A roundtable discussion on anemia management in myeloproliferative neoplasms, featuring moderator John Mascarenhas, MD, Mount Sinai; Andrew Kuykendall, MD, Moffitt Cancer Center; and Gabriela Hobbs, MD, Massachusetts General Research Institute.
The following is an unedited transcript of the video:
Let’s talk about agents that we’ve seen. Top line data that we’ve seen with combinations of therapies where, you know, maybe we’re seeing some benefit on anemia or at least lessening of anemia that we’d expect with JAK inhibition.
We were all very excited, for having two phase three studies that were presented at that time and, pelabresib. So we didn’t hear that much about it this year, but we certainly heard of other inhibitors, the Insight compound. And I think there’s definitely a signal there, both in monotherapy for pelabresib and the Insight BET inhibitor that it’s anemia friendly. There’s definitely a signal that it can help improve hemoglobin in those patients. So that’s definitely something that’s caught my attention.
We did present the updated 48 week, data in a poster at ASH 2024. So showing that you can maintain spleen asymptomatic benefit over that 48 week period of course that’s still kind of short. We got to continue following the patients. But what I think still holds true is that delta between the two arms in terms of the hemoglobin mean hemoglobin levels continue. So you get like blunting of the anemia that you expect. That’s pretty predictable with ruxolitinib. And then you know, and then the sense that you, you maintain that and even improve it over time with pelabresib in which again, anecdotally, for whatever it’s worth, I do have patients long term now that have been transfusion independent on that drug too. So I think it’s, it’s it’s interesting and it’s helpful to get a sense like when we combine these drugs other than deepening spleen and symptom, are we also offsetting things like anemia. And for that matter, any other data that you’ve seen combination wise that look good for anemia?
Yeah, I mean, I think certainly the data I think is probably the most exciting from the combination, data, you know, seeing the long term outcomes. I think it’s going to be really important for any combination. Right. We have to see durability in the I think certainly the nasemic, got presented this, this meeting the disc, agent. And that was both in combination as well as as a single agent, I believe, as a disc. 0974 and, starting to get a decent amount of patients on that study, most of them enrolled at her center. So she was able to speak to her experiences. With the agent. Seems to be, very few Ads that were reported out, negatively with that agent and really, really impressive kind of anemia responses in both transfusion requiring and patients that were just anemic but not requiring transfusions. And you know, I think, I think that that’s another one that’s targeting that kind of hepcidin pathway by being a monoclonal antibody. The that, that that helps to kind of decrease and down regulate hepcidin and altered iron for better iron utilization. So, you know, I think the question that I have a lot with these agents is, you know, are we, are they there to kind of restore anemia? Is there a prognostic benefit of making that better, or is there a prognostic benefit in allowing full dosing of a JAK inhibitor? Are we using these in isolation. Are we are they always going to be combination partners. And you know, I think that the one thing that comes up and I know there’s ongoing studies looking at is, okay, well, if it if pel is able to blunt the anemia response, are the anemia detrimental, anemia, effective Ruxolitinib. And what happens if you use it in combination with momelotinib, pacritinib, and luspatercept you know, the potential of combining that with other agents too is attractive.
Well so to that point, you know, one data set that that I think is intriguing is if you look at the simplified data, you know, more so than in momentum where they had crossover but simplified, which was momelotinib versus ruxolitinib in the SIMPLIFY-1 in the upfront setting. They did a nice analysis that actually would correlate anemia improvement with overall survival. And that’s actually the first time I’ve ever seen that. So it’s speaking to your point that may be improving anemia. You know, not just removes that negative but but maybe even improves the outcomes of patients. In that case, it’s probably not necessarily linked to spleen reduction because the other arm had spleen . You know, the people who didn’t get the anemia did still have the spleen reduction, and that didn’t seem to drive it. What about, maybe less focus on anemia, but what other combinations, novel combinations do you think are potentially promising coming out that will read out?
Yeah, I mean, probably the most exciting one right now that’s in late stage development is going to be with selinexor. We’ve seen kind of early phase data showing remarkable response rates with ruxolitinib and selinexor. Certainly selinexor is not a new drug to us, right? It’s been used in a lot of different indications, but at different doses, right, with different tolerability profiles there. I think there’s a lot of curiosity with that study, not just to see kind of what the response rates are going to be, but how’s the tolerability. And then also given kind of what we saw with pella and navitoclax last year in terms of that symptom issue is, is how is that going to be impacted and is the tolerability going to be, you know, something that that hurts that.
So selinexor I think is is an interesting drug. I think mechanism of action wise, you know activates p53 down regulates NF kappa B also indirectly affects JAK/STAT signaling and other pathways that are probably relevant to the pathobiology of disease. So you can appreciate where this drug would have activity. And then activating p53 is a theme I would say in at least in our map that’s caught on. The drug that I think has been most impressive in that way has been navtemadlin, the oral Mdm2 inhibitor from the Boreas study. We presented results here at ASH, both looking at the clinical outcomes as a single agent in the JAK inhibitor relapse or refractory setting, but also as a combination. Well, the POIESIS study, I should say, is going to be a combination study that’s activated, global trial randomized phase three, interestingly, and sort of innovatively taking patients who are JAK inhibitor naive enrolling. Then suboptimal responders are the patients that can that can randomize the addition of that navtemadlin same dose and schedule a single agent. The relapsed refractory setting. And then, placebo is the control arm. So looking to see can we move navtemadlin which has shown clinical activity spleen and symptom reduction as a single agent in the relapsed refractory setting up earlier as an add on strategy.
