Claire Harrison, DM, FRCPath: Hello, I'm Claire Harrison from Guy's and St. Thomas' Hospital in London, United Kingdom. Welcome to this program titled: "New Targets for Old Challenges in Myelofibrosis." Joining me today is Professor John Mascarenhas from the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York, United States. Today we're going to be talking about a difficult phenomenon in myelofibrosis, which is a rare, tricky blood cancer with many issues for our patients. We've seen the introduction of ruxolitinib as a JAK1 and JAK2 inhibitor now for almost a decade for our patients. We've been experiencing those patients who lose their response or become intolerant to this agent.

Today we're going to have a conversation about the challenges that we face in our day to day practice, how common this is, because we know that many patients will not experience a problem initially with ruxolitinib. Most patients experience some responses, and primarily we're looking at spleen and symptom responses. However, over time, problems develop either related to toxicity or inability to get a good dose due to thrombocytopenia, for example, or anemia, or infections. Underneath all this, the disease may progress and cause further problems.

What we're going to be discussing today will focus on how do you know when your treatment is failing, how common that is, and what have we got in terms of novel agents that our patients might be benefiting from now or in the future. Dr Mascarenhas, I wonder if we could start by, how common do you think it is for patients to be running into problems that lead to discontinuation of ruxolitinib?

John Mascarenhas, MD: Well, I think as you stated, the benefits of ruxolitinib are pretty obvious and most patients have some, at least initial benefit, of ruxolitinib, even if it's not the classic 35% spleen volume reduction. I think it's rare upfront to have primary refractory disease, but over time we definitely see patients either developing cytopenias that limit the ability to deliver appropriate doses of the agent or frank progression of spleen. We're talking symptom burden, sometimes frank evolution of disease where it accelerates to a blast phase disease. Then as you mentioned, there are also infectious complications or other non-hematologic complications that require us to either dose reduce or stop the medication, or as we'll talk about with other strategies to try to synergize with ruxolitinib. The data suggests a median time of about 3 years, at which point 50% of patients are expected to discontinue ruxolitinib. I think that's also probably true in clinical practice. Of course, with clinical trial options we start to look even earlier when we observe patients who appear to be failing treatment.

Dr Harrison: There are certainly some patients that we know in day to day practice are likely to fail earlier; a good example would be a patient with thrombocytopenia. Even in clinical trials we see that these patients usually step off earlier and there is some data that patients who have so called high molecular risk mutations, or more than ≥ 3 mutations may fail quicker. Other factors include long time from diagnosis or enlarged spleen. The other issue is how do you define a failure. I mean, how do you do that in your practice, Dr Mascarenhas?

Dr Mascarenhas: I think it's a moving target. There is no consensus definition that everyone agrees upon. I think failure is defined on how the patient started off and what's happening at that time that you're evaluating them. Then the reality is what other options do they have? There's an appetite for a certain degree of failure, if we do not have other reasonable options to give them. It's a very tricky discussion. We probably could speak 15 minutes at least on the definition of failure. Failure is loss of that initial response for the quality of life; there is obvious suffering. The spleen is getting bigger, where cytopenias are limiting the ability to deliver the drug and red blood cell transfusion-dependence is developing or limiting thrombocytopenia.

Dr Harrison: Sure. We need to help our colleagues because framed or clear guidelines on this do not exist at the moment; that something we need to work on. As you rightly say, I think defining failure also depends to some extent or taking somebody off treatment, depends what we've got available. Should we just have a chat about that? I think that's the interesting and exciting aspect. Maybe first we could start with touching on other JAK inhibitors. More recently, fedratinib was approved in the United States and has been approved in the last 2 years in Europe. Then we've also got the 2 other JAK inhibitors currently in phase 3 trials, but we know quite a lot about them, both of us having been involved in momelotinib and pacritinib clinical development. I mean, Dr Mascarenhas, you've got experience with fedratinib. Do you have any thoughts on particular aspects with that agent?

Dr Mascarenhas: I think fedratinib is a great commercially available new agent now, also in the EU that can be used as a second-line option. If you have someone particularly who's experiencing progressive spleen, I think that's a reasonable option in order to switch the patient to an alternative option following ruxolitinib. You've published recommendations on how to effectively and carefully switch patients from ruxolitinib to a different agent. For patients who are failing ruxolitinib, particularly from a spleen perspective, I would use fedratinib. I think that's a reasonable option for patients who are having issues with thrombocytopenia. Fedratinib is a drug in development that I think offers the potential to deliver upfront or potentially even second-line for patients who have significant thrombocytopenia; perhaps IRAK1 inhibition provides an advantage over currently available JAK inhibitors. Then we have momelotinib which has a lot of exciting data as it relates to anemia, perhaps related to ACVR1 inhibition. I think there are many options that are emerging and hopefully one day we'll have a whole array of JAK inhibitors to choose from.

Dr Harrison: For sure. For our listeners, if they're interested in those, there are several ongoing trials, including the FREEDOM trial for fedratinib. For momelotinib, there's the MOMENTUM study, and there's the PACIFICA study for pacritinib. I think momelotinib, as you say, might be useful for patients with thrombocytopenia; it certainly shows good durability of response according to the data that was shown at ASH 2020. We definitely need more than one JAK inhibitor. Our colleagues in CML have more than one TKI available for use. However, we are also going to have a conversation now about other targets that we're looking at in MF. And the first one is the BCL-2/BCL-XL inhibitor navitoclax. Actually, biologically it is quite interesting.

I remember when I was doing my MD thesis more than 20 years ago, there was a very nice publication in the New England Journal of Medicine pointing at increased BCL-XL expression in polycythemia vera. We know that this is intricately linked to the JAK stat pathway, so potentially hitting those 2 nodes in patients, JAK-STAT signaling with a JAK inhibitor and then adding navitoclax, as a BCL-2/BCL-XL inhibitor, could be interesting. There is certainly emerging data presented at several meetings now, with regards to that agent. Some caution with regards to thrombocytopenia, but definitely some interesting responses for spleen and symptoms; not too many difficulties with thrombocytopenia certainly in our hands. I personally think there's a good biological rationale for that and I like the idea of hitting 2 signaling nodes. I don't know what your thoughts are on that, Dr Mascarenhas?

Dr Mascarenhas: No, I agree in that the rationale is clear. We know those 2 proteins are important in the pathogenesis of the disease. I think the phase 2 data was very compelling and we just need to be cognizant of the thrombocytopenia in order to effectively dose the patient. I think it will be the most important next step.

Dr Harrison: Yes. Well going ahead, we'll be looking at this as a single agent in frontline, and then second-line; we have a good biological rationale for using this in patients. Another agent of interest of course is targeting telomerase with imetelstat; we know telomerase expression is altered in these diseases. You've presented a lot of data at the ASH meeting with regard to that. What did you think was exciting?

Dr Mascarenhas: We had previously shown that imetelstat, a telomerase inhibitor, which was given to patients at 9.4 mg/kg was an effective drug in terms of what looked like a survival advantage. If you look at historical data that would suggest in patients after previous treatment failure there is about a 29 months or so overall survival advantage; that was very exciting. Then at ASH, we presented more of the correlatives, to demonstrate on-target engagement and pharmacodynamic effects that are associated with not just spleen and symptom benefit, but also survival benefit, as well as the fact that there seemed to be a statistically significant correlation between bone marrow fibrosis reduction and overall survival. It sort of tied in the whole story that the target was relevant, that we were hitting it with imetelstat, and that there did seem to be this survival benefit, which I'm excited to see how it rolls out in the phase 3 study, which is the only way to prove its efficacy.

Dr Harrison: I'm very excited about that study, too, because the endpoint is survival, which is of course important. We'll come back to it, but I like the idea of correlating benefits with fibrosis grade reduction, but let's come back at later in the conversation about endpoints. Another exciting, slightly different compound is one that may provide better inhibition, which we've had a bit of a checkered relationship with in myeloid malignancies. We've been looking at CPI-0610, which was developed initially as an area of interest with your team and Mount Sinai. That has been a comprehensive series of presentations with regards to data for this compound. What are your thoughts, Dr Mascarenhas?

Dr Mascarenhas: I think this is an exciting oral agent in contrast to imetelstat, which is given IV. It's not associated with significant toxicity in terms of myelosuppression. It can be delivered either alone or in combination with ruxolitinib as the MANIFEST study had 3 different arms, a monotherapy, and then an add on arm. I think the way the drug is being moved forward is probably the most exciting, which is changing the paradigm to upfront treatment, adding it to ruxolitinib in JAK inhibitor-naive patients, to see if we can improve upon spleen and symptom response. In my opinion, it is important to improve upon the durability of that response because we'd like to stop talking about ruxolitinib failure, or at least try to delay that time to onset.

Dr Harrison: I think it's super exciting that we're trying to look at these therapies in the JAK-naive setting. Interestingly, a lot of these agents also looked at patients with those higher molecular risk mutations and responses. Just getting back to that for imetelstat, just for a moment, I was intrigued by the fact that there seem to be a big benefit for so called triple-negative patients. Any thoughts on that?

Dr Mascarenhas: I don't know that we know why or whether triple negativity may be a surrogate for telomere biology that lends itself to the drug. I'm not quite clear, but it was striking that the triple-negative patients, as you know, they do poorly. In this study, imetelstat provided them promising benefits that seemed to be impressive; that'll be definitely an area along with high molecular risk mutations in the phase 3 study that we'll have to pay attention to.

Dr Harrison: Finally, again, a different target is the LSD1 inhibitor, IMG7289, or bomedemstat. This is an oral agent. Interestingly again, when you use it, you have to target therapeutic efficacy against thrombocytopenia. We've seen some results with this agent now in a couple of meetings, with more data presented at ASH. Fairly modest improvements in spleen volume, but definitely improvements in symptomatology. Some nice data with regards to molecular responses. No dose-limiting toxicity, because we know these patients are often frail, so that's quite reassuring. Then out of this data popped up a new gene that we might be interested in, BOD1L1, with relevance to myelofibrosis in particular; that's quite interesting. I think also interesting is the fact that both this agent, bomedemstat, and CPI-0610, will be taken forward to look at in patients with essential thrombocythemia, which is an orphan disease for which we haven't had any new therapies for a while. Any other kind of targets or therapies that you thought were interesting or you might want our listeners to hear about, Dr Mascarenhas?

Dr Mascarenhas: Yes. There were a number of drugs that were presented at ASH that had really good or at least compelling early clinical signals of activity like tagraxofusp, the therapy that's approved for BPDCN. That has also rationale in myelofibrosis as well as data using a PI3 kinase inhibitor in combination with ruxolitinib as a salvage therapy option; this will also be moving forward in both the phase 3 testing as upfront therapy in relapse refractory disease. Then previously we've saw nice data with the MDM2, inhibitor KRT-232, in which the P53 pathway seems like an important target to aim for in these chronic diseases. I think there's a lot of interesting data that still early that's moving forward, that we'll keep an eye on.

Dr Harrison: Certainly, as I was also struck by this idea of pegylated interferon plus ruxolitinib solution, certainly could be of interest because we know that targets patients with molecular burden, especially for those who are becoming resistant with blast progression, I think it may be a useful combination. Then I was very intrigued by this mouse model only data where they studied a calreticulin antibody; I think that's very interesting.

So, that was a fantastic discussion with loads of data to include. I think some of our key points were around identification of ruxolitinib resistance and intolerance. I think Dr Mascarenhas, you gave us a good kind of tip that you should look at your patient. What was the original aim of therapy? Remember that it can be multidimensional in terms of defining resistance or intolerance. Clearly maintaining kind of the maximum dose or maximum tolerated dose of ruxolitinib is important. We discussed different targets, other JAK inhibitors, some of which have different off-target effects such as ACVL1 or IRAK1. Also, the data with these novel targets was interesting; targeting apoptosis either through P53 or BCL-2 family proteins, the LSD1 inhibitors, and also lastly anti-telomerase agents. I think that was a great discussion. Thank you very much, indeed, Dr Mascarenhas, for giving us this time today. Thank you, our audience for participating in this activity. Please do continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.