Current Management of Myelofibrosis (MF) — Professor Claire Harrison

PROF HARRISON: Hello, my name is Claire Harrison. I’m a hematology consultant working in London, in the UK.

So today I’m delighted to cover a Year in Review for conventional management of myelofibrosis. I’ll be covering some of the 4 JAK inhibitors we have available for our patients and some consensus criteria for general practice.

The first study I want to talk to you about is a study concerning dosing and clinical outcomes of ruxolitinib in patients with myelofibrosis, and this is an Italian observation or study appropriately called ROMEI. So this study included 508 patients, and what’s already been reported is data concerning results at 24 weeks about symptoms and spleen responses. But what the data I want to share with you is about dosing, and the finding in this study that about a third of patients receiving ruxolitinib in this real-world study in Italy may well be undertreated, and what the consequences of that are for these patients concerning disease control and survival outcomes.

So the paper concerns an interim analysis at the 1-year timepoint of patients according to their starting dose. So they’re grouped into 2 groups AsEx, so as expected for the platelet count. If you remember that we dose ruxolitinib according to baseline platelet count. They had 174 patients and LtEx, or less than expected, which was a good number of patients, 132 patients.

So let’s take a look at the patients who fitted into this less than expected dosing. And it probably won’t surprise you that colleagues in Italy were more cautious about the dose of ruxolitinib that they gave to older patients. So the less-than-expected patients had a mean age of 71 years versus 68 years, and they tended to have this phenotype that we’ve been calling in the field cytopenic myelofibrosis. So these patients were more likely to have had previous transfusions, so just around a quarter of them had that, they had a lower hemoglobin, and they also had a lower platelet count.

Now let’s discuss what actually happened to these patients grouping them again in as-expected or less-than-expected. So symptom responses were initially better for the patients that received the as expected dosing at 4 weeks, and this benefit lasted until 24 weeks but at 1 year, 48 weeks, these proportions of responders was similar. So the message is, if you treat with a recommended dose, symptom response is faster. Spleen responses, both at 24 and 48 weeks in the as expected dose were significantly better, so 50 versus 30% and then at 48 weeks almost 60% versus 45%. And median time to response was 3 months versus 11 months.

So this does suggest that spleen response in particular is very sensitive to dosing. Importantly, there is also a message for survival. So median survival was not reached for the as-expected dosing but for less than expected dosing, it was 4.7 years, and this was statistically significant. So the message for us in practice is that it is important to remember to try to dose patients according to the recommended started dose for ruxolitinib. This is according to baseline platelet count and this dosing leads to more rapid symptom response, more rapid and significantly higher responses at 1 year and a survival benefit. Of course, these clinical features that I already called out as limiting or relating to the dose that colleagues gave to patients may also have impacted survival, so these reflect age, anemia, et cetera. Nonetheless, these are important messages for us to bear in mind in clinical day-to-day practice.

So next, I want to talk about clinical outcomes for patients who have intermediate-1 risk disease. So this is another real-world study. This time it’s called the RUX-MF study. And in this study they accumulated 595 patients, so another big study treated in the real-world who had intermediate-1 risk disease.

This is important data because the data from the randomized studies only included patients with intermediate-2 and high-risk disease and we know that there are patients who have intermediate-1 risk disease who have adverse survival and also who suffer with splenomegaly and symptoms. So spleen and symptom responses in this real-world study were consistent with the literature. So spleen response, 35%, was about 26% of patients, and symptom responses occurred in 67.9% of patients. This is slightly low perhaps for SVR35, especially considering what has been published, for example, from the JUMP study, the ROBUST study and others, but it does call into question the utility of using SVR35 in real-world practice.

What factors were associated with spleen response in this study? Well, again, they were lack of cytopenia, interestingly lack of raised blasts and also importantly, no high molecular risk mutations. So that, just a reminder for listeners, would be mutations in ASXL1, EZH2, IDH1 and 2, NSF2B3. Ruxolitinib discontinuation and overall survival as well as event-free survival, it won’t surprise you, were all superior for intermediate-1-risk disease.

So in conclusion, outcomes for patients with intermediate-1 risk disease in terms of overall survival, event-free survival and discontinuation were better for intermediate-1 risk patients. This may be related to lower disease burden and better hematological status at baseline. And overall, these data are important as they confirm the benefits of ruxolitinib treatment in earlier disease. And this is in accordance with some of the other data that we’ve seen published recently suggesting that response rates, and indeed survival benefits, are better if we treat patients within the first 12 months of their diagnosis. So this should be able to give colleagues more confidence in this aspect of managing disease.

One of the problems for us in day-to-day practice in using ruxolitinib, of course, is the dose and disease-related anemia. And this often limits the dose that we feel able to give patients because we’re afraid of inducing transfusion requirement.

So what I want to share with you next is an abstract that was presented by Vachhani and colleagues at ASH, it’s number 4546, and it relates to data from the very large Phase IIIb JUMP trial, which has already been published. And it’s a post hoc analysis of patients who had baseline anemia. They were in 2 buckets, less than 12 or less than 10, who were not receiving supportive care for anemia at enrollment but initiated an ESA or indeed, danazol. These are 2 common agents that you might use in day-to-day practice to manage anemia for your patients receiving ruxolitinib. So what they shared data with was with regard to patients who weren’t receiving those drugs but had a hemoglobin of less than 12 at enrollment, initiated those drugs within 3 months of enrollment and remained on for 3 months. The clinical outcomes that were evaluated were spleen length response.

So interestingly, there were quite a big number of patients, mainly that initiated an ESA agent, so 98 initiated an ESA and 3 danazol within 3 months and most of those patients were patients who had a hemoglobin of less than 10. For both cohorts, less than 12 hemoglobin or less than 10, similar time to first dose of the supportive therapies was reported, slightly shorter for the more anemic patients but the range was the same.

So did the need for an anemia supporting agent influence spleen or symptom response? And the answer is, no. So spleen length response was 42% of patients at week 12 who had a hemoglobin of less than 12 and similar for those with a hemoglobin of less than 10. And at week 24 this was around the 30% mark in both of those 2 groups. Symptom responses were around 26 and 25% for these patients. And again, this is similar to the whole JUMP cohort.

So the message is that for those patients who received an anemia supportive care, mainly ESA, in the first 3 months of starting ruxolitinib, this did not impact at all on spleen and symptom responses and these data reinforce the use of supportive care for anemia, which is important as there are, of course, other options for anemia management for these patients such as luspatercept, momelotinib or the drug that we will now come on to speak about, which is pacritinib.

So this is some data concerning patients treated with pacritinib in the 2 Phase III studies, PERSIST-1 and PERSIST-2. And this is an ad hoc analysis looking at the impact of baseline blood counts on efficacy according to baseline platelet and hemoglobin levels from the pooled data of these 2 studies. So the data, as you can see in the table, relates to baseline platelet count and baseline hemoglobin. Hemoglobins are presented in 3 different buckets. There were 276 patients included in the analysis, the median age was 67 years, 51% of them had Grade 3 fibrosis, 70% had primary MF and because we included the PERSIST-2 study, some of these patients, 16%, not a high percentage, had a prior JAK inhibitor exposure. And they are split pretty much 50/50 between baseline platelet count, less than 100 or more than 100. Interestingly, this split was slightly different for baseline hemoglobin. As you can see, a hemoglobin less than 8 was 11%, between 8 and 10 about a third of patients, and the remainder of patients had a hemoglobin of more than 10.

So now let’s take a look at dose intensity of pacritinib. What you can see reflected on the right here are dose intensities for pacritinib according to the 3 hemoglobins and the 2 platelet counts. And you can see in line with the dosing advice for pacritinib in the study and tolerability that actually these patients mostly received a full dose of pacritinib, that is 200 mg twice a day in day-to-day practice. And interestingly, spleen and symptom responses were pretty consistent across these buckets of patients and particularly of interest, pacritinib happened to show greater reduction in symptoms in patients who had severe anemia at baseline. So that resulted then in deeper and more rapid reductions in symptom burden. And if you look, there was just 1 graphic showing stability of hemoglobin for these patients as well.

So this is a post-hoc analysis of pooled data from 2 Phase III studies. And it’s important because it tells you a bit about what you can expect from pacritinib in patients with different hemoglobins and different platelet counts. Appreciating that you will generally in practice only be using this drug per label, which is platelets less than 100, but you can see that there were nice responses across all of these groups of patients. And the authors conclude that these findings suggest that pacritinib may be able to successfully improve underlying disease and general condition in severely cytopenic cases and particularly point out the pretransplant settings worrying about exacerbating cytopenia, although this data doesn’t, of course, relate to transplantation.

Now, let’s move to talk about momelotinib, which of course, is the most recently approved JAK inhibitor and the one that you might be thinking about for using to treat patients who have anemia. And here you can see another subgroup analysis of patients according to hemoglobin and this is being performed on the basis of the SIMPLIFY 1 study. SIMPLIFY 1 was the only study that was a head-to-head study between 2 JAK inhibitors, momelotinib and ruxolitinib in the front-line setting. And this, as I said, is a post hoc analysis of response according to baseline hemoglobin.

So here you can see baseline characteristics. Apologies, it’s a rather busy slide. It shows you that in this group they’re showing data according to an intent to treat analysis and then again 3 buckets of hemoglobin, less than 10, 10 to 12 and greater than 12. And in this analysis, just focusing first on the line graphs, what you can see is in orange momelotinib treated patients, in the gray arm across the 3 buckets of hemoglobins, that the hemoglobin dropped with ruxolitinib and then returned back towards baseline during the course of the study but not quite up to baseline. And when these patients swapped over to receive momelotinib, the hemoglobin went back to that tracking for the momelotinib patients.

What you see in the middle panel is a rather complicated shift table analysis, which shows you what happened to the patients in terms of their hemoglobin, did it get better or not? And then on the right you can see data with regard to spleen and symptoms. So you can see that the 2 agents, momelotinib in orange and ruxolitinib in the kind of gray color are roughly equivalent for spleen but that ruxolitinib is probably slightly superior for symptoms, particularly in those patients who did not have baseline anemia. And then you can see, certainly for the patient groups with a hemoglobin of less than 12, so 10 to 12 and less than 10, that the anemia-related parameters, so becoming or maintaining transfusion independence was superior for momelotinib, whereas this was not quite so marked, of course, for the patients who were already transfusion independent and who had a hemoglobin of more than 12.

So in conclusion, what this publication is telling us, is that momelotinib demonstrates benefits across all of the anemic subgroups. But the benefit of momelotinib in nonanemic patients with a baseline hemoglobin of more than 12 is less clear. It was equivalent at best for spleen. And remember that it did not hit noninferiority for the sample in the study originally, and it was not superior for symptoms and these patients don’t really have an anemic problem.

Both of these drugs require dosing modification for thrombocytopenia. And what was also presented in this paper was stability of the platelet count over time with momelotinib, which may support its use of that full dose in more patients compared to ruxolitinib, especially those patients who have cytopenia because anemia tends to go alongside of thrombocytopenia.

And the next piece of data I want to discuss with you today is some data regarding now a subanalysis of the sister study to SIMPLIFY 1, which is SIMPLIFY 2. And here, this is for patients who received momelotinib in the second-line setting, after they were either relapsed or refractory to ruxolitinib. In this study we swapped patients straight over to receive momelotinib. There was no washout. And in this paper what we looked at was a post-hoc analysis and the subgroups were either patients who had a hemoglobin of less than 100 or required transfusion. And in the study, just to remind our listeners, that transfusion independence is the absence of transfusion requirements and no hemoglobin of less than 80 in 12 weeks before randomization.

A few patients received anemia supportive therapies other than red cell transfusions, for example ESAs, and so these patients were also included in this analysis. What you can see is subgroups of these patients. I’m looking at hemoglobin and anemia responses. On the right-hand side, the graphical representations of hemoglobins for these patients in the study and you can see that once they crossed over to momelotinib the hemoglobin rose and was stable. And then if you look on the left-hand side you can see both, what’s called a terminal 12 weeks or a fixed 12-week response in terms of achieving transfusion independence or maintaining transfusion independence, or a rolling, adjusted over fixed 12-week periods analysis. So this is a novel analysis and again showing benefit for momelotinib.

If we also now consider spleen and symptom responses, as you can see, these were numerically superior for momelotinib, but there was no statistically significant benefit here largely perhaps due to small numbers of responders, which you can also see represented.

So in conclusion, what this subanalysis showed us is that momelotinib was associated with comprehensive anemia benefits. This is already known but I suppose it’s another way of looking at the data, specifically the rolling 12-week analysis is a novel way of looking at this data. And these benefits included higher mean hemoglobins over time, increased rates of transfusion independence versus best available therapy, which was ruxolitinib for most patients. But the authors pointed out that these anemia supportive therapies, such as, for example, adding ESA or adding danazol don’t actually treat the underlying disease, whereas choosing a JAK inhibitor, which can also address anemia, can address the underlying disease.

What’s important in day-to-day practice was, as I mentioned in this study, we were switching patients directly from ruxolitinib to momelotinib, and indeed we did this in the SIMPLIFY 1 study at the crossover stage. So for you who are listening, in day-to-day practice, if you’re considering switching a patient from ruxolitinib to momelotinib, you can safely do a straight switch. You don’t need to do a washout. And that’s important, perhaps, in day-to-day practice.

Now the next study I want to talk to you about also relates to transfusion independency. You’re getting a real top up on information about anemia in myelofibrosis today. This is a paper, which we published, looking at a longitudinal assessment of transfusion intensity. I introduced this topic when I was presenting the last study. And what we looked at in this study was looking at patients, either JAK inhibitor-naïve or previously treated, who were now treated with momelotinib. And we wanted to visualize changes to the red cell transfusion burden during treatment. And we analyzed patients in ordinal bins based on baseline and treatment period intensities of transfusions that were received every 28 days. So these could be 0, 0 to 1, 1 to 2, 2 to 3, 3 to 4 and greater than 4. I’m sure you get the idea.

So what I want to share with you is an example from the SIMPLIFY 1 study. And what you see, if you’re looking at slides, is that those patients who were treated with momelotinib had a shift. So they had a shift in requiring less transfusion. So the dotted line, which is on treatment, was above the line for baseline. And for ruxolitinib, the dotted line is below, reflecting the fact that they required more transfusion. If you like to look at that in the context of a shift table, you can look at the graphic on the right-hand side that shows that, for ruxolitinib treated patients there are more patients requiring more transfusions. So there are more numbers in the darker blue hatch there than there are compared to the momelotinib treated patients, which is in the red graphic.

And then, if you prefer numbers, these are shown in this table below. Here you can see improvement from baseline in terms of the different studies. So improvement from baseline in terms of transfusion intensity was seen in 41 patients. That’s 19% in the SIMPLIFY 1 study versus only 11% for ruxolitinib, and 48% versus 39% in SIMPLIFY 2. And here we’re also looking at the MOMENTUM study, which is a final Phase III study where we compared momelotinib to danazol and here you can see improvement in 65% versus 52%. That study also told us, of course, that danazol is an effective treatment, it’s just not as effective as momelotinib. And then, importantly, if you perhaps wanted to look at the last line in that table, this is about worsening of requirements for transfusion from baseline. So the first message is worsening did occur in some patients treated with momelotinib. You can see 13% in the up front study, 23% in the second-line study and 15% in the MOMENTUM study. So this is still an area of unmet need, but that worsening was more in the control arm, so 46%, 39%, and 37%.

So in conclusion, this is a novel way, again, of looking at transfusion burden, because traditionally we’ve looked at can we achieve transfusion independence. But surely if you as a patient can go from requiring 4 units every 28 days, to requiring only 1 unit, that is a significant benefit. And it’s a benefit for us as well in terms of thinking about how we have to provide therapy for those patients. Think about iron chelation, et cetera. And it highlights that just simply looking in a binary way at transfusion independence, response versus no response, may not fully capture anemia benefits, in this case, of momelotinib, but in other cases relates to other agents as well.

So another thing you might want to know about with regard to momelotinib is what about survival benefit for patients? So this is data that was presented at ASCO last year, and this talks to overall survival and leukemia-free survival and a rank preserving structural failure time analysis, which is a tool that is used to correct for crossover in clinical trials. And this is an FDA approved tool. So if you look at the figures here you can see 2 figures, one for overall survival at week 24, and the other one for overall survival at week 48, and similarly for leukemia-free survival at week 24 and week 48.

So here you can see at week 24 we had clear evidence of overall survival benefit for momelotinib and also leukemia-free survival. For leukemia-free survival by week 48 this appeared to still be perhaps the case, but it was attenuated in terms of overall survival by this time point.

So in conclusion, in these post-hoc analyses of the Phase III MOMENTUM study, which is our latest Phase III study with JAK inhibitors in myelofibrosis, this rank preserving structural failure time, or RPSFT analysis, showed prolonged overall and leukemia-free survival in favor of momelotinib. At a later timepoint, the unadjusted hazard ratios were attenuated and thus this appeared to show that there wasn’t a longer term benefit. But given these benefits, medians weren’t reached in most analyses. These highlight the potential value of this therapy in prolonging survival and it may be important in your conversations with your patients.

Now the last JAK inhibitor we’re going to talk about is fedratinib. That’s been around and approved for a while but there have been 2 Phase III studies, which we’ve recently published data from. The first is the FREEDOM-1 study, and this is a rather attenuated study where accrual was cut short with only 38 patients recruited, so I don’t want to dwell on this one for too long. However, the data from this study, which was not randomized, showed that there were spleen and symptom benefits in line with previous studies. However, what we know about fedratinib is it can be difficult to manage in day-to-day practice. And the messages I want to give you from this study are shown on the next slide, which is that this time now, we see gastrointestinal side effects could be well managed with prophylaxis. So do give your patients prophylaxis for GI side effects. Do tell them to take fedratinib after a meal. In this study we observed some thiamine reductions with fedratinib. And if you remember, this is a drug that was put on a full clinical hold for Wernicke’s encephalopathy. So please do monitor thiamine and if you’re in my practice I would routinely give thiamine supplements to my patients, but I still do monitor thiamine levels. And then also, lastly, there were a couple of patients in this study that had an acute kidney injury and you’ll see that reflected in the next study. So this is a small study, FREEDOM-1. It supports the efficacy of fedratinib, but it emphasizes the need for GI prophylaxis and thiamine monitoring.

What we’re going to look at next is the FREEDOM-2 study. So this is a study that we did in the rest of the world. FREEDOM-1 was done in North America. So in the rest of the world we did a study, which was 2 to 1 randomization, second-line study for fedratinib, called FREEDOM-2. It was an open-label study and patients could continue ruxolitinib in the best available therapy arm but they didn’t have to.

And so in this study you can see that fedratinib produced highly significant benefits in terms of spleen and symptoms, and even if we looked at 25% reduction in spleen volume, which is something we’re beginning to look at in the second-line setting. These benefits occurred whether patients were ruxolitinib refractory or intolerant, and also occurred for whether patients had a baseline platelet count of between 50 to 100 or greater than 100. And in fact, there has been a recent presentation talking to the benefits of fedratinib for patients with platelets between 50 and 100. Again you see that GI toxicity here was relatively low, and again there was a renal signal. So important to monitor renal toxicity with this drug is one of the take-home messages that I have had.

So in conclusion, these data from the FREEDOM-2 study confirm the efficacy of fedratinib compared to best available therapy, which includes ruxolitinib for second-line and beyond, and adverse event mitigation. So as we’ve discussed, giving prophylaxis, monitoring and giving thiamine are effective for the use of this drug. So it is still a useful drug. Generally, in my practice, I would use it as second line for patients with large splenomegaly, and I might consider it for patients with thrombocytopenia.

Now lastly, I just wanted to talk about some work that we did with some colleagues across the globe to pull together some consensus recommendations from a global group, and we did this bearing in mind the problems that we all face in clinical practice. So we wanted to come up with some messages for you about how to manage patients with myelofibrosis in our day-to-day practice in clinic. So we used modified Delphi methodology. We had a truly international steering committee, colleagues from across the globe and then we had an extended faculty who were involved in voting on recommendations that included more hematologists and also patients. So that was something that was novel in this approach.

So I just wanted to highlight to you a few of the key recommendations from this paper. First of all, what current and emerging treatments to improve anemia should be considered for myelofibrosis or treatment-related anemia? So the recommendations were not to forget to workup your patients fully for anemia. Don’t get caught out with a patient that has bleeding varices, might have vitamin B12 deficiency, et cetera. I’ve been caught out by that and we wanted to make that point to colleagues. And the recommendations were that combinations, such as we’ve discussed with ESAs, danazol, luspatercept if it’s available, or an IMiD may be appropriate and can overcome dose adjustments that might be needed with ruxolitinib or fedratinib, or you could consider momelotinib or indeed pacritinib monotherapy. And the last recommendation concerns an older fashion surgical therapy, which is splenectomy, often associated with hazards and indeed mortality for our patients. But this could be considered as a last resort.

Next, aside from access and reimbursement, which factors guide selection of JAK inhibitor therapy in patients with MF and anemia? So the recommendations here were you should consider this according to baseline hemoglobin. So if a patient has a hemoglobin of over 12, we already heard that momelotinib may not be beneficial. How well your patient is likely to tolerate anemia, that will depend on their comorbidities, so coronary artery disease et cetera. Baseline thrombocytopenia, we know for example pacritinib is approved and useful for patients with platelets of less than 50 and that momelotinib can be used for patients with platelets down to 25. But we know that some of these agents have differing efficacy in terms of symptoms. There were some other drug-specific side effects, such as immune suppression, skin cancer, and infection risk, nutritional status and tolerability in terms of GI toxicity, which you may want to bear in mind.

Next, sadly, we all encounter relapsed or refractoriness in terms of JAK inhibitor therapy. So how do we define this in clinical practice? There are very few internationally recognized criteria for that. So in this consensus approach, we describe 3 buckets of patients and recognize that this was often difficult, and that these criteria, for example intolerance, can often lead to lower dosing, which leads to relapsed disease. So in the criteria, which we took from the JAKARTA-2 and FREEDOM studies, these include ruxolitinib for more than 3 months with spleen regrowth, following initial response, refractory patients who had ruxolitinib for at least 3 months with adequate dosing with a less than 10% spleen volume response, or less than 30% reduction by palpation. And then intolerant, say this would be, for example, ruxolitinib again complicated by a need for transfusion of more than 2 units a month for 2 consecutive months, bearing in mind that you may need to support the hemoglobin initially but the hemoglobin will return towards baseline, or Grade 3 or above thrombocytopenia, or nonhematological adverse events on ruxolitinib. So hopefully that’s helpful for you in day-to-day practice.

Now I’m sure your patients will want to know, how do I know that I might have a long-term survival outcome or survival benefit when I’m receiving these treatments? And so what we did in this paper was summarize the literature and put this out as a recommendation, which achieved, I’m pleased to say, 100% consensus. So these are the variables that you might want to think about for your patients. Are they getting a good spleen size reduction? That has been correlated with survival benefit for all the JAK inhibitors. Mutational complexity, so the presence of molecular risk mutation has been shown to be linked to worse survival outcome with ruxolitinib. No data for the other drugs. If your patient’s on momelotinib, and they are transfusion-independent, or gain transfusion independence, that is linked to survival benefit. Then, just to reflect factors that reflect poor outcome in terms of survival, don’t forget the RR6 score that was published recently. So this relates to requirement for transfusion, dose of ruxolitinib less than 20 mg twice daily or lack of spleen response. So these are collated in the RR6 score. And if your patient’s falling into a bad group on that score you might want to think about changing to another modality. And then finally the emergence of clonal progression, and just want to call out here particularly RAS mutations and P53 mutations.

And lastly, something that’s at the front of all of our minds, how can we have broader inclusion in clinical trials and how can we have better clinical trial endpoints? So we would like, as disease experts, to include patients who have got low risk disease, who have accelerated disease, who are otherwise ineligible even though that, for example, their HIV may be well controlled, and a big group of patients who relapse after allo-SCT. So that was a message to folk who are designing clinical trials. These are areas where we think we don’t reflect the patient population.

So finally, we wanted to touch on an important point in the field. How can we actually also improve clinical endpoints in trials? We’re very stuck in this field at looking at spleen and symptoms. But actually what we really would want to do, and I suspect our patients want us to do, in addition to that, we want to make tractional benefit for our patients in terms of overall and leukemia-free survival. So we had some thoughts about how we might do that. We could look, for example, at driver mutation or additional mutations, use AI. That’s very topical isn’t it, AI, to look at the marrow and perhaps also look at cytokine levels. So these are things that we’ll be looking at and you’ll hopefully be seeing coming through in clinical trials in the future.

So I’d like to thank you for your attention as we ran through the current data with regard to conventional JAK inhibitors available in your day-to-day practice. I hope you found it helpful and I hope you find that the discussion of these consensus points also helpful. Thank you very much.

DR LOVE: Wow. That was great.

Just a couple of follow-up questions. Could you describe a patient where — I don’t know what the regulatory constraints might be, but theoretically, a patient where you would start as initial therapy momelotinib?

PROF HARRISON: So for me, a patient that I would want to start on momelotinib would probably be a patient with what we would describe as cytopenic MF. So they would be already either requiring transfusions or have a hemoglobin of 80 or less, and probably have a platelet count of less than 100. I think the tension is when might you use ruxolitinib compared to that? So for me I think it’s the anemia and the thrombocytopenia that are an issue.

DR LOVE: So another question, in terms of earlier starting of ruxolitinib that you alluded to, and my question is, are there any situations where you would treat a patient with myelofibrosis with ruxolitinib who was asymptomatic?

PROF HARRISON: Sure. First comment, if the patient has intermediate-2 or high-risk disease, and a big and enlarging spleen, even if they’re not symptomatic, I think you should be thinking about ruxolitinib. And then what we often observe in clinical practice is we give them the drug and then they go, oh I did have this, and I was a bit itchy, and I was a bit sweaty, and it got better. So I think there are some hidden symptoms. I think of course we have to be careful about using a drug. So I wouldn’t if the patient didn’t have a big or enlarging spleen. But the issue in the field is we know that myelofibrosis is a difficult and progressive disease. So we’re still watching and waiting low risk patients sometimes even if they’re proliferative. In my practice I’m tending to use interferon then. But I think it’s quite tricky when you think this is a disease that’s definitely going to shorten someone’s life. We know that a therapy can prolong life. And there is some example now about ruxolitinib causing clonal regression for some patients.

I have a patient, just to digress, who’s been on ruxolitinib and panobinostat for 14 years. We just did her JAK2 VAF, it’s 1%.

DR LOVE: Wow. Panobinostat?

PROF HARRISON: Yeah. We did that in a study. It’s an HDAC inhibitor. We did it in —

DR LOVE: I know but I mean —

PROF HARRISON: She’s still on it.

DR LOVE: And the patient’s still on it?

PROF HARRISON: Yeah.

DR LOVE: Wow. Incredible.

PROF HARRISON: She’s doing great. If it’s not broken I’m not going to try and fix it.

DR LOVE: Awesome. Interesting. Another question. What about antibody-drug conjugates or CAR-T?

PROF HARRISON: So we don’t have any ADCs and I don’t know of any that are in the pipeline. But there is a CAR. It’s an academic CAR-T that’s being developed by some colleagues in the UK. So it was presented at EHA and ASH, Alex Rampotas, and it’s being worked on with the group at UCLH, they’re just the other side of the river, who’ve got well established pedigree, Claire Roddie and people like that. You’ve got good pedigree in CAR-Ts.

The thing is how toxic that would be for some of our MF patients. So it’s a way off going into the clinic yet.

DR LOVE: Also any attempts to target in the same antibody or bispecific, JAK2 or MPL?

PROF HARRISON: Not yet. There is a TPO blocking bispecific that’s being developed. Nothing yet for JAK2. So for JAK2 we’re really looking at these more specific kinase inhibitors.

DR LOVE: But I mean is there some reason you couldn’t have a monoclonal antibody to JAK2? I mean would it hit some normal tissue?

PROF HARRISON: It’s not expressed on the cell. Yeah, it’s not expressed on the cell surface. That’s the problem. So it would be penetrant.

DR LOVE: Got it.

PROF HARRISON: So whereas mutant calreticulin is secreted and exerts its effect by binding to MPL.

DR LOVE: Right.

PROF HARRISON: You could think that you could get a MPL blocking antibody. That’s possible. I think there is probably one of those in development. In fact, I know there is.

DR LOVE: A couple other questions. I see that you’re doing a study on ruxolitinib first-line, p vera.

PROF HARRISON: Yeah.

DR LOVE: What are you expecting to see?

PROF HARRISON: Well, we did that study based on the academic study we did, MAJIC-PV, that we published in the JCO in 2023. And in that study we showed that event-free survival was superior for ruxolitinib in the second-line setting. But we also saw deep clonal responses, including sorting stem cells and seeing reductions in JAK2-positive stem cells. So the next logical step was to take ruxolitinib into the front-line setting and patients can choose what they would be randomized against. So they get ruxolitinib or interferon, ruxolitinib or hydroxyurea. And we’re hoping to see if we use this drug earlier in the disease course that we might see better disease modification. We’re also looking at JAK2 VAF, et cetera, trying to build that into routine care for PV.

DR LOVE: Another question, I see you’re doing work with selinexor in ruxolitinib. Are you excited or not really?

PROF HARRISON: I’m excited if the patients can tolerate it. Our patients so far seem to be doing okay. It’s a blinded study. I think there are at least 4 ways that selinexor could be helping myelofibrosis. So we’ve got area of unmet need, so I think it’s interesting. I also think the POIESIS study, which is also ongoing, suboptimal responder study with navtemadlin is also interesting.

Novel Investigational Strategies — John Mascarenhas, MD

DR MASCARENHAS: Hi, I'm John Mascarenhas from the Icahn School of Medicine at Mount Sinai and today I'll be presenting Myelofibrosis, A Year in Review.

So I'm going to first start with what I think is the most advanced in clinical testing and relevant to the community. And this is a theme of combination therapies, JAK-inhibitor-based combination therapies, particularly in the up-front setting. And this has led to the MANIFEST-2 study, which I'm showing you updated results here at week 48. And MANIFEST-2 is a randomized Phase III study in JAK inhibitor-naïve patients combining ruxolitinib plus pelabresib, the oral pan-BET inhibitor versus ruxolitinib plus placebo. And pelabresib is orally administered 2 weeks on, 1 week off. A lot of preclinical rationale why synergizing these 2 drugs is more effective for trying to modulate the malignant clone. And then the Phase II data was very favorable in terms of both spleen and symptom response and other disease markers of modification. So we saw the week 24 data previously, now published in Nature Medicine last month, demonstrating superiority of spleen and nominal improvement in symptom burden. But what we are committed to doing is following the patients out longer term.

And this is the week 48 data. I remain very enthusiastic and excited by the fact that you still have superior spleen response. So SVR35 percent at week 48, 57% versus 37.5% with placebo. And then if you look on the right, you can see the durability of that spleen response remains superior, in blue, with the combination versus ruxolitinib alone. And then below on the table, if you look at that closely, you can see that if you look at any time because there's nothing really specific about week 24 or week 48, you have a higher frequency, 82%, meeting that SVR35 percent versus 60% or 57%. And then interestingly and importantly you have less frequent loss of response. No matter how you define it with the combination versus single-agent ruxolitinib. So clearly deep spleen responses and more durable loss of spleen response with the combination.

You also seen improvement in symptom burden. So there's a nominal improvement of about 2 points on the total symptom score when looking at the absolute change in symptom score at week 24 and week 48. So it's durable. The graph on the right makes an important point that might be missed by the casual observer, which is you can't really improve the symptoms better than a nonmyelofibrosis controlled population. So the issue here is ruxolitinib is quite good at improving symptoms, and although you get a nominal improvement by adding pelabresib, it's very hard to show a very significant, statistically significant difference. So very dramatic spleen improvement but also nominal symptom improvement.

And just to end with that abstract, you know, we'll continue to follow these patients out. The durability of the spleen and symptom improvement, progression-free survival. I will say, I didn't show it here for sake of time, with pelabresib the AE profile actually was very tolerable. And although there was an initial significant concern regarding blast transformation early on, as we follow the patients, we don't see that phenomenon increase. So it's not quite clear to me whether there truly is a concern about BET inhibitor induced leukemic transformation here, which was a very small number of patients, that was imbalanced. We continue to follow these patients out, but I think the community at large is very interested to understand whether this combination approach will be beneficial up front.

On the same vein of BET inhibitors as a group, these are active agents. The next few slides I'm going to talk about an oral potent pan-BET inhibitor in a Phase I study presented by Dr Watts and colleagues at ASH. And here's the schema. Basically patients who have been on ruxolitinib and were deemed by their physician to be relapsed refractory to their prior JAK inhibitor, which was basically ruxolitinib. And then they were given this novel BET inhibitor starting at 4 mg once daily. And there's 2 cohorts. The first cohort was the monotherapy. You fail rux and then you got on the single agent drug. In the second cohort, it was the patients who had a suboptimal response. So they still had spleen or symptom that wasn't well controlled and you could add-on the oral pan-BET to their stable dose of ruxolitinib.

And although this is an early study, I wanted to show this because I think it proves the point that as a class of agents, BET inhibitors are active here. This is some of the monotherapy data showing the spleen volume response. You can see the columns going down demonstrate reduction in spleen volume. So even as a single agent without a combination of a JAK inhibitor, you're getting reductions of 55%, 48%, 40%. So pretty significant reductions in spleen volume response at week 24. And then if you look at symptom improvement, clear improvement in symptomatology. And this makes sense. The same thing with pelabresib. You downregulate NF-kappaB, which is potently upregulated in these inflammatory diseases and patients will feel better because you get significant reduction in inflammatory cytokine expression. So significant spleen responses, significant symptom responses in this early phase dose escalation at different doses. These are color coded.

And then if you look at what happens when you add it on. And this is an attractive approach because I think monotherapy gives you a sense of what the drug does alone. Combination therapy tells you probably how can we be best utilized in the clinical setting? And here you can see it nicely salvages patients with ongoing residual splenomegaly on ruxolitinib and the columns going down demonstrate the extent in which that spleen volume is reduced.

So to go back to combination therapy I gave you a taste of advanced testing with pelabresib, follow-up for safety and overall survival and durability of response, a little early data for a new BET inhibitor on the block. And now let's go to selinexor. Selinexor is an XPO1 inhibitor. I think the audience is probably familiar with this drug in the context of B-cell malignancies. By inhibiting XPO1 it reshuffles the distribution of proteins and messenger RNAs and essentially targets 2 pathways that are relevant to multiple diseases but namely myelofibrosis. Upregulation of p53 pathway sending cells to either cell death or cell senescence. And then downregulation of NF-kappaB, which again BET inhibitors also do, so downregulation of inflammatory cytokine signaling.

And this is an abstract that was presented by our Chinese colleagues looking at the combination of selinexor at a lower dose than is used in myeloma, once weekly scheduling to patients who are on ruxolitinib with a suboptimal response. So that's another common theme is, do you add rux up front, the drug X up front to rux in JAK inhibitor-naïve or suboptimal responders? This is a suboptimal responder evaluation of selinexor plus ruxolitinib and they're dosing either 40 or 60 mg once weekly of selinexor, which, of course, is orally administered with GI prophylaxis. And again, 25 patients, so not 100 something patients, but a good data set demonstrating again reduction in spleen responses, as you can see here. Spleen length by palpation or spleen length by imaging were used as well as reduction in symptoms by the total symptom score patient reported outcome. So selinexor, which may have a history of having tolerability issues in myeloma when added to ruxolitinib with some antiemetics, in fact, does have significant spleen reduction potential and symptom improvement as well. And this is from the Chinese data set.

This complements and leads to the SENTRY study, which I'm showing you here. And this builds off of the data of selinexor plus ruxolitinib and a JAK inhibitor in a naïve patient population. Again, there's 2 themes here. Do we add the drugs up-front or do we add them as a salvage therapy? This is going back to like the MANIFEST-2 approach. Take JAK inhibitor naïve patients and they are randomizing, this is an ongoing Phase III global study, to selinexor 60 mg once weekly plus ruxolitinib at the appropriate dose based on platelet count versus ruxolitinib plus placebo. So everyone gets ruxolitinib but like MANIFEST-2, is the combination more potent in SVR35 at week 24 and do we see better reduction in total symptom score by the absolute reduction in mean value from baseline to week 24? And of course we stratify for the usual variables that can affect outcome. And this is a highly anticipated study that will hopefully complete accrual by the summer of 2025 and then ideally by 2026 we'll have some results of this and we'll be able to compare it to MANIFEST-2 that I showed you before. How does it look in terms of the extent of spleen response, symptom improvement? And then most importantly to patients and physicians, are these responses durable? Do they warrant combination therapy with additional potential toxicity and additional potential financial toxicity?

So I'm going to continue on this theme, I think you can appreciate, with imetelstat. Imetelstat, which is now approved in transfusion dependent early forms of myelodysplastic syndrome with an endpoint of improving anemia, has also been evaluated in myelofibrosis. And the randomized Phase II study determined what looks like a survival benefit in the relapsed refractory setting with imetelstat at 9.4 mg/kg intravenously administered every 3 weeks. So that study is ongoing. I think that's one of the more important studies that we have because it focuses on survival in the relapsed refractory setting where the median survival is somewhere around 12 to 14 months after failing ruxolitinib. And in the Phase II we were able to see survivals that were approaching 30 months. So we'll see in this randomized Phase III study whether single-agent imetelstat further improves survival compared to best available therapy. But this abstract that I'm showing you is more along the theme that I've been presenting, which is add-on strategy. So as that Phase III is reading out, we're looking to see, can we add imetelstat to patients who are receiving ruxolitinib who have an inadequate response? Again same theme as was shown by the Chinese selinexor study. And this stems from preclinical data published by the Ron Hoffman Lab here at Sinai demonstrating synergy, particularly if it's sequenced, against specifically CD34 MF cells with imetelstat and ruxolitinib.

So this is the IMproveMF study, Phase Ib study. I like to get right to the bottom line. No DLT. So we dosed all the way up to the highest dose that we were going to evaluate in combination with a stable dose of rux and we did not see a dose-limiting toxicity. Most of these toxicities you see listed here are Grade 1/2 and were not really a reason for discontinuation. Even the pain in extremities at 41% was sort of an odd one. I really don't know what to make of that. We didn't really see this in the single-agent setting in the Phase II and I'm not sure if this is a real drug-related issue but an interesting observation. If you look on the right, there is some cytopenias that are associated with imetelstat. It can be myelosuppressive but really interestingly, I think the audience can appreciate that you don't see thrombocytopenia on that list. So we didn't actually see Grade 3/4 treatment emergent thrombocytopenia. Why do I stress that point? That's usually the dose-limiting toxicity for most therapies that we give in myelofibrosis. So here we're seeing an add-on approach with imetelstat with the absence of significant thrombocytopenia. And, of course, the cytopenias that we do see with imetelstat are not permanent cytopenias, they're reversable. And that's why the drug, in this setting, is dosed every 4 weeks to give the bone marrow an opportunity to recover some hematopoiesis. So I would stay tuned to see how this rolls out. We're going to show more data at EHA and ASCO. You will notice I'm not showing you the clinical data yet only because it's too premature to really say anything of substance. We saw some spleen and symptom improvements, but I think the fuller data will give us a better sense of what to expect from an efficacy standpoint. And that is more to come later on in 2025.

One last word about cytopenias. I show you these curves to demonstrate that the mean values for hemoglobin, white count, neutrophil counts specifically and platelets remain relatively stable through the core stud even at the higher doses of 9.4 mg/kg, which is what I'm showing you here.

So that has really been, I think, the interest in the combination space. And as I mentioned, the ongoing randomized Phase III study called the IMpactMF has yet to readout. This one is really exciting because this is the single-agent relapsed refractory setting against best available therapy, which does exclude a JAK inhibitor, that's an important point, with a primary endpoint of overall survival. And we don't have a trial yet in myelofibrosis that has been executed or reported for that matter with a survival endpoint. It's really been focused on spleen and symptom and I think the belief here is that this is an anticlonal, antistem cell–directed therapy by inhibiting telomerase that could likely affect the disease course and improve survival. So important study and we're hoping to get a readout of this in the near future.

And just so the audience is clear, these are patients who have failed ruxolitinib. These are not the suboptimal responders, these are not the newly diagnosed patients. These are the patients who have documented failure of ruxolitinib but have platelets greater than 75,000 as a minimum and have measurable spleen and symptom burden that would be enrolled in this patient population and overall survival primary endpoint. Of course, we're going to look at all of the other key secondary endpoints but overall survival as a primary endpoint in which you can compare across these 2 randomized arms.

So with that, I'm going to bring us to what I think is some of the most exciting single-agent data that we've seen in the relapsed refractory setting. This is the BOREAS study with navtemadlin, an oral MDM2 inhibitor. So these are drugs that bind a negative regulator of wild type p53. So they activate the p53 pathway. p53 is rarely mutated in chronic phase MF. And by activating p53, you induce cell senescence and apoptosis. And this has been shown very nicely again by the Ron Hoffman Lab to occur in the CD34 or the MF stem cell pool thereby leading to a higher likelihood of disease modification, disease course modification.

So this study took navtemadlin as a single-agent and randomized patients who had failed ruxolitinib to the drug 7 days on, 21 days off, so 28-day cycle versus best available therapy. And what you can see here is that, as we expected with this class of agents, there is GI toxicity but this is very easy to control GI toxicity in the overwhelming majority of patients. So it's mostly Grade 1 and 2. It's mostly early on in the treatment. It can be significantly mitigated with antiemetics, so the similar sort of discussion that we had with selinexor. And that's probably the biggest differentiator between navtemadlin and BAT when you look across this treatment emergent adverse event profile. Cytopenias can occur but they're often recoverable. And to make that point, I'd like you to see on the right, the platelet count on the top and the mean hemoglobin on the bottom. You get relative preservation of hematopoiesis with navtemadlin as a single-agent 7 days on, 21 days off in a 28-day cycle in this relapsed refractory setting. So very advanced patient population often with baseline cytopenia. So this is a deliverable drug where you can manage cytopenias and manage GI toxicity. And what we saw here is tripling of spleen volume response, 15% of the patients met the SVR35 at week 24, this is by central review of the scan, versus 5% with the BAT arm. And what's important is that there's nothing magical about 35%. But if you look at the extent of response, you can see much deeper and much more frequent responses with navtemadlin versus BAT. Same thing with symptom improvement. Doubling of symptom improvement here. TSS50 of 24% versus 12% and some of these patients had very significant improvement in their MF-related symptom burden with navtemadlin.

And then we had a second abstract, and I tried to consolidate it here for time efficiency, looking at the various aspects of disease modification including very significant and rapid reduction in circulating MFC34 cells and correlating that with navtemadlin therapy with spleen volume response. So correlating biomarkers with a clinical outcome measure. And here I'm showing you the reductions in driver mutations as a surrogate for disease burden. So 21% of patients treated with navtemadlin monotherapy had a 50% or greater reduction in their driver mutation whether it was JAK2, CALR or MPL versus 12% with best available therapy. And you can see some of those responses, molecular responses, were quite deep. And again these do all seem to track with better spleen response, symptom response and correlate with reduction in CD34 cell number and reduction in bone marrow fibrosis, which was also significantly more frequent with navtemadlin in which 47% had at least a Grade 1 improvement in their bone marrow fibrosis score at week 24 versus 24%. So again, doubling, tripling here of efficacy endpoints whether it's clinical or biomarker with navtemadlin. And with the toxicity profile, that can be managed with antiemetics and dose modifications when needed. So this is an important drug. It's very rational. It's clearly active. It's a single-agent in the relapsed/refractory setting.

But where I think a lot of the excitement has now quickly pivoted to is the POIESIS study, which is the abstract that I'm showing you here. And this was a study that was built off of navtemadlin's addition to ruxolitinib in suboptimal responders. That was presented previously. And this is an ongoing study. This is now going to ask a different question than MANIFEST-2 or SENTRY, which is, you enroll patients who are JAK-inhibitor naïve and then at some latter timepoint, 18 weeks or so, you reassess the patient from a spleen and symptom perspective. Patients who have a spleen and symptom response are responders. They're off the study. Patients who have no response are primary refractory. They're off the study. It's everyone in between that's a suboptimal responder who hasn't gained sufficient spleen or symptom response are then randomized at that point to the addition of navtemadlin to ruxolitinib, so salvage approach, versus placebo. And then looking at the ability to hit that co-primary endpoint at the randomized period of targeted SVR and TSS reduction after 24 weeks. So adding an active agent at a latter timepoint with the standard of care, ruxolitinib, in the suboptimal responder. So we're really, I think, seeing a spectrum of approaches to drug development in MF both up-front and again as an add-on strategy. And this was built off of earlier data demonstrating very significant clinical activity and tolerability even at low doses of ruxolitinib with navtemadlin in this salvage setting.

So I'm going to quickly pivot to something I would say a little bit different than what we've been talking about. This is nuvisertib or TP-3654. This is a selective PIM1 kinase inhibitor that has presented updated results. And I show this because this is monotherapy data. It's a signaling inhibitor that, you know, I think it's interesting because this group of investigators had done a dose escalation and then had determined that 720 mg of the drug was the active dose of this oral PIM1 kinase inhibitor. And what they saw early on was they didn't see a lot of myelosuppression. If you'll remember from one of my earlier comments, thrombocytopenia often limits the ability to give a lot of these active agents to patients. It's one of the biggest vulnerabilities that we have with drug development in myelofibrosis. And we didn't really see that with this selective PIM1 kinase inhibitor whereas previously with pan-PIM kinase inhibitors in years gone by that was the dose-limiting toxicity. It really was not easily administered to patients. So here you can see a platelet count of 25,000 or greater was some of the eligibility criteria that allowed patients to go on. And what the investigator showed was with the single agent you get some pretty significant symptom improvement. And this is 18 patients at the optimal recommended Phase II dose of 720 mg twice daily. So you can see these columns going down. Very significant symptom improvements. And then you can see with these icons you also had patients that had low platelets and low hemoglobins that were garnering these benefits. Why point that out? Just emphasizing the fact that one can deliver this drug even in cytopenic patients at the full dose and still get that symptom improvement. And if you look on the right, it was all the different symptoms within the TSS that were really coming down. So it wasn't driven by one specific symptom, it was spleen-related symptoms, cytokine systemic related symptoms, the whole gamut of symptoms were improved with this selective oral PIM1 kinase inhibitor.

And then to reinforce the point, well tolerated from a blood count perspective. You can see that stability in the hemoglobin on the left and the platelet count on the right suggesting in my mind great drug as a combination partner as we move drugs forward either with a JAK inhibitor or maybe as a novel-novel approach. I think, you know, things for the MF community to think about as we move these drugs forward.

On the theme of thinking beyond sort of disease focused drugs and signaling pathway inhibitors, I want to spend a few minutes here just talking about a drug called elritercept. This is an activin ligand trap trapping activin A and other TGFbeta family ligands like GDF8 and 11. So really affecting multiple aspects of signaling pathways that contribute to the cytopenias that are challenging, as I keep mentioning in MF. And this drug, which is subcutaneously injected, really I think caught some attention because of its early results.

So this is a Phase II study called the RESTORE study that was administering elritercept at 0.75 mg/kg all the way up to 4.5 mg/kg subcutaneously administered in patients with myelofibrosis that had anemia. So here it was really trying to add-on a therapy. So patients could either be monotherapy or combination on a stable dose of rux to see can we improve anemia. A little bit different maybe than the other therapies that are clearly anti-clonal or stem cell directed as I've been mentioning. Here this is really can we affect different pathways that mediate the anemia that plagues our patients and complicates their treatment and is associated with a poor outcome.

And what we saw, first of all it was a pretty well-tolerated drug. In summary, we didn't see significant concerning treatment emergent adverse events and even the ones that were characterized are often part and parcel of the disease rather than likely contributed by the agent. So from a toxicity standpoint this was a well-tolerated agent.

And then as monotherapy, as I'm showing you here, we did see improvements in hemoglobin levels whether it's looking at 1 g/dL increase, you know, nearly 51% of patients versus 1.5 mg/kg increasing hemoglobin, this was over a 12-week period of time, occurred in 20% and 2 grams in 10%. So seeing improvements in anemia as monotherapy. If you look down below in combination with ruxolitinib, which many of our patients might have spleen and symptom benefit but continue to have significant anemia or transfusion dependence, we saw 55% of patients had at least a 1 g/dL increase. And you can see some of those increases are quite substantial even with patients hitting 2 grams and greater in this Phase II study. So this was an exciting study that's rational. A lot of data on inhibiting TGFbeta superfamily members to remove repression of normal hematopoiesis. So it's a double negative allowing for better responses. What I'm not showing you here for sake of time was we even saw responses here in improvements in platelet counts and we have no drugs that do that. So that was an interesting finding. I was not anticipating that. We'll have to understand the biology behind that a little bit better. But also improvement in spleen, which I can't totally explain, but maybe speaks to a broader application of this drug rather than just anemia focused. But clearly anemia has a potential here and this will continue to develop across MF and MDS and other related diseases.

And here I'm just showing you in those patients who were receiving transfusions, both as monotherapy on top and as combination on bottom, significant improvements in reduction in their transfusion burden. So 40% reduction in, at least 50% as monotherapy, 24% had transfusion independence, which is quite significant. And then as combination we saw almost 40% of transfusion independence and 62% had a 50% reduction. So if you ask me where is this drug looking the best? I would say in the transfusion dependent population particularly in those patients who are receiving ruxolitinib. And that's an unmet need.

Lastly, totally different than anything I've talked about before. This is cellular therapy. You don't see a lot of cellular therapy in the MF space, at least not yet. This is a Phase Ib study from the investigators coming out of mostly MD Anderson led by Dr Masarova. And this is with a really interesting unmanipulated T cell regulatory component, allogeneic component that's infused into patients who have a suboptimal response to ruxolitinib with myelofibrosis that have unmet need. And again you don't really see this in most clinical trial portfolios. But here they were taking cryopreserved non-HLA matched CXCR4 enriched T regulatory cells and infusing them into patients with myelofibrosis that were on ruxolitinib with a suboptimal response. And, of course, for a Phase I study it sort of limited patients so far. So you're looking at safety first and then efficacy second. And it looked very safe. There wasn't CRS, there wasn't significant infusion related reactions. So from a safety perspective it looked very safe actually.

And then we saw some preliminary data, in some cases very significant spleen responses with these T regs infused. You can see that patients in green with a spleen of 2,680 cm³, a normal spleen is 350, so that's quite big, having an over 50% reduction in their spleen volume. So some early data suggesting activity from a spleen perspective. And then on the right, also reductions in symptoms, particularly symptoms related to spleen, so early satiety so tying in some symptom burden with spleen reduction. And then nicely, and the part that I always appreciate about these studies, is the correlatives demonstrating very significant reductions in TGF-beta1 level. So TGF-beta1 is massively, as you can see on the right, massively elevated coming from the MF megakaryocytes and monocytes and well known to be part of the disease process with both a fibrogenic cytokine and it negatively regulates normal hematopoiesis. And here with these T reg cell infusions, you are seeing very significant, in green, in this heat map, very significant reductions in TGF-beta levels again which look like they might correlate with improvements in spleen and symptom that were observed clinically. So more to come here, but I just wanted to give you a little bit of flavor of where this field is going stepping into the cellular therapy arena.

So here are my highlights for 2024, you know, now we're in 2025, I remain super excited about what we're doing here. We're seeing durable responses at week 48 with pelabresib, the oral pan-BET inhibitor with ruxolitinib in the JAK inhibitor naïve patients. That's the MANIFEST-2 study. Stay tuned. We're going to continue to follow those patients and provide updates.

With the oral potent pan-BET inhibitor 57643, we saw some very early but exciting data both monotherapy and combination. We'll see where that goes and where they're going to take that drug.

Then we saw some additional data from China on selinexor activity as an add-on salvage approach to patients who are having suboptimal responses to ruxolitinib. And I think this complements really nicely the work that's being done in the SENTRY Phase III study of JAK-inhibitor-naïve patients combination selinexor as a rational agent.

And then we saw some data with imetelstat very early on in the IMproveMF study adding it to ruxolitinib in suboptimal responders. We'll see some more mature data coming up to see how much clinical activity we're seeing there. But the IMpactMF is the randomized Phase III study that many of us are looking forward to seeing the results of with an overall survival endpoint. First time ever.

Navtemadlin. I still remain very bullish about. This is a very active MDM2 inhibitor. Activates p53 pathway. We saw some very significant responses both from the spleen and symptom with good tolerability in the monotherapy and the relapsed refractory setting. And now we're moving into the randomized Phase III study, the POIESIS study, in the suboptimal responders. Can we convert patients to double responders spleen and symptom by adding on navtemadlin to ruxolitinib aft about 18 weeks of therapy if they don't have an optimal response? So I think a very important question being asked in the field.

And then we see some early data of nuvisertib, the PIM1 kinase inhibitor, really lacks myelosuppression. We see some pretty significant symptom improvement. I think it would be a great combination partner.

And then elritercept is this activin ligand trap reducing TGF-beta family member signaling pathways. We saw early on some significant anemia particularly in combination with ruxolitinib from a transfusion independence perspective but also improvements in platelet count and symptoms and spleen and we need to see where this is going to go. So we look forward to updated data here.

And then lastly, the CK008 T reg infusions. Early data looking like it has some signal of activity. Very well tolerated. Need to see some more mature results. And looking forward to that as well.

So with that, I'll end, and thanks for inviting me.