iwMPN 2026 | Novel agents and approaches being explored in second-line myelofibrosis

Claire Harrison:

Hello, my name is Claire Harrison. I’m a hematologist from London, UK, and I’m delighted to be here at IwMPN/MDS in Washington with my lovely colleagues who are just going to introduce themselves. 

Naveen Pemmaraju:

Hi, thank you, Claire. Naveen Pemmaraju, Professor of Leukemia at MD Anderson. 

Joseph Scandura:

Joe Scandura from Weill Cornell in New York City. 

Lucia Masarova: 

Lucia Masarova from MD Anderson in Houston. 

Rupali Bhave:

Rupali Bhave from Wake Forest Baptist in Winston-Salem, North Carolina. 

Claire Harrison:

Excellent. So we just had a very nice discussion about second line and novel agents in the setting of myelofibrosis. And most of the discussion actually was talking about targeting of anemia, TGF-beta, and also hemojuvelin. So maybe we could start off with you, Lucia, actually, talking about your study, because that was probably one of the earliest ones with earlier data. 

Lucia Masarova: 

Yeah, the earlier with no human data, so that’s easier. [laughter]

Claire Harrison:

Exactly. 

Lucia Masarova: 

Yeah, so I brought up a topic of a potential role of a medication called tasquinimod, which is an alarmin inhibitor, to use in myelofibrosis patients. Kind of more on the preclinical data that were generated in patients with MPNs, showing that the agent could inhibit TGF-beta and other inflammatory pathways to not only block inflammation and fibrosis, but possibly restore hemopoiesis, which kind of fit with the other agents being evolved in the space. There are no clinical data yet, but there are two clinical studies running currently with the agent. One is a monotherapy in a refractory setting in patients failing JAK inhibitor that’s conducted by the Holman Group in Europe. And the other one at the MD Anderson that has either monotherapy for patients refractory to JAK inhibitor or not being able to take JAK inhibitors, and then a combination to ruxolitinib and momelotinib where there is preclinical data that indeed the cells that drive the fibrosis and inflammation are very closely interplayed and connected with the JAK/STAT pathway, which is the major hallmark for myelofibrosis. So exploring new agents that could help inflammation and JAK/STAT pathway and kind of adding to the synergies would be probably something that we should look at. 

Claire Harrison:

So one of the things I really liked about the session was actually thinking outside of JAK/STAT. And so this agent’s been given to patients with other diseases or not? 

Lucia Masarova: 

Yes, the agent has been tested in other non-hematologic and hematologic diseases. It actually has run a large phase study in over 1,500 patients with prostate cancer, where it has not met its primary endpoint for disease-free survival, which may be a little hard with patients with prostate cancer. But they did have a sub-analysis showing patients that had bone disease particularly benefited from bone pain and a couple other. And they actually might have better survival, but it was not powered to show. And then it has also completed phase one/two study in myeloma patients, where they, they include patients that actually failed 15 lines therapies, unimaginable, what are you talking about? And there it did actually show a very safe report with disease, at least stabilizations, but I think in such a competing space, it’s a little hard to really show that endpoint. But nevertheless, they haven’t shown any safety data, which I think it’s very important for agents like this to move in with this kind of like patient. 

Claire Harrison:

Fantastic. And then, Rupali, you spoke about DISC-0974. So that’s something that’s a little bit newer in the space as well. 

Rupali Bhave:

Yeah. So DISC-0974 is a first-in-class monoclonal antibody to hemojuvelin. And as a result of doing that, it is geared towards decreasing hepcidin, increasing iron, and thus improving anemia. And I focused on presenting the two data from the phase two study, where they’re looking at anemic MF patients who are both non-transfusion and transfusion-dependent, either on or off a concomitant JAK inhibitor. And really across the board, anemia responses were seen both major and minor, and importantly, patients both on and off a concomitant JAK inhibitor benefited. And so, you know, I think we all know that anemia is a significant disease burden in our patient population. And I think having more drugs in our armament either early on or later on is helpful because I think, especially later on, you know, I think disease modification and things like that are all the goal. But I think we all have these patients, especially, I think add-on strategies are helpful, we all have these patients on JAK inhibitors where they’re probably better off on than off. But if you can do something to augment, you know, their anemia, I think it’s helpful. 

Claire Harrison:

Definitely true. And then we’ll just skip over very quickly the Luspatercept story, which I think it’s very salutary in terms of sort of endpoints, but it also speaks to potentially wider benefit, but also specifically elritercept, which is a little bit newer, slightly different targets, and some quite intriguing data with regards to sort of spleen responses, which we haven’t really seen with the DISC agent, but perhaps slightly more modest hemoglobin responses. But the patient population is quite different, more modest transfusion-requiring patients, slightly more patients with a very long disease duration, still got splenomegaly on JAK inhibitors. So we saw lots of potential options for patients, lots of thoughts and comments about endpoints. But I loved your comment, Naveen, in the session, actually, about, you know, broader benefits in cardio-oncology. And Joe, you also spoke about patients in terms of pulmonary hypertension and the wider effects of anemia, actually, on patients. So how might we look at these drugs in the future? And any thoughts from you guys? 

Joseph Scandura:

I mean, I think that, you know, like many of the complications of these diseases, we tend to focus on the hematological part of the story. And yet blood is in every tissue necessarily and interacts. Our blood cells are interacting with every tissue. And many of the symptoms and morbidities are related to the consequences of that. We think treating the underlying disease will make all of that go away, but there may be a point of no return, or there may be a different approach that we need to treat the reaction to the blood cells. So pulmonary hypertension is something that seems to be related to the duration of an MPN. Maybe those inflammatory mediators that have been around for a while, leading to remodeling of tissues, remodeling of the vasculature. And drugs like elritercept are appealing because they’re cousins of drugs touching the same pathways that have been shown to be useful in pulmonary arterial hypertension, which is a subset of pulmonary hypertension. But still, the proof is already there. And so what happens in our patients doesn’t make an important impact in addition to increasing their hemoglobin. 

Naveen Pemmaraju:

And if I can add to that, I think the discussion is engaging because we’re at a time now where we’re trying to look for all-cause mortality in our patients. So as Joe mentioned, the interplay between the blood, vasculature, and the heart, our patients can often die before their normal life expectancy. And oftentimes, Joe, as you mentioned in the session, we don’t always know the cause of death. I think so if we can analyze even on the most smallest of scales, so ECHOs and EKGs in almost every patient in the MPN clinic, whether on or off trial, can we move into collaborating with the cardio-oncologist and pulmonary team to do right heart CATs and other previously thought of as highly invasive procedures now much more commonly done? And then can we build it into our prospective clinical trials? And also, may I add, Joe as well has published on this, Gabby Hobbs and others, the inflammatory component. So GLP-1s, statins, metformin. Can we aim to combine those drugs to decrease cardiovascular mortality? Can we check it? And then you introduce drugs like Sotatercept, elritercept, which Professor Harrison showed, which may have interplayed through TGF-beta and other pathways. I think this is a huge chance for us to collaborate with cardio-oncology. 

Joseph Scandura:

Professor Harrison and Joe. [laughter]

Naveen Pemmaraju:

Yes, that’s right. 

Joseph Scandura:

I picked up on it. 

Claire Harrison:

Thank you so much, Joe. [laughter] Okay. So on a serious note, though, so for listeners who are thinking about patients, so the DISC study is open. Your study is open in Hovon. The elritercept study is just recruited as first patient. And there’s also a study open with elritercept in MDS as well, because that’s quite nice data. And then just wanted to bring you in, Professor Scandura, with regard to the data you talked about with regard to the PIM inhibitor, which, we’re really thinking about other pathways here outside of JAK/STAT complementary, so nuvisertib. 

Joseph Scandura:

Yeah, I mean, nuvi would suggest new, but PIM kinases have been known and implicated in hematological malignancy for literally decades. They’re an interesting class of kinases. And there is data suggesting that there’s a strong interaction between JAK2 and downstream PIM to manifest the full phenotype of an MPN. And, you know, so it’s relatively early days, but not at the beginning, very beginning. There’s clinical trials looking mostly in the post-Ruxolitinib setting. And I would say the most remarkable thing in Nuvisertib is the strong symptom response, which is something that’s been a challenge for other agents that we think that we might want to add on to JAK in addition. And it seems as though Nuvisertib, that’s its sweet spot – it’s a strong symptom benefit drug. 

Claire Harrison:

And we’ve seen quite a lot of data. You didn’t show all of it today because there is really a lot about cytokines and cytokine correlations which I think it’s really nice to see the scientific basis behind some of this so I’ve seen a lot of very nice cytokine data. What I think is probably important for us though, with this myriad of drugs, is to start to yes be thinking about their broader benefits and I definitely think important not to forget pulmonary hypertension is probably a really important cause of fatigue as well for our patients. But which patients might better be suited to these agents? Not sequence through them, but we need to really in the field be looking at: which patient should perhaps have the DISC drug versus Luspatercept or maybe go to Nuvisertib because they’ve got a symptom issue? Is there anything about PIM expression or anything that might tell us about early responders? 

Joseph Scandura:

There is an effort to identify exactly that because PIM is regulated at the level of expression. So protein level indicates kinase activity. And so we are looking in bone marrows of patients trying to correlate across the disease spectrum, but also then to feed that into the clinical trials to identify those patients who responded well and those that didn’t and whether or not that correlates with all that. 

Claire Harrison:

So important because we expose patients to these agents and to clinical trials. They’re giving a lot of their time, energy, and financial contribution as well sometimes. 

Joseph Scandura:

Time toxicity. 

Claire Harrison:

So time toxicity is really significant. And then lastly, I think the last agent we discussed in that session was actually imetelstat, another drug where there’s an overlap between MDS and MPN. So we’re really intrigued to see now the data that’s going to come from this study that we’ve been running for a really long time, looking at imetelstat, the telomerase inhibitor versus standard of care as a second line. And we’re not seeing the data yet, but we’re all really intrigued to see that. 

Naveen Pemmaraju:

Yeah. I think one of the more interesting aspects of this imetelstat program, first-in-class telomerase inhibitor, is that this trial, the primary endpoint, is overall survival, which may mark the first time in such a large prospective study. Of course, in the relapsed setting, as you mentioned, Claire, two to one randomization. But overall survival, we’re intrigued to see that. Can we move beyond spleen and symptoms to ask the question, just to begin to ask, are there other parameters that might be important in the MPN patient, particularly in myelofibrosis? And then are there some suppositions that we can draw from that, even if you don’t modulate spleen and symptoms where you improve overall survival? I’m eager to see that as well. 

Claire Harrison:

Yeah, me too. And I think this is what our patients would want to see too. 

Naveen Pemmaraju:

That’s right. 

Claire Harrison:

Thanks all for joining for this panel discussion. And we had a really invigorating session. So I hope some of you are watching online or maybe you get the opportunity to look online and see the slides and the more detailed discussion we had in the session. Lots of new options for our patients, but a lot of work still to do and some really important practice ready points. Thinking about anemia early, thinking about multifaceted causes of anemia, not missing pulmonary hypertension for our patients, and looking out for some of these newer agents and also for the data with a imetelstat when it comes. Thanks very much for listening and thanks all of you for joining us here today.

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