S2 Episode 4: JAK Inhibitors: Too Many Choices or Not Enough?

Medscape

08-05-2025

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, 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