MDS updates from iwMDS-iwMPN 2024 | Updates in HR-MDS therapies: IDH inhibitors, challenges with transplantation, and more

Gail Roboz:

Hi, everyone. My name is Gail Roboz. I’m a professor of medicine and I run the leukemia program at Weill Cornell Medicine in the New York Presbyterian Hospital in New York City.

It is my great pleasure to have a recap opportunity of what was an outstanding session at this outstanding meeting. I think all of us have been blown away by how excellent the meeting has been for doctors dealing with myeloid diseases, MDS, myeloproliferative diseases, AML. And here, with great colleagues from the last session, I am going to allow everybody to recap a little bit about what they discussed and then maybe we’ll have a couple of minutes for some questions.

So I am going to pass from colleague to colleague, and allow everybody to introduce themselves and give their affiliations. So you’re first on the hit list.

Marie Sebert:

Thank you, Gail. So I’m Marie Sebert. I’m working at the Saint Louis Hospital in Paris and I’m here on behalf of my colleague of the GFM, the French Group of MDS. My topic was about the IDH inhibitors in MDS patients with IDH mutation.

Yes, the aim of the topic was to highlight that in AML we learned that IDH inhibitors could be very efficient and in MDS patients, we are trying to do the best to give the patient the opportunity to have this efficacy, and also not to have so much toxicity.

We are conducting two trials in the GFM team, proposing IDH inhibitor in high-risk MDS as a first-line therapy, and also in relapsed refractory patient and also in lower-risk MDS patients having failed EPO. And we were able to show that as monotherapy, IDH, actually IDH1 inhibitor in the IDIOME study, gave very interesting results with a high response rate and with durable response and prolonged overall survival. And we are waiting for the IDEAL study. I think we were able to show the result at the ASH meeting and we are very excited on this response rate.

Gail Roboz:

So I wanted to, before we move on just with colleagues, to talk about the IDH results for a couple of seconds, because I think they’re incredibly provocative, so we know these drugs work as a single agent, they’re well-tolerated.

The whole field of AML got more fun as we got targeted agents, we started having more fun as AML doctors. We can pull off FLT3 now, we can pull off IDH. Even for AML, we have AGILE looking at the combination of ivosidenib actually with azacitidine, turned out to be a little bit easier even than venetoclax.

So, in MDS, we’ve been lost without that. We don’t have our targets. We’re going to have Amy talk about a potential target. So we know this. So should we do this, do you think? Should we be pulling out MDS patients and trying to make sure that, at least at some point if they are IDH mutated, that they get treated with an IDH inhibitor if available, and try to follow what happened in AML to grab the molecularly targetable patients?

Marie Sebert:

Yeah, thank you for that question. I think there is a different paradigm in MDS compared to AML, because we have inhibitor when we the activating mutations. So, in AML you have this FLT3, but we don’t have this in MDS because it’s not so much a proliferative disease, and it’s hard to find activating mutations to inhibit because it’s more difficult to reproduce like in TP53, the protein who has failed.

I think the IDH is a good example. I don’t know yet if it’s an exception, but I think we have this activating mutation, that’s why we have inhibitors. And in this point of view, we can learn from AML, yes, for the efficacy. Then the reposition of the drug will be different, I think, in MDS patients because the goals are not the same. Some of them can be transformed but the majority will not, and I think we have to think about that. And then, I think we should find other targets like Amy proposed for. And I think, yeah, it could be a way to understand the biology and to understand the target, and maybe to have some groups leading the treatment, yes.

Gail Roboz:

Yeah, no, I think your points are amazing. And I think we should also bring up, and I actually was part of trying to get this across the finish line, but getting it across the finish line for MDS. The companies at that point have, there are very few patients, there’s not a clear path to approval, there’s not a clear path to utilization. So it was really kind of a hurdle actually to cherry-pick and find the MDS patients with the IDH mutations who would benefit.

Forgive me, but maybe we’ll skip since we’re in the targeted land before we get to aza/ven fixing everything, which I’m not sure it’s going to do, but maybe another target.

Amy DeZern:

Sure. So my name is Amy DeZern, I’m at Johns Hopkins, I’m the Vice Chair for Hematologic Malignancies. And today, I had the opportunity to talk about the RAR-alpha agonist that we have, which is tamibarotene. We talked a little bit about how it works as a differentiating agent and how one can select in the peripheral blood RAR-alpha, or RARA-positive patients as a biomarker. So a little bit different than a targeted agent, but certainly again, pulling out patients and who we hope to have a better response with certain therapies.

And the SELECT-MDS-1 trial has not yet had its readout. I alluded to the fact that the data cut off is essentially today and we’re hoping that we’ll be able to present some of that data at ASH but the time will tell.

But I think we can learn a lot from earlier phase studies that were done in the AML population. Oligoblastic, less than 30% blasts, less fit AML patients who have molecular signatures that are perhaps more akin to higher-risk MDS. And we’ve seen nice and deep CRs that has some durability over a year in some, in this oral very well-targeted drug combination with azacitidine. And so I think we certainly need randomized data, but I’m optimistic that this is something we have predictive capacity a priori for the patients to respond, we know it’s not very toxic, and I’m interested in learning more.

There’s another Phase II in AML that’s actually a study of the triplet. So drawing in some of the AML aza plus venetoclax data. And I think it’s something that can be combined with other medicines that we find other combinations of doublets that work because it’s relatively non-toxic. So I have a lot of optimism for it as a new mechanism of treating high-risk MDS patients.

Gail Roboz:

Well, it would be very exciting to see you at the plenary, if that works because I think after the bruisings that we have all experienced in the Phase IIIs for MDS, that would just feel great. So venetoclax makes life better. So if you add Venetoclax to pretty much anything, including possibly orange juice, it seems to make things better, and yet we’re squirming a little bit about MDS. So introduce and talk.

Yazan Madanat:

100% yeah. Hi everyone. Yazan Madanat. I’m an assistant professor and the leukemia director at UT Southwestern Medical Center in Dallas, Texas.

So we had a pretty nice discussion at the high-risk MDS session and I presented some of the data pertaining to venetoclax use in high-risk MDS. And the theme that we see from two prospective studies, one in relapsed refractory MDS, and the other Phase Ib study in newly diagnosed high-risk MDS is… The vast majority of patients who we’re seeing the outcomes for are really the ones with the high and very high-risk revised IPSS patients.

And then the second theme is the majority of those patients with 70 to 90% across all the studies and even in retrospective analyses have blasts that are anywhere between five or more than five to 19%. So those with higher blasts were those with higher risk disease per the revised IPSS, and particularly high or very high-risk subtypes are the ones where we have some data suggesting its benefit. And the benefit, really, that we’re seeing so far is in quite high response rates and then the ability to get patients to transplant where in some of the studies about 50% of patients actually proceeded to transplant.

I think the second important thing to think about with venetoclax and, with particular focus on subtypes, is we do see some benefit particularly in IDH2-mutated patients, although they are 4 to 6% of patients with MDS. But in those we have learned from the AML studies, both AGILE and Viale-A, that the median OS for patients with IDH-mutated AML when we use HMA monotherapy or azacitidine monotherapy is about six months compared to a great survival advantage with the combination.

And in the relapsed refractory study, we saw 83% response rates with IDH2-mutated relapsed refractory MDS with a median OS of 17 months, which is very impressive. So although… Again, I think focusing on targeted subpopulations is probably the way to move forward in higher-risk MDS.

I think we’re all eagerly awaiting the Phase III randomized VERONA study looking at ven/aza versus aza placebo in higher-risk MDS. I think that the caveat is the population is not what we saw when we saw those responses in early phase trials, and that worries me. I think patients with intermediate revised IPSS are included irrespective of blast percent, and so these differences worry me, but we’re still optimistic and we still hope for a positive Phase III study in higher-risk MDS and moving the path forward.

Gail Roboz:

Well I think so that’s a nice toss of the ball to me because, so here’s the thing you said, and we know aza/ven in higher-risk MDS has a higher response rate and gets people to transplant. That happened, irrespective of what the data are for VERONA, we know that. And the organizers of this meeting pulled a little bit of a trick because they put the non-card-carrying transplanter with the card-carrying transplanter. So Amy is my friend and my colleague, but we refer to each other as such. I do not carry that card and she does.

And I got charged with the, “So who are we transplanting and why?” And I think it actually was a really good discussion because there are including recently published data that kind of are making us all squirm about what are we doing when we’re treating patients, MDS patients, prior to transplantation.

Well we know what we’re doing, we’re trying to waste some time and prevent bad things from happening until the transplants get organized. We don’t want them to get worse. But there are recently published data suggesting A, that your therapy, even if it downstages the patient may not make a huge difference. B, that if you are not responding to the therapy that you have given, then everything is even worse. So you are either selecting out worse clones, or you are just defining biologically bad disease. So you just said the therapy that we’re waiting for is to get more responses, to get people to transplant. And my talk was that we’re over-treating people and giving them all kinds of stuff before transplant, which is messing up their transplant or potentially, actually worse, we have to invite transplanters to the meeting that’s on camera now, but we all said that the problem is that we have weaponized the transplanters to now not take our patients in, because well, you’ve got to get rid of this mutation and you’ve got to have your blast count go down and you’ve got to have all kinds of things happen.

So how do we circle that?

Yazan Madanat:

I think one of the main issues is we talk about like MRD or minimal residual disease in MDS and we don’t have drugs that target MRD. And I think that’s the main difference in AML is like we talk about therapies but getting cytogenetic or molecular responses with HMA therapy is not happening, and even for those mutations intensive chemo is not the answer either. And so I think if we have better therapies, a good treatment before transplant probably makes sense. But then until we get those treatments that get to deeper remissions in a good biologic sense, I think until that point, I think an example would be an IDH inhibitor before transplant. If we can get these responses and patients are not neutropenic or not getting in trouble, I think you can speculate that that would be a positive approach.

Gail Roboz:

I think there is a movement in the direction, though, of realizing that first of all, that tons of induction-level type of chemotherapy, we don’t need to do that. That doesn’t seem to be working. It’s causing harm. Nobody is thinking of repeating multiple cycles of prolonged HMA and venetoclax at this point, because I think there is substantial evidence that you’re going to possibly mess up your transplant rather than make it better.

So, then the final question that we were addressing is that in terms of clinical trials, okay, we would like to have a biomarker, hopefully Amy will deliver that. We know that some targets we can parse out. But in the middle of that, do we have to design trials that are fundamentally not for the transplant population of MDS patients for right now, and do we have to do what happened in AML, which is nobody wants this to be age-based, but the Ferrara criteria for AML was not restricted to age, there were lots of patients who weren’t going to get a transplant.

Do we have to think about that? And that was the kind of philosophical question that we ended with maybe that if we know that the goal is to get all the patients to transplant, is it going to be too hard to develop an agent that delivers the overall survival down the road after transplant and also is credited with getting the patient to the transplant.

Philosophical question that we ended with final thoughts from everyone?

Marie Sebert:

Maybe before going for patients who cannot have transplant, maybe we are all talking before transplant, but I think mainly in MDS we have to think on transplantation as a time during the treatment. And we are not talking about post-transplant therapies, and mainly for again IDH inhibitor, in AML we have the study giving IDH inhibitor after the transplant, and I think also we have to think about that in MDS. Because I totally agree with you about the toxicity before the transplant, and some of patients who are planning to go to transplant who gave aza, maybe aza/venetoclax, they were not able anymore before because of the toxicities. But we have to look at the relapse rate after and then we have to think also I think on post-transplant.

Gail Roboz:

Fantastic point. I mean post-transplant, maybe save some things for-

Marie Sebert:

I think we have to design a trial again to think the transplantation as a part of a whole and maybe to know when we have to put it.

Gail Roboz:

Final thoughts?

Amy DeZern:

Well, I think the community has done ourselves a few disservice, as you’ve alluded to, but I’m very careful with my verbiage, to always say to a patient that transplant is a potential path to cure. In drawing in what you said, it’s not just this finite procedure, it’s one of the therapeutic modalities.

So we don’t beat them up too much. We optimize our time, we use transplant in suitable patients, maybe not everybody.

And I think you’re right, that designing trials with that intention, where it transplants in a very uniform way is part of the procedure, it makes sense. And if we can do maintenance in a way that’s meaningful and not toxic, it can extend things. That’s just a very hard sell, I think to the pharma community, because that is a big try.

Gail Roboz:

Texas has the last word. What do you think the final conclusion for the audience from our high-risk session?

Yazan Madanat:

I think high-risk MDS has been a struggle for us in the MDS community. And I think we hope to see improvements and a kind of light at the end of the tunnel as we learn more about how to optimize and strategize the tools that we have in our toolbox. And as we get more perhaps targeted therapies, and ways to optimize things before transplant, but now considering post-transplant therapies as well, if we can identify accurately those at highest risk of relapse. And there are some newer data emerging pertaining to that, and looking at stem cell sorting and molecular analysis of stem cells post-transplant to predict relapse.

So, thank you very much.

Gail Roboz:

Fun meeting, fun session. A lot to learn. Thank you guys very much, and thank you audience for watching and we hope that you found the meeting and the insights as stimulating as we have.