Emerging Therapies in Low-Risk MDS

Transcript:Vinod Pullarkat, MD: That’s a good segue to our next point, which is the newer therapies for the lower-risk patients. There are some exciting developments in this area, and we want to talk about what’s coming out and what we can expect in the next few years.

Rami S. Komrokji, MD: I think the first thing that is jumping really now at this point is the TGF (transforming growth factor)-beta inhibitors. I think what’s changing, obviously, is our understanding for the disease. What we’ve done in the last 5 years, while we did not have a drug approved in MDS, we learned a lot about the biology of the disease. And I think we look at the disease now almost in phases. You have a pre-MDS phase where you have some of those somatic mutations at low level and inflammation going on, and immunity affected. The first part of the disease really seems to be there is inflammation that sets this genetic instability, and, at one point, the disease gets clonal. It’s really clonal evolution after that. So, that window of the disease is inflammatory, let’s say, or the inflammation is a major contribution.

People are starting to look at new agents, and that had been exciting because we’ve never had, other than the traditional cytotoxic therapy, looked at that and in this setting. One of the things that started first was looking at these TGF-beta inhibitors. So, it turned out that this pathway is over expressed in MDS patients and it contributes to myelosuppression. There are downstream proteins that are upregulated, and there are drugs that were originally used for targeting TGF-beta to improve osteoporosis, like sotatercept. The toxicity observed in healthy volunteers was erythrocytosis.

It turns out those drugs work on terminal erythroid differentiation, improving erythroid production. And there had been some studies in cancer-related anemia—renal anemia, thalassemia—that are promising. So, 2 agents have been tested in MDS. We tested the sotatercept and our German colleagues tested luspatercept. Both of them demonstrated a good signal of response, particularly in the patients who were not heavily transfusion-dependent. But, then there was that signal that, basically, maybe, the patients with ring sideroblasts had very high responses, ranging in 60% to 80% of the cases. Now the luspatercept has been moved forward. It’s one of the few studies that are in phase III in MDS as a registration study where patients with ring sideroblast subtypes—lower-risk, after ESA failure—are randomized to luspatercept versus best supportive care. And if that study is positive, I think this will be, hopefully, a drug that will get approved in MDS. So, the TGF-beta inhibitors are interesting.

There are some medications that are fusion trap proteins, so they bind the ligands before binding the receptor. But, there are also some tyrosine kinase inhibitors that are looking at the same pathway, so those are in development. And then, that theme of targeting inflammation we heard at this meeting, very early data on phase I with the toll-like receptor to monoclonal antibodies; In a phase I study, there were responses seen, hematological improvement, which is interesting. We are looking at also neutralizing trap protein for a protein called S109. So, we are targeting the inflammation in the early phase, and I think that’s a promising thing.

When the disease becomes more clonal, I think we are starting to look at those mutations or if we can target those. So, as in the ring sideroblast, since we were talking about those, those are very highly enriched in splicing mutations. We are seeing now the first in-human studies with splicing inhibitors in patients with MDS. That’s very exciting. Those are disease-initiating events that, if you could eradicate the clone, you make an impact. We heard at this meeting about IDH2 mutation, which again happens…

Vinod Pullarkat, MD: In a smaller subset.

Rami S. Komrokji, MD: Exactly, in 5% to 10% of the patients, but it seems that there are responses, whether it’s like an eradication of the clone or differentiation. One of the things that is emerging as very difficult to treat or challenging is the p53 mutation. Patients that have p53 mutations—typically this is seen in higher-risk complex setting. But, there is even a subset of deletion 5q that have that mutation. They do respond up-front nicely to any therapy like others, but the duration of response is very short-lived, and the survival for those patients, unfortunately, is less than 1 year. So, there also are agents going in clinical trials trying to modulate or target the p53 mutation. There are several things. I think in early MDS, inflammasome, and in later MDS, we are targeting mutations. I think we heard a little bit about checkpoint inhibitors in MDS, which is a modality that’s been tested in every disease. It’s too early to tell where are we going. I think we know some safety, but we are still far away from assessing efficacy.

Vinod Pullarkat, MD: I think it’s a very exciting time in the MDS field after many years of having no real therapies with clinically significant benefit. Now we are seeing all these agents. I just want to stress the importance of enrolling these patients on clinical trials because these are low-risk patients. Some of them may not even need any treatment for a long time, but I think they will have the option of going into these trials if they are referred to appropriate centers. So, I just want to stress that point.

Thomas Prebet, MD, PhD: Even just in registry studies there’s a large effort now to try to have a majority of the patients registered in a national or local registry. That’s really important. We learn of the pathology of the disease, especially in the early events.

Ellen K. Ritchie, MD: Rather than putting a low-risk patient on a hypomethylating agent, there are, for the first time in a while, a lot of choices. There’s the phase III of the luspatercept trial.

Vinod Pullarkat, MD: We just have to make sure the patients have access to these newer therapies. I think that I just want to make a point that all these patients would benefit from referral to specialized centers.

Rami S. Komrokji, MD: To that point, I think Thomas published a paper in JCO looking at the outcome of patients after HMA failure, and, actually, the best outcome for patients were either if they went to transplant or they were enrolled on clinical trials. So, we do help the patients by enrolling them on clinical trials, whether it’s just because of more monitoring and being on top of things, but those patients benefit from enrolling on clinical trials.

Ellen K. Ritchie, MD: And we don’t learn otherwise unless we can enroll patients on clinical trials. Our ability to move forward, and move this field forward to more therapies that actually are successful, depends on us being able to enroll patients on trials.

Thomas Prebet, MD, PhD: I think it’s also important to stress that, for the moment, all this therapy that we have, with one notable exception, are disease-controlling therapies, but not disease-eradicating therapies. The only exception, which is unfortunately not available for all the patients, is allogeneic transplantation. And so, that’s also something that needs to be stressed. We need to refer the patients to specialized centers for a good assessment of the disease from the diagnosis to what kind of therapy we can use. But, there’s also the question of transplant.

Transcript Edited for Clarity