Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we talk about the management of myelofibrosis. We have a great faculty today: Professor Claire Harrison from the Guy’s and St Thomas’ NHS Foundation Trust in London, United Kingdom, and Dr John Mascarenhas from the Icahn School of Medicine of Mount Sinai in New York City.

As in all of our programs we will be discussing the use of unapproved agents and regimens so please consult the package information for each product that we talk about today.

As with all of our programs, I met with each of the faculty individually in the last couple weeks to record presentations, and these are 2 really great and very comprehensive presentations. They’re in the chat room if you want to see them now, and then when we send out the replay of this we’ll also include that. They cover a lot of papers and presentations. Here are some of the papers — or the papers that Claire covered, and here are the others that John covered. So quite a few papers. We’re not going to go back through all that, but I sat down after going through these papers and tried to pick out what I thought would be the most interesting things to talk about.

So we’re going to start out talking about some new things I heard that were really fascinating, just to get started, then we’ll dive into treatment of myelofibrosis in 2025, particularly specifically the use of JAK inhibitors, including ruxolitinib of course. Then we’ll talk about some exciting new agents that maybe are going to be coming up being available in the not-too-distant future, BET inhibitors, navtemadlin, a really fascinating agent. We’ll talk about selinexor, as we’ve talked about, and also elritercept.

New Biology of Myelofibrosis

DR LOVE: But I wanted to start out, you know myelofibrosis is always a challenge for me because there’s amazing biology that you all really put out. And I just want to begin, before we get started, with just some general comments, particularly for people who may be new to oncology or not know that much about myelofibrosis, related to the biology.

So John, when you were talking about BET inhibitors I decided to put BET inhibition into Google, and the first paper that came up is this amazing paper from Signal Transduction Targeted Therapy, not a journal I guess everybody reads, but I was just amazed at the amount of biology discussed in this paper and many other papers in myelofibrosis. Most of this is — I don’t know if the audience follows these kinds of graphics, but to me they’re very challenging.

But John, I just wanted to take a step back and kind of figure out where we are now, 10 years or a little bit more than that since the COMFORT studies were presented and ruxolitinib came into practice, particularly in terms of our understanding of the biology of the disease. What it seems like from what I’ve heard talking to you all over the years is that these JAK inhibitors that we’re using nowadays don’t necessarily affect so much the underlying clone as they do the phenotype, the JAK-STAT pathway that gets enhanced with all — regardless of the mutational profile. Can you talk a little bit more about your understanding about the biology of myelofibrosis, how JAK inhibitors work, and what are some of the new ways that we’re thinking about trying to attack this disease?

DR MASCARENHAS: Sure. So first I’ll start off by saying it’s fantastic to have this program with you and to be joined by Claire to talk about this topic, which I think has really blown up in the last 10 years in terms of the understanding and the application and the development of novel therapies.

So when we first started out here it was all about inhibiting JAK-STAT. Of course ruxolitinib was the first one to come out and clearly had a very significant impact on the outcomes of patients, both in terms of spleen reduction and symptom improvement, but ultimately due to probably survival benefit, as Claire had alluded to earlier in our discussion, simply by making patients feel better, eating and reversing cachexia to live longer. So there’s a clear benefit to a JAK inhibitor, and ruxolitinib really set the stage. And now we have, in the US at least, 4 JAK inhibitors that are approved.

They all share the same thing, they inhibit JAK2, but there are some nuances, some off-target nuances that likely explain differences in toxicity profile. So maybe some more GI toxicity with fedratinib and pacritinib, as it’s a FLT3 inhibitor, but also some benefits that we see now with anemia that we don’t really classically expect with ruxolitinib in terms of AbcR1 and hepcidin modulation with drugs like pacritinib and momelotinib. So it’s a fascinating area because we’re still dealing with JAK-STAT, which is fundamental to the disease process, but I don’t think it’s the only target of relevance. And although 4 JAK inhibitors exist, today we’ll talk about a lot of different alternative strategies that exploit other vulnerabilities of these cells, whether it’s epigenetic aspects of the disease, other signaling pathways or, as we’ll talk about today, the expression of aberrant proteins that allow for immunotherapeutic approaches.

DR LOVE: Claire, anything you want to add to that? And also the immune effects that we think we may be seeing with JAK inhibitors. We were talking before we got started here. I was really astonished when you told me about the incidence of second cancers in patients on ruxolitinib that you found. Can you talk about some of the immune issues that come up with these agents?

PROF HARRISON: Sure. I mean just thinking about ruxolitinib, I mean it’s almost 15 years since we reported the COMFORT studies and that agent was approved, and as always we’re learning more about efficacy of that drug. It gets used nowadays also for graft-versus-host disease, so that tells us that it’s a powerful immune-suppressing drug. Now whether that’s just because of its effect on JAK2 or also it’s other effects on JAK1 we really don’t know, but it probably is a drug, as we know and learned, through our cost and the cost of our patients in pandemic, that it affects T-cell function and dendritic cell function, et cetera.

We saw a small signal in the COMFORT studies, and then over time we’re increasingly aware that these patients are at risk both of (1) opportunistic infections, so common practice now would be to check patients for hepatitis B/C, HIV, think about tuberculosis, think about zoster prophylaxis. Right now all our patients are getting an active shingles vaccination for example. That’s something we wouldn’t have done 15 years ago.

But we also see in these patients, and some of them have had a lot of treatment with hydroxycarbamide, which we know can increase the risk of skin cancer, but some of these patients are getting quite significant problems with nonmelanoma skin cancer. And I just want to say we don’t have any clear evidence that ruxolitinib increases the risks of other cancers, in fact there’s quite large data series suggesting it probably doesn’t, but it’s particularly the nonmelanoma, so squamous and basal cell skin cancers. And our recent audit, this is what we were chatting about earlier, in the UK suggested that 42% of our patients treated with ruxolitinib were getting nonmelanoma skin cancers. And some of these are really minor, but some of them can be very aggressive and treatment resistant.

And then there’s a problem for us in our day-to-day practice. Do we stop the JAK inhibitor and risk losing control of myelofibrosis, or do we carry on and try to manage what can be a very aggressive skin cancer? So I believe that this is probably a class effect, I think we would probably see it with all of the JAK inhibitors, but we do need to understand that a little more.

DR LOVE: John, you were saying something interesting, too, about that. You think you see this more with snowbirds who aren’t — who come from New York down to see me here in Miami and all of a sudden have a lot of sun exposure. What do you see clinically? Are these aggressive tumors, skin tumors?

DR MASCARENHAS: So yeah, they can be. There’s always this concept of like the weekend warrior, the person who gets the intense sun for short periods of time, and it’s usually the sun-exposed surfaces. So we see a lot of actinic keratoses and then it gets progressive to squamous cell carcinoma. I definitely reinforce, particularly to my older patients, my Caucasian patients, the ones that are getting a lot of sun exposure, to — well everyone, but particularly those patients to get dermatologic evaluations at least once a year if not twice a year.

And some of the cases can be quite aggressive, and then it leads to what Claire was saying, making a very important decision about continuing the JAK inhibitor or not continuing the JAK inhibitor. Truth be told, we don’t really know if once you take a JAK away, I don’t know if that actually improves or reduces the risk in the subsequent issues with skin cancer too. So I think it has to be weighed on a case-by-case basis, but I’ve definitely been in the situation where we’ve switched MPV patients, for example, who were on ruxolitinib, we switched to interferon, where I have less of that concern, to try to control the disease. So it can be a real issue.

DR LOVE: So one of the best things about doing this Year in Review series is I get to talk to the faculty, and before they start presenting a bunch of cases I go, well, what’s coming up in the future. And Claire really surprised me by telling me about a new antibody that she actually — she can’t talk about, I guess, but she’s used in 100 patients. All I can say is she has a very pleasing smile on her face, which is always a good sign, but it hasn’t been presented.

But I jokingly, Claire, referred to this as the new trastuzumab because this is only patients with calreticulin, and it is an antibody. And of course in breast cancer trastuzumab is an antibody against HER2, which is only in 20% of patients. This is a minority in myelofibrosis. I know we’ll see with the data hopefully going to be presented very soon what happens with this. But Claire, anything you want to say about this fascinating idea and where you think it might be heading? Do you see this maybe coming into first-line therapy?

PROF HARRISON: Well, I suppose I just want to say I haven’t treated a hundred patients myself. This has been a real kind of international effort. But the interesting thing about the biology of calreticulin is we know that the mutant — any of the mutations generates this novel extraterminal domain. So there’s a novel feature of mutant calreticulin regardless of which mutation, number 1, which can then be recognized by the immune system. And secondly, that mutant calreticulin, as we can see in this schematic, is actually excreted, so it’s visible to the immune system.

And then one of the ways that we think that it’s exerting its effect is it binds to MPL, the thrombopoietin receptor, and then causes dimerization and signaling. So then if we used an antibody we could then recognize cells that have mutant CALR. That may well mean that we’re not only recognizing mutant cells, of course, but it would block the mutagenetic effect, potentially, of calreticulin.

Now of course it may have other mutant effects, but there was a beautiful publication looking at a mice model. We all have our views on mice model and how well it recapitulates human disease, but it certainly looks very effective. And antibody therapy is generally very well tolerated, right? So this is just a straightforward antibody.

There is a CAR, and there are bispecific antibodies also being actively tested, both in ET and myelofibrosis patients, and it would be great to see some data hopefully soon in the public domain about these.

DR LOVE: John, any thoughts? And speaking of HER2 I just saw that the T-DXd first-line trial’s going to be a plenary presentation. To you out there, just to alert you, first-line therapy of HER2-positive breast cancer may be changing at the ASCO meeting.

John, what about this target? It’s not the majority of MF. Where do you see this heading? And also, could this same strategy apply to JAK, or it’s not outside enough to be targeted outside the cell?

DR MASCARENHAS: Well, I think this is an example of how we’re moving now in 2025 to more of molecularly defined targeted therapeutics. So mutant CALR, which is MF and ET patients, so you can see this application in broader number of patients than myelofibrosis. And I think, as Claire pointed out, the expectation since — it’s really a peptide. It’s a naked protein without a payload, so the toxicity expectation is quite low. It’s super selective for the mutant form, which is aberrantly expressed on the surface of the cell. So if it can hit the right cell population, meaning the malignant stem and progenitor cell population, we could see things that would allow for the calling of remissions and deep responses that might really transform the way we treat these patients, hopefully with a very low toxicity burden.

So I think it’s exciting because it would then maybe carve out a group of ET and myelofibrosis patients that would then go on to get immunotherapy. Whereas, as you pointed out, we wouldn’t necessarily be going after JAK2 V617F as an intracellular signaling pathway with immunotherapy but maybe the small molecule inhibitors that are now in development, like Ajax’s Type II compound, or Insight’s JAK2 V617F selective will then carve out those patients for a mutant-selective approach.

So it’s pretty exciting. I mean, as Claire pointed out, 15 years ago, plus when we were using ruxolitinib, it really is mutation agnostic. There’s nothing specific to it in terms of dampening the malignant cell population, which is why you get myelosuppression and why you can’t get really to doses that really — that really target the stem cell. So this may allow us to do something that we really were not able to do or not able to do with the current JAK inhibitors.

DR LOVE: And who knows? Maybe this will divert out into an entire different approach to CALR-mutant disease. You can see here the typical numbers we talk about. So it’s the red that you see there with ET or myelofibrosis that would be targeted.

Novel Regulatory T-Cell Infusion Therapy

DR LOVE: So Claire, another thing that John told me about that completely shocked me, I’d never even heard of this, but something that’s still got numbers, but basically T-reg, allo T-reg cell infusion, Claire. As far as I know this is the only place or maybe a couple other unusual situations where these are being used. Any thoughts about this strategy? It looks like maybe it has some activity. But just the whole idea of allo T-reg cells. Can you comment on that, Claire?

PROF HARRISON: Yeah. I love this presentation, actually. It was made by Lucia Masarova from MD Anderson. This is kind of off-the-shelf immune therapy. And so what we increasingly understand about diseases like MDS, but also myelofibrosis, is that these are diseases where there is disordered inflammation, and that disordered inflammation is important in the manifestations of the disease but also in terms, probably, of progression. So inflammation then can lead to progression of clonal hematopoiesis. And so these are off-the-shelf therapies, relatively safe, and as Lucia showed pretty well tolerated.

Here you can see some reduction of TFG-β levels, so reducing inflammation. And then you can also see in the colored bars patients were getting some spleen and symptom responses. Now we could get into a discussion about how really meaningful and how biologically relevant we think the spleen and symptoms as kind of a therapy target are, but the reality is these are the regulatory endpoints that we have right now in this disease.

So I thought this was great, really interesting, very well tolerated, but how are we going to measure success for these patients and where it goes from here is really of interest I think.

DR LOVE: John, you discussed this in your presentation. I don’t know if there’s anything you want to add. But also you mentioned these new JAK inhibitors, one INCB and a bunch of numbers. It looks like at least in vitro it has interesting activity. What’s the difference? And then there’s another one. These are all the slides we kind of went through there. You mentioned this A-11 — 11095. Can you talk a little bit about these new JAK inhibitors? And do they hit the clone more than just the JAK-STAT pathway? Is that the idea there, John?

DR MASCARENHAS: Yeah. So I think just to add on to what Claire said about the Cellankos’ T-reg, super fascinating, a little early to draw total conclusions, but I think it’s — I think for the reasons it excited you, we haven’t seen that in MF. So it’s just exploiting the fact that there may be T-cell regulatory dysfunction, and that we may be able to overcome that with an off-the-shelf core blood-derived product is very cool.

But then we go back to basics with these studies, which are really taking the concept of inhibiting the JAK-STAT pathway but trying to do it more potently because the current 4 JAK inhibitors are Type 1 JAK inhibitors, they’re ATP-competitive inhibitors, whereas in the case of the Ajax compound, that’s a Type II inhibitor, it binds to both the on and off version of JAK2, so it is more potently able to downregulate that signaling pathway. And particularly in modeling it seems to do that in patients who have JAK2 inhibitor-persistent signaling, which is a phenomena that might explain why JAK inhibitors can work for a period of time and then stop working, because the pathway can learn workarounds.

So it is possible that we may be able to overcome some of these deficiencies, to hit the clone harder to get deeper responses. The Insight compound is specifically targeting the mutant form of the protein and essentially binding to it in a different — and creating a confirmation to allow it to become more of a wild type or normal protein activity, so it’s trying to restore normalcy to that signaling pathway.

All that preclinical data really points to having a more profound effect. But I think, as Claire pointed out and it’s well understood, is that that doesn’t always translate perfectly into the human. We’ll have to see with these ongoing Phase Is whether (A) they’re safe, we don’t get too much myelosuppression, and (B) they really do differentiate themselves from the current Type I inhibitors and we get deeper, more meaningful responses.

DR LOVE: Alright. Well, let’s jump back into — Claire?

PROF HARRISON: Yeah. I just wanted to say I think there’s something about biology here, as well, right? So although you showed the mutations that we see in these patients, increasingly we’re using next-generation sequencing, as colleagues will be aware, to look for other mutations. And so as we use these mutation-specific therapies what we really need to also learn is what is it doing to these — the other clones. Are there clones also with a JAK2 mutation, so would they be targeted? Or are there clones without? And for JAK2 disease we certainly know that half of the leukemias that these patients get are not JAK2 mutated, whereas a little bit the opposite is true for calreticulin. So we may end up using these therapies but using them much earlier when the disease has a more simple molecular level, I think. So just kind of an interesting point, I think, in terms of how we may use them if they’re successful.

DR LOVE: Really interesting. We could spend the entire webinar here talking about these new agents.

Myelofibrosis 2025: JAK Inhibitors (Ruxolitinib)

DR LOVE: But let’s get back to what’s happening today. And we’re going to go through a bunch of papers that Claire went through particularly related to the use of ruxolitinib, which of course now has been out there for a while. And I’m really curious. We’re not going to go through the specifics of all these papers, you’ll see that in the presentation, but more using these papers as a way to get into some general issues about how patients are managed, John. And also, I know you see a lot of patients in second opinion that have been managed by other docs primarily. I’m curious, maybe some of the misconceptions that are out there about that.

So first, Claire went through this paper, which I thought was really interesting, where — I guess from Italy where they were able to go through a bunch — quite a few cases and pick out what they thought were patients — a small minority of patients, I think around 15%, who from their point of view were underdosed, so looking at counts, et cetera, appeared to be treated less aggressively up-front, and those patients didn’t do as well, and Claire can kind of go through that. But I wanted to use that, and feel free to refer to the study, Claire, but in terms of what your thoughts are about the optimal dosing strategy up front with ruxolitinib, how you think that through, and maybe what are some of the — I’m not going to say errors, but things that people do, what people did in this study, that maybe you wouldn’t do.

PROF HARRISON: Yes, I thought this was a really interesting study, actually, and around a third of patients in this Italian study were actually dosed at a less than expected dose of ruxolitinib. And generally what they showed was that this was driven by patients having what we call in the field “cytopenic” myelofibrosis, so they had anemia, thrombocytopenia. And what they showed was that these patients had good symptom control, their spleen response was slow, but really importantly their survival trajectory was not as good. And so for me the lesson was we’re all a little bit tempted to avoid the jeopardy of marked thrombocytopenia or marked anemia for our patients, and there are some frail patients where this is a problem, but the starting dose of ruxolitinib does relate to platelet count, and generally these patients were underdosed on that basis.

This is not the only piece of evidence that suggests that dosing of ruxolitinib can — optimum dosing is important. So recently, in the last 18 months to 2 years, we’ve seen a prognostic score called RR6, which basically relates to patients having a dose of ruxolitinib of 20 mg BID or less, and if they have a lower dose they don’t do as well.

DR LOVE: So John, I’m going to ask you if you want to add to that, but also Claire reviewed a paper here looking at intermediate — intermediate-1-risk patients with myelofibrosis, which wasn’t, I guess, included in the original COMFORT studies, where again they saw treatment benefit, and to me this leads into the question of when do you start ruxolitinib in a patient with myelofibrosis, and are there situations where you would start a patient who’s asymptomatic, for example? So anything you want to add to what Claire said about dosing? And how do you decide when to start treatment, for example, in an asymptomatic patient?

DR MASCARENHAS: So I think over the years we’ve come to the realization that with ruxolitinib in particular, which led the field, that dose matters, that the depth of spleen response probably is a surrogate for better outcomes down the road, which is why a lot of investigation is trying to understand how are we actually using ruxolitinib in the real world, because I definitely would agree that there’s probably significant underdosing. And there a number of studies from claims-based databases here in the US that would suggest that two thirds of the patients who are on rux are on doses that weren’t actually used in the COMFORT studies.

So I think 1 principle is you have to believe or buy into the idea that the more you shrink the spleen the better the outcome, not necessarily because the spleen is smaller but because it’s probably right now the best clinical biomarker we have for on-target JAK-STAT inhibition. So the harder you hit the pathway probably the better the patient is going to ultimately do, with the caveat that you can get more myelosuppression, so that sometimes limits the ability. And that’s why there are these cytopenic patients in which maybe the other JAK inhibitors are better suited for, whether it’s pacritinib or momelotinib, so you can get the full doses in.

So I think dose matters. Timing probably does matter. I think as a general rule if you wait too late you’re going to get less benefit from the drug.

I think the bigger or more important question is what you’ve posed here, is when do you really start it. I think most people would agree at this point you don’t need to be intermediate-2 risk to start a JAK inhibitor. Intermediate-1-risk patients likely deserve it. I would even argue there are low-risk patients that I see that should be on a JAK inhibitor.

I think the question then becomes more complicated when you have maybe a lower-risk patient who doesn’t have significant splenomegaly and is asymptomatic at that point, maybe even with some cytopenias, that may not be the best patient to start a JAK inhibitor, because I think the goals of intervention there are not going to be as clear. But I’m pretty quick to start it, so if I see a patient — and I really ask a really good review of systems, and I just don’t assume people are feeling well, because sometimes patients don’t realize it. If you’re noticing that they’re starting to develop some night sweats, fatigue, bone pain, things that they don’t always readily report or under — I really get on that.

So I’ve definitely shifted over the years to one where I really reserve it until patients seemed really sick, to now I start it earlier. And we know that the half-life of enjoying that drug is such that if you wait too long you’re also probably going to get a shorter benefit of response. One of the things that I’ve heard Claire say before, which I totally agree with, is you don’t want to really wait for patients to get very advanced. You want to start bringing out what we — the best drugs that we have and start using them, whether it’s monotherapies or we’re going to talk about combination therapies up front, because I think it’s really harder to salvage the more advanced — it’s true with solid malignancies, the more advanced patient if you wait too long.

DR LOVE: So Claire, any comments? You mentioned to me that you think in general people usually need to be treated within a year of diagnosis. Anything you want to add to what John said in terms of timing of therapy?

PROF HARRISON: Well, actually, we did show in an analysis of the COMFORT studies that those patients who were treated within 12 months of diagnosis generally did better, but that was in intermediate-2 and high-risk patients.

I just wanted to bring the perspective of another JAK2-mutated disease, PV actually, where we have recently shown in the second-line setting that ruxolitinib can improve event-free survival, events being thrombosis, hemorrhage, transformation, death. And so many of us view myeloproliferative diseases as being part of a spectrum, and truly I think advanced PV is not that far off MF. So yes, I agree with John, I would treat earlier. And I think it’s quite surprising you treat patients then they say oh, I did have some symptoms, actually, and they’ve gone away. So yeah, I would agree exactly with what John said.

DR LOVE: So another paper that Claire reviewed was really interesting. It kind of reminded me of the St Gallen Consensus Conference in breast cancer, and there are many others where you try to gather investigators to put together a comprehensive view of how to manage patients and literally get very practical. This was an effort focusing on patients with myelofibrosis and cytopenias. They dealt with a lot of issues.

I don’t want to go through all the details, but again, that’s in Claire’s presentation, but more, get both of your takes from a practical, concise point of view of some of the key issues that came up here. And one that they bring up here is defining when a patient has relapsed/refractory disease to a JAK inhibitor, usually it’s going to be ruxolitinib, or intolerant to JAK treatment. So Claire, again, not necessarily all the details of what you went through in this paper, but from your point of view what are the key issues you look for in trying to define relapsed/refractory disease?

PROF HARRISON: Well, I think the first thing is where is the patient in terms of the parameter that you are treating in the first place. If they had a 10-cm spleen, where is it now? If they had a symptom burden, where is it now? What dose of drug are they on? So sometimes you can overcome a growing spleen by optimizing dose. We have had quite a good discussion about optimizing dose. Oftentimes when I see a patient I’m increasing the dose.

But there’s also the idea of intolerance, and that’s — it often comes together, but intolerance, as we were discussing in this consensus paper, really relates often to the issue of cytopenia, the need for new transfusions, which you can’t overcome perhaps by adding an erythropoietin-stimulating agent, thrombocytopenia, and then some of these issues that we were also talking about, skin cancer, opportunistic infections, those are all intolerance. So what we were trying to do was to pull together the things that you need to recognize in practice, but I would say recognize but also be sure that you’ve optimized the dose.

DR LOVE: So John, anything you want to add to that? And in terms of deciding, do you find that people maybe in practice are giving up too early or too late?

DR MASCARENHAS: Well, I think what I notice frequently when I talk to physicians in the community, which have a much harder job than I do, where they have to understand and manage different types of cancers, that their sense of who’s succeeding and who’s failing could be quite broad and different depending on the physician and their viewpoints. So I do see often that patients will sit on low doses of ruxolitinib with significant splenomegaly, significant symptom burden, and are probably not garnering the full benefit of the drug and then don’t make a switch, either don’t go up on the dose appropriately or don’t make a switch to the next JAK inhibitor in a timely fashion. So that’s, I think, probably pretty common, probably more common than not.

And then sometimes the problem I’ll see is that patients will get very high doses of rux to start with and then get significant cytopenias and then end up discontinuing probably prematurely without enough time to really enjoy the benefit of that drug. So I think depending on the type of practice and the flow of the practice it could absolutely influence the way physicians are appreciating that response, whether it’s spleen or symptom, that then dictates whether they’re getting enough rux or on it long enough. And then of course making the difficult decision to move on if it’s not working because a lot of times patients will just linger on these drugs too long, and then it’s very difficult to transition to the next JAK inhibitor or the next clinical trial.

DR LOVE: So Claire, another issue that was realized early on is when you stop ruxolitinib you have to be concerned about withdrawal and usually the drug needs to be tapered. Can you comment on how you do that? And also, do you need to taper if the patient’s going to switch to another JAK inhibitor, for example a patient who becomes anemic and goes to momelotinib?

PROF HARRISON: Yeah. See, that’s another tricky thing in practice. So one of the things I tell my patients that are going on a JAK inhibitor is don’t run out of tablets, please, and don’t suddenly decide you’re going to stop. And especially in the context of the pandemic this was a really tricky thing.

So switching JAK inhibitors. We certainly know for momelotinib that it is feasible to just switch straight from one drug to the other. There’s no need to taper. We did that in the SIMPLIFY study. We just went straight from ruxolitinib to momelotinib, and indeed vice versa, so you can go straight from momelotinib to ruxolitinib.

The situation with fedratinib is trickier, and John and I, we’ve discussed this quite a few times, and we often, at the beginning when that drug was available early on, were having email interchanges going well, what should you do. I mean, I think if the patient’s on a low dose of fedratinib — sorry, a low dose of ruxolitinib they’re probably not so dependent on the drug, and you can probably just taper off. I usually taper by 5 mg every 2 to 3 days. You’re supposed to taper off and then start fedratinib. What I do increasingly in clinical practice is I overlap the 2 drugs for a couple of days. I’m interested, John, in what you do there.

There are other ways of managing withdrawal, as well, of course, by using steroids, but I think patient education is really critical in this setting.

DR LOVE: So John, before you —

DR MASCARENHAS: I agree exactly.

DR LOVE: Could you also comment? I’m really interested. It was a great practical point about telling patients not to run out of pills. Like how long does it take before they start to have symptoms, John? Is it a couple days?

DR MASCARENHAS: It could be a couple days for some patients, and we’ve seen it between 7 and 14 days in other patients. I think it depends in part on what dose they were on. So there are these patients who are more JAK inhibitor addicted at higher doses with probably a more inflammatory disease state. If you take that away quickly you get this very significant rebound, and in some patients it can be catastrophic, actually, which is why Claire makes that point. The worst thing is, and this has happened to a few of my patients, they go on a holiday, and they forget their ruxolitinib —

DR LOVE: Wow. Wow.

DR MASCARENHAS: — and then you get this frantic email that they’re somewhere in Southeast Asia, and they don’t have their ruxolitinib. And that’s frightening because you can get this rebound that can be hemodynamic instability, and then there have been bad outcomes at times.

So it’s interesting, though, because then I have other patients — it’s one of those things in life. I have other patients who have just stopped the drug for no reason whatsoever, or no clear reason, and they come to the next appointment, they’ve been off it for 3 weeks, and they have no rebound at all. It’s also not easy to predict who’s going to have it, but I’m very careful to make sure they understand it’s not the kind of drug you want to stop cold turkey.

You want to be plugged into the medical system and have a plan, and then as Claire pointed out you want to have a taper strategy. You want to get down to at least 10 twice a day if not 5 twice a day, maybe overlap, depending on if you have the next JAK inhibitor it's maybe one with a longer half-life. And then if I’m really worried about the patient, as Claire pointed out, I’ll even give some pulse-dose prednisone to just try to, again, blunt that cytokine rebound that can happen.

DR LOVE: So Claire, in your talk you spent a lot of time talking about one of the most common questions that we get from oncologists, which is anemia in the patient. This was dealt with also in this consensus paper that we were talking about that I really recommend people to check out.

But a number of other papers related to momelotinib and anemia in general, the SIMPLIFY studies. I refer you to Claire’s talk on the details.

And interestingly enough, as we were talking about it, one of our champion chat room docs, KS Kumar from here in Florida, from the Florida Cancer Specialists, says, in the chat room, “I have a 50-year-old patient with a big spleen that was increasing in size, normal CBC, waited for a while, but then started rux due to increasing spleen. Good response, but now the hemoglobin’s 8.5.” So maybe that’s a good place to start in general. And also the patient who starts out anemic, Claire, how do you decide whether you go with rux or momelotinib? So any comments on those 2 scenarios?

PROF HARRISON: Well, I mean, great to have the choice, right? So now we do have the choice of these 2 drugs for our patients. I mean, I think the consensus paper, and John was a key contributor to that paper, as well, we did some pains to point out that I’ve been caught before by a patient who’s had bleeding varices, and I’ve assumed the anemia was due to disease or JAK inhibitor, so I’m a bit of a stickler for checking all the common things occurring for your patient that’s got a hemoglobin of 85. And we know the dynamics of hemoglobin tends to fall in the first 20 weeks and then come back up a bit.

So I think it’s really about how bad the anemia is, how big the spleen is, how big the symptom burden is, because momelotinib was certainly noninferior for spleen response but perhaps a little bit less effective for symptoms. Definitely more effective in terms of anemia.

For this patient that’s been mentioned by our colleague in the chat, there are other options here, as well, which there were some papers that we were discussing, for example adding erythropoietin. And there was a nice analysis from the JUMP study with 2,000 patients showing that actually adding erythropoietin, although it’s a bit counterintuitive because the EPO signals through JAK, of course. But remember the half-life of ruxolitinib’s relatively short, so there is a time when the EPO’s working, and that can be a good strategy. So rather than jump to momelotinib you could add erythropoietin, and then you don’t have so much subjective switching between drugs.

There are different toxicities of the drugs as well. So momelotinib does have some first dose hypotension, a little bit more GI intolerance, some liver function abnormalities, and some neuropathy linked to it. No reason to think it’s any different in terms of immune suppression. So I think it’s really about if I’ve got a transfusion-dependent patient I would probably go with momelotinib. If the platelet count’s sub-50 I would go with momelotinib. If they’re a bit in the middle it’s kind of tossup, and it might depend how symptomatic they are and how big the spleen is. But there’s the option to flip between the drugs. John, I don’t know what you’re doing in practice on that.

DR MASCARENHAS: I agree, and I think one of the key points, maybe, as it relates to the question that was asked about this person who clearly needs a JAK inhibitor but might have already some degree of anemia, is I’m definitely not afraid to induce some anemia with ruxolitinib. So if you give rux, and you get anemia, it’s pretty predictable. It nadirs within the first 2 to 3 months. It usually sits 1 gram/dL from where you started. As Claire pointed out, you can supplement with an ESA, darbepoetin/epoetin alfa. You can give them luspatercept even off label. It’s now always that hard to get, and I suspect the label will change once the INDEPENDENT study reads out. So there are ways of trying to mitigate that hemoglobin.

And importantly, for those of you out there that are treating MF patients on ruxolitinib, and you get some degree of anemia, I will say most of those patients don’t feel anemic. They don’t feel worse, actually. And the analyses that Claire and others have done would show you that it doesn’t impair or negatively impact spleen, symptom or survival outcome.

So the anemia that’s disease related, which obviously is adverse, is different than the anemia that is therapy related that we see with ruxolitinib. As hematologists anemia is anemia. It’s not really going to stop me from treating, and that’s one thing.

Now, if the patient’s becoming very transfusion dependent, and that’s a big quality-of-life issue, I think that’s really where you’re really thinking about particularly drugs like momelotinib or even pacritinib that might be able to offset that aspect.

DR LOVE: So you’re getting the chat room very interested. We’ve got lots of cases and questions. As you said the word luspatercept it came in on the chat room from Bakalrishna asking about it. I’ll just pick one real quick one for you, Claire, from Venu, who has a patient with intermediate-1 risk MF with thrombocytopenia, platelet count 40,000, normal hemoglobin, mild splenomegaly, fatigue and night sweats, started on pacritinib. Venu wants to know — she was actually started on pacritinib at a tertiary center, now she’s following her. Should she expect to see the platelet count to improve, Claire?

PROF HARRISON: Probably not. It may drop, actually, but there is documented safety of that drug. I mean, I would say that kind of patient, that degree of thrombocytopenia is a poor prognostic indicator, so I would be thinking about transplant for that patient if they’re eligible. But no, I wouldn’t expect the platelet count to improve. Hemoglobin might.

DR LOVE: Interesting.

BET Inhibitors: Pelabresib

DR LOVE: Alright. Let’s talk about some things that maybe are going to be coming into practice in the near future, really exciting data, a lot of it came out at ASH. I showed that paper on the BET inhibitors. We won’t get into the mechanism of action and all the places BET inhibitors are being studies right now because we could probably spend the whole hour talking about it.

But John, you presented this MANIFEST-2 study of pelabresib, which there was a lot of excitement about. There’s also another new BET inhibitor that doesn’t have a name yet, INCB with a bunch of letters after it, which you showed some kind of interesting and encouraging data. Can you talk about pelabresib? Do you think this is coming into practice? How was it used in the study, and what did you see?

DR MASCARENHAS: So pelabresib is for sure an interesting drug. It’s a BET inhibitor, so I like to think of it as an epigenetic therapy that affects the expression of a lot of gene sets, but namely NF-κB. That’s the transcription factor that regulates a lot of the inflammatory markers, so it’s a potent anti-inflammatory drug, and it really synergizes beautifully with ruxolitinib.

We saw this in preclinical modeling, and then Claire and I ran a Phase II study that demonstrated its real activity in combination in the JAK inhibitor-naïve patient population. Very deep spleen responses, symptom improvements, and even anemia responses, as well as other biomarkers of disease modification, whether it’s reduction in fibrosis, reduction in JAK V617F allele burden, and then very potent reduction in inflammatory cytokines from the plasma, including IL-8. And IL-8 is one of these nasty cytokines that’s been shown to have adverse prognostic impact and is elaborated by the malignant cell population and is really implicated in disease biology.

So this drug makes a lot of sense. It should work. And as you pointed out, BET inhibitors in general have been evaluated across the spectrum of disease, and they continue to be, but it really has found a nice foothold in myelofibrosis. And there are a number of BET inhibitors that are being evaluated, as well, from other companies, but pelabresib is for sure the furthest along. It’s now a Novartis compound.

We published in Nature Medicine just several weeks ago the 24-week results, which was the primary analysis of the randomized Phase III study called the MANIFEST study, which was looking at JAK inhibitor-naïve patients randomizing them to ruxolitinib, so standard of care, plus placebo versus ruxolitinib plus pelabresib 2 weeks on, 1 week off. And what we saw there is that it mirrored what we saw in Phase II, doubling of spleen response, a nominal improvement in symptom burden, and Claire can probably explain to you why it’s probably impossible to ever really beat ruxolitinib squarely on symptoms.

But we saw everything align. We saw the symptom/spleen. We saw the fibrosis. We saw the cytokines, the mutation levels. It all moved in the direction of benefit with the combination, and surprisingly with a toxicity profile that was quite favorable, meaning we didn’t see more — we saw less, actually, Grade 3/4 treatment-emergent adverse events with the combination than with single-agent ruxolitinib. So that’s kind of unusual.

There’s some toxicities that are expected, like reversible thrombocytopenia, with pelabresib, some alteration in taste, low-grade GI toxicity. These are toxicities that are definitely not overburdening.

And then there was a concern that I think is always important to point out. The concern mostly on the FDA side, I don’t think Claire and I necessarily shared their concern, but a concern that there was an imbalance in patients who developed accelerated and blast-phase disease. I think as most people recognize, if you have AML that’s a very aggressive form of leukemia, but if you have MF-related AML that’s a particularly aggressive and poor-outcome disease. So there’s a lot of scrutiny if there’s an imbalance there. And these numbers were small, and early on I would argue can’t be explained after rigorous review. And now, after longer follow-up, we’re going to show 72-week follow-up at EHA, that difference has really diminished and is probably not meaningful.

So for those reasons we continue to follow the patients out longer on this important MANIFEST-2 Phase III study to see if we can actually discern over time event-free survival, progression-free survival, overall survival differences, but I think the unanswered question is how the drug will be ultimately developed further.

And again, I think Claire and many others would say that there’s a clear benefit there, but the onus is on us as investigators to prove that that benefit is clinically meaningful, that we’re really bringing value to the patients. And just spleen alone is — I think we all recognize is great, but it’s not enough. We need to make sure that that durability of response is there and ideally that that translates to a progression-free/overall survival to patients, which I think is really the ultimate goal of a study like that.

DR LOVE: So Claire, just curious. I mean, with the data we have right now on pelabresib would you like to use it? Do you think it provides enough benefit in terms of the risk/benefit ratio, putting aside cost, et cetera? Or do you think more data is necessary?

PROF HARRISON: Well, I think do look out for the 72-week data at EHA. It’s been presented as an oral. Alessandro Vannucchi will be speaking to it. I think the biological benefits that we’re seeing that John spoke to are very strong. And what the updated data, even the 48-week data, suggests is actually we did see a small excessive leukemia, but actually, as you said, John, I think if the figures were reversed, and we saw that amount of leukemia in the control arm, and the amount that we saw in the control arm for pelabresib, we would never say pelabresib is suppressing leukemia.

So I think this it is a concern. We do need to see longer data. But I have patients that have been treated with pelabresib for a long time that are still on the study. You get hemoglobin benefit. And we have been treating patients with ET with this drug. So my belief is it’s a safe drug. My belief is it’s very effective. Spleen and symptoms benefit for patients is still double beyond 24 weeks, which I think is a meaningful benefit. And boy, we need new therapies for this disease, so yeah, I think it’s exciting.

DR LOVE: So to be continued. It wouldn’t surprise me if we wake up one day and it’s approved, and we’re going to have to figure out how to use it.

John, you also talked about imetelstat. I’m curious. This was presented at the ASH Meeting, and you talked about data looking at combining imetelstat with ruxolitinib, also a trial comparing it to best available therapy. Can you talk a little bit about what imetelstat is, what we’ve learned about it over the last — recently, and where you think it’s heading?

DR MASCARENHAS: So imetelstat is a telomerase inhibitor. It’s an infusional agent. It’s now approved, as many viewers will appreciate, in transfusion-dependent lower-risk MDS here in the US for anemia responses, and in MF we have Phase II data demonstrating what looks to be a survival benefit in the relapsed/refractory setting. So JAK inhibitor failures median survival is estimated somewhere between 1 to 1.5 years, and in the randomized Phase II perspective study we saw an overall survival at the 9.4 mg/kg IV every-3-week dose of nearly 30 months. So we saw a significant improvement, almost tripling of survival than what you would expect from historical controls.

And I think that’s where the excitement got kicked off for evaluating this drug as a single agent in the relapsed/refractory setting in a randomized Phase III study with overall survival as the primary endpoint, which is, as you can garner from this discussion today, not usually what we’re looking at. It’s always spleen and symptom, which are aspects of the disease, but this is the first study I’m aware of that’s going for a regulatory endpoint of survival in MF, which is limited when you fail a JAK inhibitor. So I think that study’s still going to read out at some point. We’re anxious to see what that shows us; if it proves the point.

And then, like most things, if things are looking good, and we think that there’s a role in the latter stages of disease, we try to bring it up earlier and not wait, so we conducted a Phase IB of adding imetelstat ruxolitinib, and this actually has rationale that comes from preclinical modeling done with human CD34 myelofibrosis cells from the Ron Hoffman lab here particularly demonstrating that sequencing these drugs seems to potentiate the effect. And blocking telomerase will essentially speed up the demise of stem and progenitor cells that are driving this disease, so it’s really an anti-clonal stem cell-directed therapy that exploits the overexpression of this enzyme telomerase that’s particular to these malignant cell populations that allows cells to continue to survive and continue to live.

And the Phase I data was — I think was surprising because I thought there’d be a lot more myelosuppression. I did not think it would be tolerable, actually, in combination with ruxolitinib in patients who are already on a stable dose of rux that had a suboptimal response. But yet we were able to add the drug and give it every 4 weeks, and we saw no Grade 3/4 thrombocytopenia, which was very surprising and happily surprising.

And in general it was a very well-tolerated drug, without a DLT. So we got up to 9.4 mg/kg, and we have some early data showing that we’re seeing some spleen responses, symptom responses, and we are looking forward to presenting the data as an oral at ASCO of the updated clinical follow-up come June. So it’s still in development, and we’re trying to figure out what is the best place to position a drug that’s IV that does have some myelosuppression associated with it but might be anticlonal and may improve survival.

DR LOVE: So Claire, any comments? And also, what’s the median survival of a patient who has progression on ruxolitinib?

PROF HARRISON: Yes. I mean generally the patient who’s progressing on ruxolitinib, well certainly in the past, had a poor survival, especially if they were thrombocytopenic or they had clonal progression. And I think if you think a patient’s progressing, we didn’t touch on it earlier, but looking in particular for RAS or CBL mutations, those patients, boy, they don’t do well. And thrombocytopenia patients, again, don’t do well.

I mean, I was super happy to see the study from you, actually, John, because right now we’re trying to enroll this monotherapy second-line study against a control arm without JAK inhibitor. We know it’s really hard to enroll the patients, but yet biologically this is interesting. And I do think JAK inhibitors will remain the backbone of therapy, so I’m super excited to see where this goes. And I wonder if it should be an up-front, but it’s the delivery as an intravenous, as you say, which is perhaps a barrier and a disincentive for patients.

Navtemadlin

DR LOVE: Alright. Let’s talk about one of the most exciting presentations at ASH looking at navtemadlin, John, the BOREAS study. Can you talk about that?

DR MASCARENHAS: Sure. So this is a drug — this is oral. This is a drug that’s an MDM2 inhibitor, so what it does is it upregulates p53, which is of course the master regulator of cell fate and induces both cell senescence and apoptosis. Tons of preclinical data that demonstrates it’s rational. MDM2 is upregulated due to JAK-STAT signaling. And this compound kills CD34 cells, and that’s what we’re trying to do, is trying to eliminate or at least deplete the malignant pool of cells that gives rise to this disease.

And in this study we were again looking at this very advanced patient population who had failed JAK inhibitor, as Claire pointed out poor survival, limited options, and patients were randomized either to this drug navtemadlin or BAT. And you can see in these 2 waterfall plots that there was a greater degree of spleen reduction in a greater proportion of patients with navtemadlin, so doubling of spleen reduction. And it was well tolerated from a cytopenic perspective. We didn’t get a lot of myelosuppression, so you preserved both hemoglobin and platelet count over the course of the study.

But as a class effect with MDM2 inhibitors, we saw this with idasanutlin and with siremadlin and other drugs, that there’s some GI toxicity. That’s somewhat expected, and that’s probably its biggest liability. And we’ve learned over the years you have to prophylax these patients. You can’t just let them go into this drug which is dosed intermittently. So we’ve figured out, I think, how to best utilize this drug.

This study really serves, I think, as a basis for why this class of compounds works, but really it informs the study you’re showing here, which we presented data several years ago at EHA showing that if you combine navtemadlin, and this is always the theme of these discussions, with ruxolitinib you get better efficacy, and you get better tolerability.

So in the POIESIS study, which is the schema shown here, it’s adding navtemadlin to ruxolitinib in patients who have a suboptimal response. And these patients are caught early on. They’re enrolled before they get JAK inhibitors. They’re followed. It’s very rigorous and regimented, and if they have a suboptimal response they’re then randomized to the addition of navtemadlin 7 days on, 21 days off versus the placebo. And here we’re looking to demonstrate that you can rescue and push patients into both a spleen and symptom response with this drug in this randomized Phase III study. So activity as a single agent in the relapsed/refractory setting, probably even better tolerated and more effective in the add-on strategy.

DR LOVE: So Claire, before we talked about criteria to decide that a patient’s not responding to ruxolitinib, but here we’re talking about a new category, at least I haven’t heard about it before, at least recently, suboptimal responders. So what fraction of patients who get ruxolitinib roughly are “suboptimal” responders, and how do you define suboptimal response?

PROF HARRISON: Well, what we know is the target is a 35% reduction in spleen response and a 50% reduction in total symptom score. Those are the endpoints in clinical trials. So that’s what’s being used here in this trial. And actually, what we know from the COMFORT studies is only 30 to 40% of patients are going to achieve SVR35. So technically quite a lot of patients then are actually suboptimal responders, and do you have residual disease.

And so I really like the design of this study. The patient’s on a stable dose of ruxolitinib, they’ve still got residual meaningful disease, and then they get randomized. The question is what additional benefit would you need to show with an add-on therapy, and for a company it’s a pretty expensive study to run because you’re going to recruit a bunch of patients, some of them are going to drop out before they get randomized, but as a patient it’s actually very attractive, I think. I’m super excited.

DR LOVE: So John, what about — no, such an interesting concept — John, how do you manage these patients when you don’t have a trial? Just keep them on the ruxolitinib until they get worse?

DR MASCARENHAS: So I try not to. I mean, I think that was the tendency prior to the availability of the other JAK inhibitors. So if I see a patient who’s “failing,” whether it’s symptom creep, they’re getting symptomatic again, or the spleen is growing back, or they’re becoming more cytopenic, I’m pretty quick to move on from ruxolitinib and to either go to pacritinib or momelotinib depending on the profile or even fedratinib, which I think is sometimes the unforgotten — or the forgotten JAK inhibitor that’s very potent, probably one of the most potent drugs we have in terms of rescuing spleen. So I would definitely encourage our viewers and our practitioners to don’t forget that we have these other JAK inhibitors, and don’t forget fedratinib, and really integrate these drugs rather than waiting for patients to do worse and worse and fail.

DR LOVE: So go ahead, Claire.

PROF HARRISON: And don’t transplant. I would say don’t forget transplant, either, right?

DR MASCARENHAS: Yeah.

PROF HARRISON: Because these are patients who we should be taking to a transplant if they’re eligible. It’s the only curative therapy.

DR MASCARENHAS: Absolutely.

PROF HARRISON: Better to do it up front if you can.

DR LOVE: Great point. So Claire and John, thank you so much. It’s been so interesting to hear about all these developments.

Audience, thank you for attending. Be safe, stay well and have a great night.

Thanks so much, Claire. Thanks, John.

DR MASCARENHAS: Thank you.

PROF HARRISON: Thank you very much.