, BMS, Takeda, AstraZeneca. Advising for: Novartis, BMS, Acceleron, Agios

Amer Zeidan – Consulting fees from: Boston Biomedical, PTC Therapeutics, Agios, Celgene/Bristol-Myers Squibb, Abbvie, Astellas, Novartis, Daiichi Sankyo, Trovagene, Seattle Genetics, Amgen, Pfizer, NewLink Genetics, Jazz, Takeda, Genentech, Blueprint, Kura Oncology, Kite, Amphivena, Trillium, Forty Seven/Gilead

Jacqueline Garcia – Institutional/trial support from: Lily, Pfizer, Genentech, Abbvie. Scientific advisory board: Abbvie

Uwe Platzbecker – Honaria: Jazz, Amgen, Novartis, Geron, Abbvie

Sign-up for our Newsletter!

Keep up to date with all the latest news with our monthly newsletter