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Medscape
10-07-2025
- Health
- Medscape
S2 Episode 6: A Futuristic Vision for Treating Myelofibrosis
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
Medscape
10-06-2025
- Health
- Medscape
S2 Episode 5: Posttransplant Monitoring in Myelofibrosis
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 everyone. We're back in our myelofibrosis for Medscape InDiscussion podcast. This is season two, and this is episode five, where we'll talk about transplant outcomes in myelofibrosis and how to address relapse post-transplant. I'm Tania Jain, and today we have our very special guest, Dr Rachel Salit, who is an associate professor at Fred Hutchinson Cancer Center and the University of Washington School of Medicine. As a hematologist-oncologist, Dr Salit specializes in stem cell transplant, focusing on improving outcomes for patients with myeloproliferative neoplasms. Her research has included developing clinical trials to enhance and improve transplant success, prevent graft-vs-host disease (GVHD), and she also works on initiatives to support patients' return-to-work journeys post-transplant. Welcome, Dr Salit. It's an honor to have you. Rachel Salit, MD: Thank you for having me today. Jain: What we want to talk about today is pre-transplant, post-transplant, and how to think about transplant. I think we would all agree that transplant is presented and thought about differently, to some extent, by different clinicians and others who see patients in the clinic. What is your approach, and how do you go about telling patients about the role of transplant? Salit: The way I approach patients with myelofibrosis is from two different sides. One is the scoring system criteria — going over the Dynamic International Prognostic Scoring System (DIPSS) and the Mutation-Enhanced International Prognostic Scoring System (MIPSS-70). That would include what their blood counts look like, their molecular profile, cytogenetics, whether they have any peripheral blasts, and whether we think they're at imminent danger for transforming to leukemia or needing blood or platelet transfusions. The second side I look at with them is their life goals — what they are hoping for in terms of longevity vs quality of life. I think we've made great strides in transplant in the last 10 years in myelofibrosis since the approval of Janus kinase (JAK) inhibitors. I talk with them about the role of JAK inhibitors in the pretransplant setting — whether they've had one or not — depending on their symptoms and splenomegaly, and how that affects transplant timing. Ultimately, it's their choice. Patients often have strong opinions. There are patients with high-risk disease by scoring systems, but who are having a rather good quality of life and don't want to rush into treatment. Then there are patients with lower risk but who, because of younger age or life goals, want to proceed more expediently. I let the patient guide me. The third component that goes into it is what our donor search looks like. I often don't know that when I first meet the patient, so I always add the caveat: This is the conversation we're having now, but once we assess sibling matches or unrelated donors, risks and benefits might change. Jain: One of the things that challenges me is that there's a lot of prediction involved in the transplant decision, especially the first part you mentioned, about leukemia progression risk. There's no perfect metric to predict someone's transplant outcomes, whether for disease control, preventing relapse, or even nonrelapse mortality. How do you play the prediction game, without a crystal ball? Salit: I think it is one of the most challenging aspects of myelofibrosis. I empathize with patients in that we consider this a somewhat elective procedure that no one wants to need. It's tougher on them than it is for acute myeloid leukemia (AML) patients, where we say, 'This is your option, and you need to do it now.' For me, I try to look at the disease kinetics. When did it develop? How long has it been stable? If they have peripheral blasts in their blood, have they stayed at 1% for 2 years, or have they risen to 2% or 3%? Have their counts stayed stable? Is their spleen growing? Are their symptoms increasing? If patients have poor-risk factors but stable disease, I'm less aggressive than I am with patients who have more benign features but rapidly progressing disease. Sometimes in younger patients, the disease progresses faster than expected, especially if they have just one high-risk mutation. Jain: I always say that one of the most important things to follow is the trajectory of disease. When counts begin to drop or blasts start to appear, that makes you pause and think about transplant, or at least do a bone marrow biopsy to help make that decision. I want to shift gears. I know you've been involved in defining remission post-transplant, which is a huge unmet need. Many disease features don't resolve quickly after transplant, yet we consider the transplant successful. The forms and shapes that remission or recurrence can take post-transplant have evolved. Can you share how you got involved in unifying the concept of remission post-transplant and what insights you can offer for our audience? Salit: I got involved in this from two angles. Clinically, it's long been unsatisfying to tell patients post-transplant that they have low counts, persistent fibrosis, or splenomegaly when we discharge them from the acute transplant service at day 100. The providers we discharge them to — often general oncologists — aren't always sure what to say. Are you in remission? How long will it last? How do we test for it? The second part came from my work on the Medicare–Center for International Blood and Marrow Transplant Research (CIBMTR)) composite study, looking at whether transplant benefits patients over 55. We've been working on this for the past 7 years. When we met to define the response to transplant, we used the newly developed International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for drug response in myelofibrosis, and we found that to be very complex for CIBMTR reporting. The people reviewing charts were not reporting consistently. I was approached by Wael Saber from CIBMTR to help develop a consistent remission definition so that centers reporting outcomes — remission, persistent disease, or relapse — could be compared. We want to draw conclusions about what regimens and donors are working best. We recognized that, unlike AML patients who go into transplant in CR1 (first complete remission), myelofibrosis patients go into transplant with active disease: persistent blasts, fibrosis, splenomegaly. We formed a committee of myelofibrosis transplant experts from the US and Europe. We wanted both CIBMTR and the European Society for Blood and Marrow Transplantation (EBMT) to have the same criteria so we could collaborate and combine data. The strongest takeaway was that the main thing transplant can do that drugs currently cannot is put patients into molecular remission. Most patients have driver mutations — JAK2, CALR, MPL — and we know the majority clear these mutations post-transplant. We recognized that patients with molecular remission may still have low counts or morphologic abnormalities. We classified these as subsets of molecular remission. We also agreed that persistent molecular abnormalities — especially if decreasing — shouldn't be considered relapse. Persistent disease can clear over time with rising CD3 chimerism and immune suppression taper. We reserved 'relapse' for patients who had previously cleared their mutation and then redeveloped it. That's a much more concerning scenario requiring intervention. Jain: That makes a lot of sense. One way I explain it to patients is that a transplant is an intervention with curative potential, but disease elimination takes time, even after donor hematopoiesis is established. It's not an immediate clinical remission — spleen and counts take time to improve. But once donor hematopoiesis is present, that can eventually trigger graft-vs-leukemia activity to eliminate residual disease. Do you know if there's a difference in how CIBMTR and EBMT capture relapse? Salit: I honestly don't know. But one of the goals of our project, with about six stakeholders from each registry, was to create a uniform definition. I think the recent New England Journal of Medicine paper by Gagelmann and colleagues spearheaded this molecular remission definition. CIBMTR and Dr Saber are very enthusiastic about this, and I think we can develop reporting forms that consistently capture remission, persistent disease, and relapse as three categories. We acknowledge there will be missing data. Not every center regularly tests molecular driver mutations. We've also discussed the role of chimerism. Fractionated chimerism is important, but most European centers don't assess it. They can do weekly molecular tests; we might test every 3 months at best. So, blood counts and chimerism will still play a role. I've piloted this approach with my patients, and they find it more satisfying. At day 100, I can say, 'You still have fibrosis, splenomegaly, and low platelets — but your JAK2 is negative. We're considering this remission.' That's much more reassuring for them than wondering why we even did the transplant. Jain: I totally agree. Bringing together the American and European efforts — making them globally unified — would be a huge advancement in research. Right now, it's hard to use or compare registry data across systems since it's not apples to apples. You mentioned you're already using this with your patients. There are times when spleen, fibrosis, or counts aren't fully normalized. Can you share your approach for relapse or 'impending relapse' when you see persistent disease features like cytopenias, transfusion needs, splenomegaly, dropping chimerism, or persistent molecular mutations? Salit: We check molecular driver mutations every 3 months — at months 3, 6, 9, and 12. If the 3-month result is negative but the patient still has low CD3 chimerism, needs transfusions, or has fibrosis, we start tapering immune suppression at day 100. We follow chimerism monthly during tapering. If it's not at 100% by 6 months, we may do a bone marrow biopsy to see if anything concerning is present. If the mutation's variable allele frequency is decreasing, that's reassuring. If it's back and chimerism is dropping — say it was 100% at day 100 and 90% at 6 months — we consider donor lymphocyte infusion (DLI), assuming they're off immune suppression and don't have GVHD. If they're still on immune suppression, we taper conservatively and wait a month before giving DLI. We only use therapy like hypomethylating agents and JAK inhibitors if blasts return in the peripheral blood or marrow, or if abnormal cytogenetics reappear. Jain: Those are tough situations — when blasts are visible, or disease features reappear. How often do you consider a second transplant in myelofibrosis? Salit: Not often. Thankfully, we're seeing only 5%-10% relapse rates. At our center, we're still doing relatively mild ablative transplants: Cytoxan/busulfan for those under 60, or decitabine/melphalan for those over 60. If a patient completely loses CD34 or CD33 chimerism, we consider a second transplant. There's concern that giving DLI in that setting could cause aplasia. If the disease burden is too high, we go straight to the second transplant. Jain: That makes sense. Well, this was phenomenal. Thinking about transplant is a nuanced process, and we loved hearing your thoughts. We look forward to reading about the remission definitions post-transplant and implementing them in the clinic. On behalf of our audience, thank you so much for your time. That concludes episode 5 on transplant outcomes in myelofibrosis. We'll see you in the next episode. Listen to additional seasons of this podcast. Primary Myelofibrosis Role of Hematopoietic Stem Cell Transplantation in Patients With Myeloproliferative Disease Decreasing Chronic Graft-Versus-Host Disease Rates in All Populations Diagnosis and Evaluation of Prognosis of Myelofibrosis: A British Society for Haematology Guideline Prognostic Value of Blasts in Peripheral Blood in Myelofibrosis in the Ruxolitinib Era Acute Myeloid Leukemia (AML) CIBMTR Myelofibrosis Medicare Study Proposals for Revised International Working Group-European LeukemiaNet Criteria for Anemia Response in Myelofibrosis Utility of Assessing CD3+ Cell Chimerism Within the First Months After Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia Clearance of Driver Mutations After Transplantation for Myelofibrosis Donor Lymphocyte Infusion and Molecular Monitoring for Relapsed Myelofibrosis After Hematopoietic Cell Transplantation Medscape © 2025 WebMD, LLC Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape. Cite this: Posttransplant Monitoring in Myelofibrosis - Medscape - Jun 10, 2025.
Medscape
08-05-2025
- Health
- Medscape
S2 Episode 4: JAK Inhibitors: Too Many Choices or Not Enough?
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, everyone. I'm Tania Jain, and I'm back with our special guest, Dr Prithviraj Bose, for our Medscape InDiscussion : Myelofibrosis podcast. This is season two, episode four, and our topic today is JAK inhibitors: an embarrassment of riches or a poverty of options? I'll quickly introduce Dr Bose. Dr Bose is a professor in the Department of Leukemia at the University of Texas, MD Anderson Cancer Center. He has been very involved and is a very prolific clinical investigator in the field of myeloproliferative neoplasms (MPNs), especially myelofibrosis (MF). We're excited to talk about this. This has been a topic that has been touched on numerous occasions but certainly deserves a very focused discussion. Let me start by asking you what your approach is with the four JAK inhibitors that are commercially available. Prithviraj Bose, MD: Great question. We have four JAK inhibitors. Where do they all fit? What are the considerations? When you pick one, how do you sequence? I'm sure there are some differences in opinion as to where people use each drug, but I think all four are very welcome to the field. Something a bit sobering that you see as you practice and see patients is that all four have a home. All four are needed. And sometimes you're surprised when a patient may not exactly check all the boxes that you would imagine from the literature, and you realize that a particular JAK inhibitor is just not right for them or another one is remarkably good for them. I do keep in mind that ruxolitinib has a proven survival benefit. That is not to say that the others couldn't. It may well be a class effect, but there is something to be said for the fact that ruxolitinib is the only one that has demonstrated that. In the same breath, I should acknowledge that with fedratinib and pacritinib, they had full clinical holds. It is never going to be possible for those, I think, to show a survival benefit. And then momelotinib was compared mainly to ruxolitinib and to danazol; certainly it was not compared to placebo. All the drugs have been studied in somewhat different populations and in different lines of therapy, so there are a lot of caveats. But then again, ruxolitinib has its survival advantage. It's a great drug for the spleen and symptoms. I tend to start with that in most patients now. I find fedratinib to be very useful in the second line in patients with a large spleen and good counts. Now, that's a bit hard to define, and we know that it has data above 50 platelets and does not need those adjustments. But again, when I have the sense that the counts are preserved, I'm not too worried about the counts tanking. If the spleen is big and it needs a potent drug, fedratinib is my drug of choice in the second line. With pacritinib and momelotinib, obviously both are more tailored, let's say, for our cytopenic patients. They both hit ACVR1 or ALK2 and have the anemia benefit. To me, momelotinib has stronger data for anemia, which is reflected in its label. Generally, when anemia is my main priority in a patient, I'm reaching for momelotinib. At the same time, when the platelets are low, either below 50 or close to 50, I'm more comfortable with pacritinib because it has the label for less than 50, and really in that space it has the best data. But also, momelotinib can cause some thrombocytopenia. I worry about that a little bit if the platelets are already in that, say, 50,000-70,000 per microliter of blood range. I'll usually choose pacritinib there. And it also helps that it has an anemia benefit. These patients don't come with just anemia or just thrombocytopenia; they usually coexist. That can be helpful. So, for anemia, my choice is usually momelotinib. If there is severe thrombocytopenia, I use pacritinib. If there are good counts and a large spleen, I'll use second-line fedratinib. Most of my frontline treatment is with ruxolitinib. I will say, though, that momelotinib has a place in the frontline too, and I think that is yet to be fully defined. But the frontline space right now is probably shared by ruxolitinib for the most part, but also momelotinib, because they have good data in the frontline setting from SIMPLIFY-1. And when you are starting with anemia, that is something you may want to consider. I think that's a bit of an unresolved question at this time. Jain: I agree. I've always wondered, in people with that borderline hemoglobin of around 8-10 g/dL, what is a better frontline between momelotinib and ruxolitinib? Especially because the spleen response is between the two. At least in one of the SIMPLIFY studies, it seems to be noninferior. I like your approach, and it's very similar to what I end up following too, with ruxolitinib still being sort of the default option. In addition to all the things you've said, the fact that we have the longevity of experience with ruxolitinib and can almost predict — whatever that word means in real life — it certainly adds to that level of comfort with ruxolitinib. I think having four JAK inhibitors is a good strategy from a JAK inhibition, JAK-STAT pathway inhibition standpoint and addressing that mechanism in this disease. Where do you think there is room for progress now? If we were to look forward, where do you think we need to invest our investigations and efforts? Bose: There are quite a few areas. Let me start with the anemia piece only because we were already talking about that in the frontline ruxolitinib-vs-momelotinib context. I welcome the development of the anemia drugs. We have luspatercept in phase 3, fully accrued, awaiting those results. We have DISC-0974, the anti-hemojuvelin — very exciting — as well as elritercept, another activin receptor ligand trap also looking very exciting. I think there is a place for these agents; even though we don't generally think of them as disease modifying or addressing the disease as a whole, these are all anemia drugs. I know there's been some interest in elritercept potentially leading to spleen symptom and anemia responses, but we'll have to wait and see how the data shake out on that. Looking at the value of these agents, and we were going back to this, ruxolitinib may be our most potent JAK inhibitor. I think there is a value to optimizing the dose of ruxolitinib. We know from the work of Srdan Verstovsek and others that the spleen response to ruxolitinib is dose dependent and correlates with survival. So, if you can give the hemoglobin a boost with these other agents — these add-on or ancillary, supportive agents — maybe you can maximize the ruxolitinib and maximize the benefit of that drug. I think there is value to developing anemia agents, even though we have momelotinib. And to that point, the ODYSSEY trial is looking at momelotinib plus luspatercept. So, clearly, even though momelotinib does a great job on its own for anemia, I think there is still an unmet need, and these anemia drugs are certainly very welcome. I'll move to perhaps what was the thrust of your question, which is all these other non-JAK mechanisms of action that we are studying. These are either with JAK or alone, and eventually all of them are, I think, studied with JAK. They start alone, and then when there's comfort with the dosing and safety, they move into add-on or even frontline. I'm excited about BET inhibition as a class. I know that with pelabresib, perhaps we had a little bit of a less-than-desired outcome, when there was a lot of expectation around the time of the ASH [American Society of Hematology] 2023 meeting that we would probably have an approval. But as you and I know, some issues threw wrenches into that with the symptoms and then a little bit of an imbalance in the blast transformation. I'm very curious to see what the long-term follow-up of that shows. I don't think the blast thing is a real concern. I mean, mechanistically, why would that be? But at the end of the day, there was an imbalance, and that's something we want to be very careful about. So that long-term follow-up is very important. The Incyte BET inhibitor is looking quite exciting and is nicely shaping up, so, certainly looking forward to that. And then there's selinexor. Selinexor is now, I think, our front-runner, if you're talking about phase 3 upfront combos. Certainly it's a very potent agent. This is after the navitoclax/pelabresib wave, which has kind of died down a little bit because of what we just said. It's shown what it can do as a monotherapy in the ESSENTIAL trial. Part one of the current trial, SENTRY, showed us some remarkable results, with 79% spleen and 58% symptom response, which we really haven't seen with other combos, not even with pelabresib. Again, that's comparing across trials and acknowledging that it was only 14 patients. That's based on part one of SENTRY, but another trial is accruing and approaching its goal of, I think, around 350 patients. We'll see what that brings. And then, of course, one has to mention navtemadlin. That's a unique trial design. We've never seen this before in the field, certainly a very interesting one. You start with ruxolitinib alone, and then if the patient does not meet both the spleen and symptom thresholds, if they're suboptimal for both spleen and symptoms, you add on navtemadlin or placebo. It's going take a while. That's going to be a big, long trial. It is 600 patients, I think, ultimately hoping to randomize 180. That's been another interesting drug. John Mascarenhas, I think two EHAs [European Hematology Association meetings] ago, presented the add-on cohort of their phase 2, where we saw 32% spleen and 32% symptoms. That was decent — actually very good, I would say — in the add-on setting. Numerically it might even be the best in the add-on setting. And there's that consistency with 32% spleen and 32% symptoms. Finally, not to be forgotten, there's imetelstat, which is already on the market for myelodysplastic syndromes. It's been a little quiet for a couple of years in MF as the IMpactMF trial continues to accrue and closes in on its goal of, I think, 320. That is in the second-line setting vs BAT [best available therapy]. It's a bit hard to accrue here in the US because of the lack of JAK inhibition on the BAT arm. It will be an important drug. It started with this promise, if you will, of a survival benefit. Certainly, it's something to keep an eye on. And then I think we would be remiss not to mention the new wave targeting driver mutations better. I think that probably sums it up. They are JAK2 mutant-selective, the type II from Ajax, which is based on very cool signs from Ross Levine's lab. The immunotherapy approaches are against CALR , whether that's bispecific or a straight-up antibody. If they can hit the driver harder, as a colleague mentioned recently, you may not need other synergistic strategies. Maybe if you go after the driver, do it a bit early in the disease, you could look at real disease modification. It's some way away from reality, but I think those are no less exciting than anything else. Jain: That's true. I think your overall notion about a lot of excitement on the horizon is very well received. There's a lot of optimism in terms of what options may be available in the future. How to position these targeted agents will become important — as an add-on or a secondary therapy, or a primary first-line kind of therapy. Especially if we start seeing molecular responses, with these agents in a reliable manner, one might argue, are we heading toward more like a CML [chronic myeloid leukemia] approach where you truly can target the driver? You brought up imetelstat; we don't talk often about it, so I'm going to probe you a little bit because this is one of the first studies, I think, in MF where we're talking about an overall survival benefit. The endpoints in clinical trials have come up in discussion time and again over the past couple of years with the navtemadlin frontline study and pelabresib — both the MANIFEST and the TRANSFORM studies — to question, what are the endpoints? We touched on this a little bit in a prior episode as well, but I'd like to hear how your excitement stands about imetelstat, or the overall thought about survival as an endpoint for an MF study. Bose: Well, I'm certainly intrigued by imetelstat. John [Mascarenhas] published in Journal of Clinical Oncology a couple of years ago that there was 28-month median survival with imetelstat, at the 9.4 mg/kg every 3 weeks dosing, in the IMbark study. And this was in the post-JAK setting. They did define JAK failure; it was not just anyone who's been on prior JAK. Because one must be careful when one looks at the studies. For example, if you look at the original FREEDOM2, there was really no definition of JAK failure, so it's important to define it, which was subsequently done right when FREEDOM2 was reanalyzed. Oh, I'm so sorry. I meant JAKARTA2 — when JARKARTA2 was reanalyzed and then the FREEDOM trials were designed, etc. Back to imetelstat. IMbark was a trial that rigorously defined JAK inhibitor failure and showed this apparent survival benefit, because we assume that it's going to be 13-14 months. Several of us have published that — us, Moffitt [Cancer Center], Dr [Francesca] Palandri in Italy — that when you fail ruxolitinib, you're looking at about 14 months median. The 28-month number was quite eye-opening. There are caveats to all these being very different studies. For example, something Dr Palandri has nicely shown is that yes, it's 14 months. But it's mostly driven by those who develop the blast phase, right? If you stay in the chronic phase after "ruxolitinib failure," I don't know if that is 14 months. So, I will throw that out. I mean, it's the totality that is 14 months, but for many of the patients, at least in the Palandri study, it was driven by those who ended up in blast phase, which you and I know is extremely bad. So, back to imetelstat. I think overall survival in the second line is very feasible. The issue is in the frontline use of imetelstat, where the spleen and symptom response has been criticized. That is true. Perhaps they are better tailored to JAK inhibitors, and that is how they evolved — as we are SVR35 [spleen reduction volume ≥ 35%], TSS50 [total symptom score ≥ 50%] — all evolved in the context of ruxolitinib and its successors. Maybe they don't apply as well to the novel agent. But the problem as I see it is that I don't know that we can, at this time, reliably say whether it's cytokines, whether it's VAF [variant allele frequency], whether it's bone marrow fibrosis, that we have a solid surrogate for survival. And that is why I feel that spleen and symptoms for the immediate future, as well as transfusion independence, is very important. I think momelotinib and luspatercept have shown us that that's an important endpoint. These things still have more teeth today, despite all their shortcomings, than some of the putative markers of disease modification, where there's not much uniformity across trials. I mean, there's a lot of heterogeneity between cytokines measured or the thresholds of VAF reduction, which makes it a bit difficult or murky to compare across trials. I guess that's where I am on that. Jain: I think that's a fair point. I'm excited that we're even starting to talk about survival. It's been a long time coming to get there. I think it's a positive move that we're starting to talk about it and think about it. It seems like, at least in theory, in concept, there may be drugs that can be considered for trials with an endpoint, or even a secondary or a primary endpoint of survival, like targeted agents or imetelstat, and maybe in combination with JAK inhibitors and so forth. As a transplanter, I try to practice both transplant and nontransplant therapies so that I'm not biased about clinical trials. I still get to do both and enjoy the MPN field as a whole. Let me pick your brain a little bit on TP53 . It's never exciting to see that. It's always a little worrisome to see that. And for some reason, I feel I've seen more of these in the past 6-12 months than maybe in the years prior. That could just be a matter of chance, but what is your approach there? Because outside of maybe managing spleen and symptoms with drugs, which I also don't think do a good job, there are not many options. And truly symptomatic TP53 patients are coming in with a lot of pain and fevers. What is your usual approach and what has worked for you, if anything? Bose: The spotlight is very much on it; we have seen more attention on TP53 in MPNs recently. There were two oral presentations on it, and what it means in MPNs, at ASH in the same session. But you're right. I mean, today we are not at a point where therapy is any different at all based on TP53 , right? And some therapies, like MDM2, will not work if TP53 is mutated. Unfortunately, I don't think it's similar to the AML [acute myeloid leukemia] field. I believe they have some leads on certain therapies that could be TP53 agnostic. Perhaps nothing has panned out yet in a major way, but at least there is some thought that certain drugs may be preferable in TP53 — certain investigational drugs, of course. But for us, I don't think we are there. I don't think therapy is affected in any way today. Now, of course, cellular therapy is generally agnostic of that. So, if you talk about the emerging cellular therapies, which are primarily against mutant CALR — and you have been involved in some of the cutting-edge work with CAR T cells — maybe those could solve this issue, to some degree. But otherwise, I'm not sure that anything right now addresses that problem. Jain: If we were to extrapolate from a B-cell malignancy world, there has been, what I would say, better success with cell therapy in TP53 , but it doesn't seem to be a home run even with that, unfortunately, at least as of yet. But similarly with transplant, right? There is certainly a higher risk of relapse in TP53 disease compared to non- TP53 or some of the other non- TP53 high-risk mutations. I think time will tell where cellular therapy strategies or targeted CALR or JAK2-targeted strategies will stand and, if there are subclones, if the TP53 is a subclone or a separate clone altogether, how these behave and respond to these targeted agents if they were to come to the mainstream. Jain: Can you share some thoughts on interferons? There's been a lot of excitement around it. There have been approvals in early MPNs, and I heard one of my colleagues make this joke — obviously in a bit of a hyperbolic sense — that she's been using it like water recently. Tell me how interferon is being used in your clinic. Bose: A lot more than before. No question. And you're exactly right. It's gained a lot of momentum. Some of it is the approval of ropeginterferon in the US in the fall of 2021. Obviously, Pegasys [peginterferon alfa-2a] was around for a long time, but then to have an approved interferon made a difference. We have that. We have top-line results on ropeginterferon in ET [essential thrombocythemia] this year, which are positive. And we look forward to, I believe it's an oral presentation at ASCO, on the SURPASS-ET trial. Maybe later in the year we might hear about the EXCEED-ET trial. One can reasonably hope that it'll get approved for ET; obviously, a regulatory approval just makes it easier. It makes a difference on the ground, in terms of being able to use it. If you look at all the data, there are a couple of things I'll point out. One is the event-free survival improvement that was seen in the PROUD-PV and CONTINUATION-PV [polycythemia vera] study. And that is in addition to the well-known effect of interferons on lowering the JAK2 VAF. PV is the best place to show that because it's all JAK2-driven. That is done nicely by ropeginterferon — a 20% rate of complete molecular response, if I remember right, from the PROUD-PV and CONTINUATION-PV studies, and that event-free survival difference. Dr [Richard] Silver has shown, of course, in the Cornell historical experience, that there appears to be an improvement in MF-free survival and overall survival with Pegasys. I think all these datasets coming out are fueling the enthusiasm that this could be truly disease modified. This event-free survival is exciting because an event is either a clot or MF, AML, or death. And if you can reduce that, it's a reasonable composite endpoint. Also, I should throw in there that we've now seen that with ruxolitinib in the MAJIC-PV study in the second line, we may be on the cusp of disease modification in PV, maybe even closer than in MF. For all the work in MF, I think the success is more in PV, which makes sense because it's a less complicated disease. It's one gene for the most part, less genomically complicated. Jain: I agree. My approach with interferons, for what it's worth, is the earlier the better, because the longer time that you can give a patient with interferons to work on that disease modification — as we know, they take time. This is years' worth of therapy, and that's what we try to tell our patients when we're presenting it to them — that this is not something to expect benefit from in 2 or 3 months. This is similar to what we saw with CML, for example, although the strategy is slightly different. It's certainly a long-term treatment. The earlier you can introduce the treatment, the better the chance of some advantage there. We loved talking about all of this, Dr Bose, and hearing your approach and your algorithm on JAK inhibitors, which I very much appreciate. I think you pointed out some of the key areas that we as a field need to continue to work on and, hopefully, move the field forward with all the exciting products in the pipeline. The newer mechanisms of action, the targeted agents, are hopefully engaging and activating some T cells to do some work beyond transplant. A lot of exciting things to think about. I wonder if we were to do this podcast 10 years from now whether we would be having a different discussion. Bose: Of course. I'm sure. Jain: Wonderful. I hope everybody enjoyed this discussion; I very much did. Thank you again, Dr Bose, and we'll sign off for this episode. Thank you, everyone. Listen to additional seasons of this podcast. Primary Myelofibrosis JAK Inhibition for the Treatment of Myelofibrosis: Limitations and Future Perspectives You Really Got a Hold on Me A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis Overall Survival in the SIMPLIFY-1 and SIMPLIFY-2 Phase 3 Trials of Momelotinib in Patients With Myelofibrosis Biological Basis for Efficacy of Activin Receptor Ligand Traps in Myelodysplastic Syndromes Study of Momelotinib in Combination With Luspatercept in Participants With Transfusion Dependent Myelofibrosis (ODYSSEY) Biology and Therapeutic Targeting of Molecular Mechanisms in MPNs Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors (ESSENTIAL) Selinexor Plus Ruxolitinib in JAK Inhibitor Treatment-Naïve Myelofibrosis: SENTRY Phase 3 Study Design EHA 2023, Abstract 210: An Open-Label, Global, Phase (Ph) 1b/2 Study Adding Navtemadlin (Nvtm) to Ruxolitinib (Rux) in Patients (Pts) With Primary or Secondary Myelofibrosis (Mf) Who Have a Suboptimal Response to Rux Imetelstat in Intermediate-2 or High-Risk Myelofibrosis Refractory to JAK Inhibitor: IMpactMF Phase III Study Design CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms Ropeginterferon Alfa-2b (ROPEG) and Peginterferon Alfa-2a (PEG) at Low Dose With Response-Based Titration (LDRT) Have Comparable Efficacy and Tolerability in Polycythemia Vera (PV) The Characteristics of CALR Mutations in Myeloproliferative Neoplasms: A Clinical Experience From a Tertiary Care Center in Qatar and a Literature Review Pelabresib Plus Ruxolitinib for JAK Inhibitor-Naive Myelofibrosis: A Randomized Phase 3 Trial TRANSFORM-1 Trial of Navitoclax in Combination With Ruxolitinib for Myelofibrosis Met Primary but Not Secondary Endpoint Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis Efficacy and Safety of Fedratinib in Patients With Myelofibrosis Previously Treated With Ruxolitinib (FREEDOM2): Results From a Multicentre, Open-Label, Randomised, Controlled, Phase 3 Trial Fedratinib in Patients With Myelofibrosis Previously Treated With Ruxolitinib: An Updated Analysis of the JAKARTA2 Study Using Stringent Criteria for Ruxolitinib Failure Impact of TP53 on Outcome of Patients With Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation SURPASS-ET: Phase III Study of Ropeginterferon Alfa-2b Versus Anagrelide as Second-Line Therapy in Essential Thrombocythemia EXCEED-ET: A Single-Arm Multicenter Study to Assess the Efficacy, Safety, and Tolerability of Ropeginterferon alfa-2b-njft (P1101) in North American Adults With Essential Thrombocythemia Ropeginterferon alfa-2b Versus Standard Therapy for Polycythaemia Vera (PROUD-PV and CONTINUATION-PV): A Randomised, Non-inferiority, Phase 3 Trial and Its Extension Study Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial
