S2 Episode 6: A Futuristic Vision for Treating Myelofibrosis

Medscape

10-07-2025

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.
Tania Jain, MBBS: Hello again, everyone. I'm Tania Jain, and we're in season 2 of the Medscape InDiscussion : Myelofibrosis podcast. This is episode 6, and we're very fortunate to have Dr Naveen Pemmaraju for this discussion on a futuristic vision of the myelofibrosis (MF) treatment landscape. Dr Pemmaraju, we welcome you to the podcast.
Naveen Pemmaraju, MD: Thanks, Dr Jain, for having me.
Jain: Dr Pemmaraju does not need any introduction, but quickly, Dr Pemmaraju is a professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, Texas. He's also the inaugural director of the BPDCN — blastic plasmacytoid dendritic cell neoplasm — program and the executive director of cancer medicine for the MD Anderson Cancer Network.
We would like to share the mic today with Dr Pemmaraju, asking him about his vision for the future of MF treatment. Let's start with where things are, and you can share about your engagement in a lot of the protocol development and therapeutics development. Which are your favorite developments in the field of myeloproliferative neoplasms (MPNs) in the recent past that you feel will stick around and we'll continue to hear more about them?
Pemmaraju: Thanks for having me on. I think this series that you're doing is great for all the stakeholders for MPN education, so I applaud you and the team. I think this is an exciting era and an exciting time to talk about what you just mentioned. There are three or four hot-topic areas that I would love for our patients, caregivers, practitioners, pharma — everybody — to know about.
One is in the early-stage MPN, in polycythemia vera (PV) and essential thrombocythemia (ET). This is an area where there hasn't been much drug development in over 20-30 years. I would lump them together as sort of before-you-get-to-MF. There are some nice developments there. There are some new classes of drugs — actual, real classes of drugs that are emerging that we didn't have 5 or 6 years ago.
For example, there are the hepcidin modulators and mimetics in PV, essentially trying to restore normalization of the distribution of iron in the body system so that folks don't have too high of a hematocrit. That class of drugs, my goodness, already has four, potentially five or six, drugs in clinical trials, in either phase 1 or close to phase 1. Even in our ET there are some novel classes of drugs, including but not limited to LSD1 inhibitors, which are — can you believe — in phase 3 randomized frontline testing and trials. For folks who think there hasn't been much movement there, I would highlight that.
And then in our MF field, as you and I and others have discussed, there are a couple of things to keep your eye on. One is the development of JAK inhibitors plus another drug, which we'll talk about. These are combinations that build on the JAK inhibitor backbone. We've had several of these combinations make it all the way to phase 3 randomized frontline trials, and there are some mixed results that we can talk about. This is a novel agent plus a JAK inhibitor.
And then lastly, the development of improving anemia in MF. I'm happy to see some movement there. Again, there are drugs that may either modify the natural history of MF, therefore improving the anemia, or go after the anemia alone. I think those are some categories that are getting all of us excited in the current era.
Jain: I think you highlighted the major therapeutic advances that are happening. For all these drugs in development, if you had your clinician hat on, how would you see these being used in the future? Where do you see the field evolving, for example, in the next 10-15 years?
Pemmaraju: What a great question, and I think it's going to define a lot of what we do over the next decade. First, I would say that stem cell transplant remains the only curative modality for MPNs in 2025. And I want to repeat that because it is something that you and others have nicely shown us and pioneered. Stem cell and allogeneic transplant remain the only curative modality.
I envision that we have an era where we still have stem cell transplant, but perhaps we're able to guide the patients earlier and quicker to transplant, or potentially delay for the ones for whom it may not be as effective. For example, say you have a high-risk, young MF patient — say, a 35-year-old patient with high-risk molecular mutations. We're not curing them with these drugs alone.
One hypothesis that I would put forward, and this is a futuristic platform: Could it be over the next 5-10 years, could we identify that super young but high-risk patient who's fit enough to take, let's say, combination therapy, so a JAK inhibitor plus your best novel agent?
And if I can borrow from the terminology of multiple myeloma or acute myeloid leukemia (AML), perhaps an induction, if you will, over X amount of time, using your two best agents upfront, debulk the disease and get it to its best response. And then from there, a branch point — allogenic stem cell transplant, which of course has to be effective and decrease morbidity/mortality — or if unable to go for transplant, then branch point two is more of a consolidation, maintenance approach. Perhaps after you do, I don't know, 3-6 months, then you get down to a single agent rather than doing a sequence. Let's see how it goes. And then by the time transplant comes around, you're neither too healthy nor too sick.
So, I put that in one paradigm for the high-risk patient. We can sense that that person's going to go to AML in a few years. Then I would say another bucket is for the patient with PV. For example, we've always said, oh, there's a low-risk PV patient who maybe doesn't need treatment.
But then, my goodness, you have the 41-year-old who has a stroke or a heart attack. Maybe it's that we haven't had good enough treatments for those patients, and so you can have a series of drugs, whether it's the interferon agents, JAK inhibitors, or the hepcidin mimetic modulators, that can be given either as a single agent or — I know this is going to be paradigm-shifting — as a combination, a hepcidin mimetic plus something else, and, again, modify the disease to the point where you don't ever have that first thrombotic event.
That's what I'm envisioning. We're not there yet, necessarily, mainly because of financial toxicity, medical complications and drug toxicity. But I wanted to put those kinds of cutting-edge concepts to you. What do you think, Dr Jain?
Jain: That sounds phenomenal. I love that approach: thrombosis-free in an early MPN. I guess if I can repeat some of your words, optimizing patients on their way to a transplant, because all of us have shown that the better the disease control going into transplant, the better the outcome.
When patients are truly high risk and transplant is sort of inevitable, can we optimize disease outcomes better from a spleen standpoint, or in general health status, performance status standpoint, or even marrow fibrosis, which we've never looked into in much detail? Can transplant outcomes be better?
And the ones who are not high risk and don't need a transplant, or a transplant may not be as necessary right away, can we stall this or stall the disease progression further? Certainly, data with interferons are now starting to guide us a little bit in that scope as well.
I think a lot of credit goes to the improved diagnostics and vital applicability of next-generation sequencing panels and such. I'm sure you feel the same way, but every time we see that young patient with a splanchnic vein thrombosis and the liver consequences as a result, it breaks your heart. This is why I do not like that terminology, "low risk," because no diagnosis is low risk.
I think focusing on the thrombosis component, where the efforts tend to be less focused when the disease seems low risk, would be a dream come true, right?
Like we have a thrombosis-free situation from JAK2, sort of delving a little more into that, in terms of diagnostics. Where do you think the untapped areas are?
Pemmaraju: I love this question. We don't talk about it enough at our meetings, and it's only a platform like this where you're given an opportunity. If we can be current, modern, and futuristic, I can identify three areas that are on my mind right now. I love what you said about next-generation sequencing. Of course, for you and me it is so common, so mandatory, but we know that not every institution has done that. We advocate for people to check beyond the big three: JAK2, MYC1 , and CALR . So please do check TP53 s and ASXL1 . A lot of these mutations are part of the modern scoring systems for high-risk transplant and may even determine clinical trial eligibility.
One area that is starting to pop up — we're using it here at MD Anderson, and I think we'll catch on in the next few years — is something called OGM, optical genome mapping. It sounds futuristic and costly, and it sort of is both of those right now. It's a way to look beyond cytogenetics and the molecular level.
We are already in the first year or two of implementation, seeing novel or at least cryptic fusions and other entities that we never picked up before. This is also a way to pick up known entities that are a little bit harder to find, like 8p11 syndrome, where you have an approved drug that you can give.
So, I think it is a deeper and more elegant method of finding these molecular and chromosomal abnormalities beyond what we have. They always start as costly and inaccessible, and then over time become more accessible. That's one approach. Another approach is the work of Daniel Royston and Adam Mead.
When they first started talking about this, my goodness, it was futuristic, but it is the development of AI and math modeling to take previously invasive methods of diagnosis and make them noninvasive. The easiest way that they've explained it to me, and the way I can explain it to folks, is starting with some of the information we get from bone marrow fibrosis, which you had mentioned earlier. This is phenomenal. Can we get to the point where, without having to use a needle or a bone marrow biopsy, we can somehow monitor what's going on in the patient's system deeper than the blood and the blood smear? That would be 3D, math, modeling, and AI. And of course, in the past year or two, AI is so well developed compared to just 5 years ago.
The use of AI in our diagnostics, I predict, is not a hundred years away. I think it's much, much sooner than that.
And then the last thing I would say in diagnostics, that I have seen help us tremendously, is the advent of the bone marrow biopsy itself, checking the flow cytometry and other adjunct tests rather than doing them at different time points. On the bone marrow, if you can pull multiple pulls, as you said, so next-generation sequencing, I would rate it highest; but cytogenetics, flow cytometry, and even this OGM could be done. So, multiple pulls on the same bone marrow biopsy. And then, obviously, pathologist reading is still important for morphology — for example, prefibrotic MF vs ET and MF. I would say, improve methods at the level of the hematopathologist. Of course, that comes from expert training, interacting with us as clinicians. Those are some of the things I see that would help, and I think it has not just academic implications. I would say the advent of the prefibrotic MF is something where, in the past 5, 10 years, you can identify a subset of patients that may be a bit different from ET, not quite to MF. The advent of checking ASXL1, TP53 , and early watching for dynamic clonal evolution, including it in your MIPSS70 score, who's going to go to transplant earlier? And then remember selecting clinical trials if, unfortunately, a patient has relapsed or refractory disease. We found a FLT3 mutation or an IDH mutation that may have an approved drug from somewhere else.
These are some of the applications I think are helping.
Jain: That makes a lot of sense. I'd love to continue to hear about the OGM platform. As we always say, genomics is driving much of this, obviously with some external second impact as well. But genomics is a big point — not just in diagnostics but also in therapeutic implications and progression, and all the decisions that we make around that.
You and others have done a lot of work in therapeutic development in MF. I hope I'm wrong, but I always feel that MF tends to remain this rare blood malignancy, and everything reaches us last, right? Like it's the wicked stepchild of heme malignancies.
In terms of therapeutics, we've seen targeted agents develop in AML and other malignancies. We've seen that venetoclax may be finding some space in advanced MF or at least being anecdotally used, or more than anecdotally used.
We've seen cellular therapy being developed in some of the other heme malignancies. What are your thoughts on the therapeutic development, outside of the drugs that are in the pipeline right now?
Pemmaraju: This is a passion area for me. I think this is so important that we can't discuss it enough. Broad strokes first. It is surprising to me — that's the word I would use — that we still have a monotherapy-based system as the backbone, particularly for these advanced patients with MF.
It's very surprising to me. It's not because you, I, Ruben [Mesa], and others haven't tried. We've tried. The problem has been with some of the early efforts, BCL-XL inhibition and bromodomain inhibition in particular. But we made it all the way to phase 3, positive primary data, which means spleen volume reduction was met.
Double that of ruxolitinib or JAK inhibitors alone. But we, importantly, did not meet the symptom burden expectation for improvement statistically. So, point number one — and this is controversial, what I'm going to say, so I want to say that not everyone will agree with me, but I'm wondering out loud — can we move beyond spleen and symptoms?
As we move beyond JAK inhibitor monotherapy, where that system was developed, and either add, incorporate, or yes, potentially even replace with overall survival, progression-free survival, event-free survival, as our colleagues in AML and multiple myeloma, and others have done. This, I think, is a central concept, and I'll advocate that every day.
Two, there are new, even more novel agents that are coming in: PIM kinase, telomerase inhibition, XPO1, MDM2. All of these are actually in phase 2 to phase 3 testing, as a novel agent by itself after JAK inhibitors, so, sequential or in combination with the JAK inhibitor. I think it's important to include some of the mechanisms of action.
Can we start to see cytokine improvement? Can you start to see biochemical evidence that the agent is working for its target? What about marrow fibrosis reversal, as you nicely said in the earlier segment? I wonder if we can have spleen and symptoms, fine. That is our backbone. But we also need to build in other outcomes — overall survival (OS), progression-free survival (PFS), event-free survival (EFS) — and the ability to bridge patients to transplant. Those are very important, successful markers of whether the drug is working. And then a third layer, biochemical correlates. These are not random. I'm not saying a random wish list, but personalized to each drug.
And then Roman numeral two is allele clearance. We used to say that we're never going to see that. Well, guess what? Claire Harrison in the JCO MAJIC study, a study that you and I know well, showed for the very first time that ruxolitinib in advanced PV — not MF but PV — not only cleared the allele burden but also correlated finally with OS and EFS. And EFS includes thrombosis-free interval — all of these important endpoints. In MF, we're starting to try to correlate these things, and we need to show that.
And finally, another area is the bridge to stem cell transplant. That's a huge success in this field if you're not curing the disease, which we have not yet, with single agents or with double agents, for that matter. As we were discussing earlier, can you at least get someone into a best response? And then because you can do that bridge to transplant, that should be a success, not a failure, that you "came off the study." What I'm calling for here, to say it directly, is that as a field, we need to follow patients for the long term. We need to follow patients not just for 24 weeks but for 5, 7 years. We need to look at transplant as a part of the journey, not an end. Now, you come off the study and, oh, we don't know what happened after that. And so the length of these studies, I think, has been a big failure really for our field. We know the realistic reason. It costs lots of money, resources, time, and effort from both the patients and the providers. But if we can commit to that, have realistic correlatives and realistic endpoints, I think we could see a huge boon in drug development.
Jain: That's a phenomenal point. As you said this, I was thinking about how posttransplant monitoring would mostly be clinical outcomes monitoring, and I wonder if this is sort of an opportunity to partner with the Center for International Blood and Marrow Transplant Research (CIBMTR).
Pemmaraju: Wow. Yes.
Jain: Perhaps this is something that companies or investigators can partner with to get a more long-term picture of what's happening with these patients.
Because it could be either way, right? It could be that these drugs are optimizing patients better for transplant, and the transplant outcomes are better. We don't know that because we're not looking at that. Or maybe there are drugs, God forbid, that are potentially detrimental to the outcome of the transplant. I think that's an important piece to be aware of as well, if that is happening at all.
Pemmaraju: To add to that, Dr Jain, I would point the viewers to a couple of different studies in that realm. You've published on exactly what we just said: transplant outcomes. You've also shown immunotherapy as a new area of something to talk about.
And then Dr Nico Gagelmann, our colleague, in The New England Journal of Medicine , perhaps just 6 months ago, wrote exactly what we're talking about. So, mutational, clearance, post-transplant. These are the first efforts, your efforts and his, and maybe several others in the field — sort of pre- and posttransplant monitoring and maintenance.
I just love what you said, so I want to put that out there. That's an essential thing moving forward.
Jain: I think Dr Gagelmann's work, and their team's work, Dr Kroger's and Dr Gagelmann, has certainly helped advance the field. You brought up immunotherapies. I can't let you get away with just mentioning that.
I'm going to have you maybe just spend a minute or two on where you think the future of immunotherapy lies. We have CALR -directed antibodies and bispecific T-cell engagers (BiTEs) and JAK2 -directed antibodies, sort of nontransplant immunotherapeutic options. Do you think they'll have a role in the MPN space?
Pemmaraju: Oh, that's great. I'm going to comment on those, but then I'm going to turn it back to you because you've given a phenomenal talk that I've seen now a couple of times on some of these novel immunotherapeutic agents. But for the ones you asked about, the ones I'm involved in, I'm pretty excited about them. I think that the central tenet that I did not realize a few years ago — correct me if I'm wrong — but since CALR , yes, it hangs out in the nucleus, but when it becomes mutated, it presents to the surface, therefore becoming susceptible to immune attack. That's changed our whole field. Version 1.0 was vaccines. So far, not yet a whole lot of clinical success. Let's see where that field goes.
Version 2.0, monoclonal antibodies and bispecifics. That's one we're a part of. Several of our sponsors, whom we've worked with for the more traditional tyrosine kinase inhibitors, have now moved into this field. Those phase 1's are ongoing and enrolling, so we hope to see data from them perhaps as early as the fall or winter in the conferences next year.
I think what's interesting there with CALR is you can attack it in any of the immune ways. So, vaccine, monoclonal antibody bispecific, even now, CAR T cells are being developed by our colleagues in Europe — Alexandros Rampotas and Bethan Psaila et al. That's really phenomenally exciting. But what's exciting is how quickly and rapidly we've moved from the preclinical observation to the clinical.
In the absence of clinical data, yes, I'm excited about the concept. Let's meet back in 6-12 months and see how it's going. JAK2 , though, even though not directly immune susceptible, at least now we have ways of targeting the mutant clone itself rather than the pathway. There are the first two different drugs, either is mutant selective or mutant specific.
But I've got to turn it back to you. You've given some nice updates on immunotherapeutics in the myeloid neoplasm, so I'd love to hear your update. You've got some cutting-edge ones.
Jain: I think you summarized it beautifully. Obviously, I'm biased around this, but I do think immunotherapy has been transforming in general in the oncologic space. It's just taken some time to get to MF, as you beautifully alluded to. There is a challenge with the targets.
You may or may not know this, but the fact that the CALR is the most immunogenic is something that Ruben Mesa and I worked with Peter Cohen, MD, on at Mayo Clinic, Arizona, back when I was a fellow. That project, like many other fellow projects, did not come to fruition. So, it's not a published project, but we had some funding around it, and we collected a bunch of CALR patient samples to work on some of the peptide sequencing in Dr Cohen's lab. This is something that's been of interest for a while, and it has been a joy to watch some of the novel ways to target CALR now being developed. I suspect we'll hear more at the European Hematology Association annual meeting and some of the other meetings.
I don't know how much I can say right now, but we'll hear at some of the upcoming meetings what the data look like and where the promise of these will be, in general. As you've mentioned, we've blocked pathways so far, and we've seen some suppression of disease or myelosuppression in cytoreduction.
We haven't quite seen getting rid of the mutant clone, which is what is needed, with or without a transplant. I would hope that these drugs can potentially get us there. Maybe not in version 1.0, as you mentioned, but maybe in version 6.0 or 3.0. We'll see, but I think at least it's getting there. At least we're thinking about it and investing time and money into it.
This has been such an enlightening discussion. Maybe if we could close this by hearing: What is Dr Naveen Pemmaraju's dream treatment paradigm for MF?
Pemmaraju: Wow, this has been fantastic. You promised me that we'd be talking about futuristic things. The disclaimer here is, yeah, this is going to be some futuristic, cutting-edge stuff I'm going to say. But let's put it out there. When we were talking earlier, it stimulated something that I want to say, which is: Can we hit this awful disease earlier before it's too late? You nicely said that because you also are one of the experts in our field who knows both MPN and transplant, and oftentimes we're sending our patients too late to transplant, when the disease is too advanced or when the body is too sick.
I would say there are two areas I didn't mention. One is CHIP. CHIP is clonal hematopoiesis of indeterminate potential. We've known about CHIP for a decade or so, I want to put out there that JAK2 is among the top five most common mutations found in CHIP.
My suspicion, at least, is we've started to see that some of those JAK2 CHIPs could either transform to MPN or maybe they already are a low-grade MPN, because these patients have thrombotic events and cardiovascular events. I don't know if the term is "chemoprevention" or "early identification," but we're seeing CHIP clinics, at your institution and mine, Sloan Kettering, all around the world, starting to develop.
But what I'd like to challenge the stakeholders, pharma, philanthropy, investigators — everybody — to is the question: Can we start to develop actual targeted therapy at the level of CHIP, at least for JAK2 CHIP? I'm only talking about our MPN field, before it turns into MPN. That is one thing that could be a decade-long effort.
Number two, as we mentioned, you said it beautifully, is, I don't like the moniker of "low risk" because low risk means we don't have treatments yet to use, and the risk-benefit balance isn't there. We want to double down. The PV field is a good one for testing.
The hepcidin mimetics modulators work that I've been part of; we're going to hear more about them in the summer and fall meetings. By themselves, they may not eradicate the disease clone. They weren't designed to do that. But perhaps they can make people phlebotomy-free. But either of those, in combination with other agents; or can we give them as solo agents to patients previously thought of as low risk? Make someone phlebotomy-free? We need to show this over time; then they can be thrombosis-free, cardiovascular event-free.
My thoughts on the earlier disease and then in MF, as we both said: Can we get to the point where it's okay to treat the disease earlier, upfront, and attack it before the clones have a chance to escape?
Could it be a combination therapy upfront, then followed by a more long-term consolidation maintenance? I'd like to see transplant moved up earlier and more often, with all the great developments that are happening post-transplant with better supportive care. And then for that large chunk of patients who are truly, truly stem cell transplant ineligible, can we do what you said earlier, which is to give them a phenomenal therapy with minimal side effects? Because at the end of the day, our friend, mentor, and colleague, Ruben Mesa, says it best, which is, can we have our patients live longer and live better? That's my dream paradigm and I think we are getting there. I think we're going to see a lot of developments in just the next 3-5 years.
Jain: What I'm hearing you say repeatedly is overall survival.
Pemmaraju: Yes. You heard that right.
Jain: We want agents that will help us achieve that. Not just overall survival, I guess, but improved quality of life. Better overall survival, better quality of life.
Well, Dr Pemmaraju, this has been a fun discussion, and the evidence of that is that this is the longest podcast that we have recorded so far. I could keep going and hearing from you about all the wonderful things.
It has been fun, and I hope our audience has enjoyed it as well. We heard about some of the early-stage developments that Dr Pemmaraju summarized, with hepcidin mimetics, LSD1 inhibitors, and then in MF, combinations, and how to use them, maybe as an initial induction and staying on a less aggressive treatment as maintenance.
I'm ever so grateful to Dr Pemmaraju for giving a shout-out to the role of transplant as well. Although I will say that if immunotherapy does the job, I'm happy to open my coffee shop and not transplant. If there are better treatments, that is what we want.
Ultimately, we'll be excited to hear about how your work with the OGM goes, the optical genome mapping. That sounds fantastic. And we talked about strategies to improve fibrosis, which we hear less about but are certainly important. There's so much to summarize, Dr Pemmaraju, and I'm so thankful to you for bringing all of these things up and sharing your vision for the future today.
Pemmaraju: Thank you so much, Dr Jain, for having me. This was phenomenal.
Listen to additional seasons of this podcast.
Manipulating Hepcidin in Polycythemia Vera
Role of ASXL1 and TP53 Mutations in the Molecular Classification and Prognosis of Acute Myeloid Leukemias With Myelodysplasia-Related Changes
Cryptic KMT2A::AFDN Fusion Due to AFDN Insertion Into KMT2A in a Patient With Acute Monoblastic Leukemia
8p11 Myeloproliferative Syndrome: A Review
What's Next? Clinical Trials in Myelofibrosis
Artificial Intelligence-Based Morphological Fingerprinting of Megakaryocytes: A New Tool for Assessing Disease in MPN Patients
Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies
The Telomerase Inhibitor Imetelstat Differentially Targets JAK2V617F Versus CALR Mutant Myeloproliferative Neoplasm Cells and Inhibits JAK-STAT Signaling
A Novel Application of XPO1 Inhibition for the Treatment of Myelofibrosis
BOREAS: A Global, Phase III Study of the MDM2 Inhibitor Navtemadlin (KRT-232) in Relapsed/Refractory Myelofibrosis
Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial
Center for International Blood & Marrow Transplant Research (CIBMTR)
Donor Types and Outcomes of Transplantation in Myelofibrosis: A CIBMTR Study
Clearance of Driver Mutations After Transplantation for Myelofibrosis
Development of a First-in-Class CAR-T Therapy Against Calreticulin-Mutant Neoplasms and Evaluation in the Relevant Human Tissue Environment