Educated Patient® Webinar: Understanding Myeloproliferative Neoplasms (MPNs) and Treatment Options

Advocacy Groups | <b>MPN Research Foundation</b>

View the full CURE® Educated Patient® Webinar: Understanding Myeloproliferative Neoplasms (MPNs) and Treatment Options on demand.

Ryan McDonald: [00:00:00] Hello, everyone, and welcome to today's live broadcast, a "CURE Educated Patient Webinar: Understanding Myeloproliferative Neoplasms and Treatment Options." I'm Ryan McDonald, Associate Editorial Director of CURE Magazine. We are pleased to bring you this webcast presented by CURE and in partnership with Bristol Myers Squibb and MPN Research Foundation. There are a few important announcements before we begin. We encourage you to ask questions during the event, which you can submit by typing them in the Q&A box on your screen. You will be receiving a survey via email tomorrow. And as a thank you for watching the full webinar and completing the survey, you will be entered for a chance at winning a Visa gift card. And now, I would like to introduce you to those who will be leading today's discussion. We are pleased to be joined today by our moderator, Dr. Srdan Verstovsek, a professor in the Department of Leukemia, Chief of the Section for MPNs, and Director of the Hanns A. Pielenz Clinical Research Center for MPNs at The University of Texas MD Anderson Cancer Center. Joining Dr.-

Dr. Verstovsek: Hello.

Ryan McDonald: Verstovsek will be Dr. Aaron Gerds, an associate Professor of Medicine and Deputy Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute, as well as Medical Director of the Case Comprehensive Cancer Center Clinical Research Office; Dr. Prithviraj Bose, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center; and David Ricci, a board member of MPN Research Foundation. Thank you for joining us today, and I will now pass things off to our moderator to begin the discussion.

Dr. Verstovsek: Thank you, Ryan. And thank you, everybody, for joining us today. So thank you, Ryan. And thank you, everybody, for joining us today. I'm Srdan Verstovsek from Houston, Texas, and I'm really pleased to have opportunity for us four- and I will call on David, Aaron, and Prithvi, and myself being Serge [ph]- to enjoy discussion among us on the topic of myeloproliferative neoplasms because this is the topic close to our hearts. This is what we do in our life and what we care about. And I really appreciate everybody joining in today for this discussion and providing input through your questions. We're going to provide the answers to all the questions, possibly, that you will post while we discuss different aspects of management of patients with myeloproliferative neoplasms. So we're going to start with a short section, let's say a ten-minute section, on the signs and symptoms of myeloproliferative neoplasms. So Prithvi, let's start with you. Help us a little bit on the topic of what are some of the more common signs and symptoms of myeloproliferative neoplasms, understanding there are quite a few. It's not only one. These are neoplasms, so there are- I would say we should probably talk about three classic ones, essential thrombocythemia, ET; polycythemia vera, PV; and myelofibrosis, or MF. Please help us out here [00:03:00].

Dr. Bose: Yes, Serge. Absolutely. Thank you. So there's a number of symptoms. Unfortunately, they are somewhat common between the three classic MPNs, as you just outlined, being the most severe in myelofibrosis and less so in polycythemia vera and essential thrombocythemia. But to some extent, to varying extents, they are there in all three. Fatigue is probably the biggest one, and it's probably the most nonspecific one, as we all know, as so many different things can cause fatigue, but extremely common in all three of them, even in ET, something like 72%. Then there are a few others. There are some that you can relate to the spleen, for example, things like feeling full after a meal, what we term as early satiety, easily feeling full, or pain under the left ribs, abdominal pain in general. And then there are some that we label as cytokine-related symptoms, which are symptoms that we believe are due to some of these abnormal chemicals which are elevated in the bloodstream of patients with MPNs. And these can be things like itching, and fatigue, of course, like I mentioned earlier, bone pain, weight loss, night sweats, trouble concentrating, so quite a few things that may seem unrelated or pretty much diverse, but maybe tie together to be cytokines. And there's others, but one way of thinking about them is the spleen-related and the constitutional or cytokine-related.

Dr. Verstovsek: And for our participants, the patients, so these constitutional, cytokine-related, these are these chemicals in blood. They're part of the disease process. Maybe we can call this inflammation or inflammatory part of the disease. You have a proliferation of the cells in the bone marrow and the blood, although many patients with myelofibrosis have too few cells. That, we're going to discuss. But you have that inflammation that also is part of the disease and causing some of these problems. But there are also some symptoms related, particularly in ET and PV, to circulation problems. Too many cells in blood. Tell us about those.

Dr. Gerds: The one that we always tend to focus on more readily is the thrombosis risk or blood clot risk. And a lot of patients that I talk with in clinic are actually confused about even that term, blood clot. They think about, "Well, blood clots are only things that you get in your legs." But it could be blood clots in both veins and arteries, in the legs, in the lungs- that's called a pulmonary embolus- in the heart. The blood vessels in the heart, it would be a heart attack; blood vessels in the brain, it could cause a stroke. And then clots in the blood vessels of the liver can cause significant liver failure. So that's something we tease out and focus on in ET and PV in particular. In addition to that, we see a lot of these things that are- they've got a generic term, like microvascular disturbances, things like headaches, and vision changes, and tingles in the fingers and toes [00:06:00]. And those tend to be a little bit more common in PV and ET as well, especially in patients who have uncontrolled counts. So like Prithvi mentioned, we put symptoms into bins, like cytokine-related symptoms and spleen-related symptoms. You can also talk about vascular-related symptoms because, quite frankly, if you put them in bins, it helps you direct your therapy. If a person's got a lot of spleen symptoms, you want to go after the spleen. If you have a lot of cytokine-related symptoms, you want to go after those. If you have a lot of vascular type symptoms, you'd want to go after vascular type drugs to make those symptoms better.

Dr. Verstovsek: And to clarify for our participants, not all of this is seen to the same degree in all conditions. It's circulatory much more in ET, PV, but maybe in some patients with MF; the big spleen, much more in myelofibrosis; constitutional symptoms, what do you call it, like bone aches and pains, night sweating, low-grade fevers, itching, maybe in all of these diseases, but much more in myelofibrosis. But there are also some others that are perhaps more specific to myelofibrosis, like anemia, low blood cell count. Prithvi, what about this part? That's relatively unique to myelofibrosis. PV and ET patients have high counts.

Dr. Bose: Absolutely. Absolutely. So myeloproliferative, just in the name, we're alluding to the fact that counts are high, but the exception being that in MF, counts are often low, particularly the hemoglobin, as you mentioned, Serge, more than the platelets or the white count. And that'll bring its own share of problems, fatigue, maybe some dizziness, just low energy levels, low exercise tolerance, sometimes need for transfusions, so absolutely a major area, within myelofibrosis particularly, that demands attention.

Dr. Verstovsek: And I would say for myelofibrosis patients, we do see patients that lose weight a lot, cachexia. That is not really much of a characteristic of patients with ET and PV because myelofibrosis is much more aggressive, affecting the production of the cell. So some patients may present in myelofibrosis early on with high counts, but majority become, very quickly, in a matter of a couple of years, anemic, and may have a big spleen, and lose weight. And that is much more aggressive condition. So David, to get your perspective here, typically, when symptoms occur, they develop gradually. Really, nothing happens overnight. These are chronic conditions, particularly ET and PV. But in those instances when the symptoms do develop at a slow pace, how should patients interpret those symptoms if they just think they're tired or fatigued for other reasons? How should they recognize them or go about them?

Dr. Ricci: So I think in [00:09:00] all sorts of different ways. We talk to patients who went in for a routine physical and found out their spleen was enlarged, which, of course, then leads to questions, and further inquiry, and tests. The MPN Research Foundation, our primary mission is to raise funds to further the research among this wonderful community, including all three of the doctors here [INAUDIBLE]. And we're here to help patients. When they begin hearing about a possible MPN, the N, the neoplasm, cancer, can be quite disturbing. And educating yourself and finding out as much as you can about these is important. So if you go to our website,, and click on Understanding MPNs, there are [INAUDIBLE] of all three of these disease types we just talked about, including a list of all of the symptoms. And it'll also help you in talking to your doctor or to ask questions and help you further your own education and knowledge.

Dr. Verstovsek: This is a really good summary. And to clarify for everybody, so there are resources. MPN Foundation can actually provide help in identifying what the problem is, guiding patients how to go about communicating their problems or identifying them as the problems to the doctor because these are not specific symptoms after all. So it takes a little bit of thinking on the part of the patients to recognize, "They may be related to my blood or bone marrow condition." Now, you also pointed out this terminology of neoplasm and cancer. Why don't we put the things to the rest here? Aaron, tell us about this. What is it that we are talking about here? What are these neoplasms?

Dr. Gerds: Neoplasm is, of course, a big, fancy word, a Greek word, that we use to describe cancer. And quite simply, cancers are diseases where mutations have occurred in cells and leads to uncontrolled, unregulated growth of cells. And so by that definition, there are mutations that lead to the growth of these bone marrow cells in MPNs, whether we're talking PV, or ET, or myelofibrosis, and they're obviously out of control. We're talking about proliferation here of these cells. So by definition, it's a cancer and has been deemed so by the WHO. And often, this [00:12:00] term is misnomered or misidentified as a blood disease or myeloproliferative disorder, which, I think, doesn't do it justice to what it really can be, particularly for patients with very aggressive disease.

Dr. Verstovsek: So the spectrum of difficulty with this cancer is from benign, like in most people with ET and PV, not affecting life expectancy, or a little bit, and to be more aggressive, like myelofibrosis, that can affect the life expectancy quite a bit, right?

Dr. Gerds: Yep. It really seems like, Serge, there's a lot of analogies in medicine, other areas of cancer medicine. So you think about, in lymphoma, you have monoclonal B-cell lymphocytosis, which people can have their entire lives, it doesn't do anything; and then more indolent diseases, like CLL and follicular lymphoma; and then very aggressive diseases, like diffuse large B-cell lymphoma, that, if you don't treat it, you can pass away very quickly. So there's a whole spectrum. And the same with the MPNs; there's a wide range of what we can see with these diseases.

Dr. Verstovsek: Now, let's go, for a second, back to the symptoms. If the symptoms are present in the patients widely, to different extents, not as much or not as serious, but present in ET and PV- and the symptom, it can get worse over time. They do. The disease changes in the nature and becomes more symptomatic, and perhaps, the numbers are not controlled very well. New therapies are necessary. The spleen starts to grow, or the anemia develops in patients with myelofibrosis. How do symptoms play a role? Do they play a role in what the plan of action usually is when you discuss that with the patients? Prithvi, what's your take on the role of symptoms in decision-making?

Dr. Bose: I think I can think of two examples right away. One, Adam was alluding to these microvascular symptoms in ET and PV, which are really disturbances in the blood flow, sluggish blood flow causing tingling, or migraines, headaches, et cetera. And that's where I think about aspirin. Even twice-a-day aspirin can be very helpful in some patients with those symptoms, specifically. And then, of course, in myelofibrosis, as I was saying earlier, particularly myelofibrosis, also in PV or ET, there are these cytokine-mediated symptoms or the constitutional symptoms related to those chemicals that are overproduced. And that is where the class of drugs called JAK inhibitors really have their greatest impact, or more than any other drug class to date. So I think those are two examples where symptoms can truly tailor your therapy choice. Of course, there are other factors.

Dr. Verstovsek: So the type and the degree of symptoms are leading to proper choice of the drug for you. And just to say, the aspirin that you [00:15:00] said, that would be baby aspirin once or-

Dr. Bose: Yes.

Dr. Verstovsek: Twice a day, right? And David, what's your take on that?

Dr. Ricci: I wanted to ask a question because many of our patients can get confused, and there's this recent news in the media about the need for aspirin, and now, even the potential risk of baby aspirin. So I'm wondering if one of you can comment on baby aspirin for MPN patients.

Dr. Verstovsek: Yes. This is a really good question because I had, actually, questions from several patients that sent email and said, "Hey, I read in New York Times about this study that showed that people older than 60 may not need or should not even take the aspirin. There is some possible harm." But in the myeloproliferative neoplasms, ET and PV particularly, we are worried about the thrombotic risk, meaning a blood clot formation in the body of the patients, because there are too many cells. And they are not normal cells. They are abnormal. They are sticky. So the role of the aspirin is to decrease the stickiness between the cells and decrease, with that, the risk of blood clotting to a large degree, particularly in younger people, where we'd prescribe aspirin as the only therapy. We don't even worry much about blood count, platelet number, in younger people with ET, or we just utilize the aspirin and phlebotomy in younger people with PV. We don't really worry about anything else. So there is established, proven role of aspirin, baby aspirin, in affecting the characteristics of the disease and contributing to decreasing the risk of blood clotting formation. Really good. So we don't see a harm from it in ET and PV patients or myelofibrosis. Perhaps, there is some from that study in healthy people, but not in patients with MPN. So when we decide on treatment options- and I think we should probably talk about, then- as you now see, from my answer on the role of aspirin here, we should probably talk about the therapy for ET and PV and a therapy for myelofibrosis in a different way. So what are some of the first- and second-line treatment options available for patients with ET and PV? And why do we use them in some and not in others? Aaron, tell us about those because ET and PV are quite similar.

Dr. Gerds: So they are quite similar, but they have different sets of data to drive our treatment decisions, really. Again, we think about a couple of parameters for treatment or things that we want to keep in our minds when we're launching treatment for a patient with PV or ET. One is [00:18:00], what is their disease risk? Can we measure or approximate what is the likelihood of blood clot? Because that helps us decide, should we be reducing their counts or not, and with what method? So I think that's a key piece. The other key piece of treating patients with PV and ET is not making their disease worse. There are certainly some instances in history where we've used different medications in PV and ET, and it's actually made things worse, accelerated the progression to acute leukemia. Another tenant is thinking about the symptoms. So we spent the last 15 minutes talking about symptoms, and that's a really big part of it, too. A patient with, say, PV who just has elevated counts and feels otherwise perfectly normal is different than someone who has a big spleen and night sweats. And you may want to approach those patients a little bit differently, so taking a look at all those things, really, and putting that together to help drive your treatment decisions. Some subtleties between PV and ET is, in PV, we have prospective, randomized data to tell us a treatment goal. There was the prospective PROUD-PV study that showed- sorry, the CYTO-PV trial that showed that by keeping the hematocrit under 45%, we can reduce the risk of blood clot-related events, where in ET, similar studies don't exist. And so it's a little bit more gray area there for when we're thinking about treatment. Likewise, we've talked about aspirin. I think there's a little bit more clear data for aspirin use in PV versus ET, and that sometimes shows when you look at different, say, guidelines or treatment recommendations for each of these diseases.

Dr. Verstovsek: And so to talk a little bit more specifically about this hematocrit of 45%, I typically tell my patients, "Look, we take blood from you and fill it to the top of the bottle. That's 100% full bottle. And hematocrit will be percentage of that bottle that are red blood cells." That is the hematocrit. So the goal of therapy is to maintain it below 45% in PV. You can do this by phlebotomy. And of course, you can give patients aspirin, baby aspirin, as we said, to decrease the stickiness. That will be for all. But then for many, you also need to give them some medication to decrease the white cells, or platelets, and perhaps eliminate need for phlebotomy completely. This is called cytoreduction therapy, the therapy that would normalize the blood cell count, basically. And that is for older people or those that had a history of blood clot. In ET, it's somewhat similar, right, Prithvi?

Dr. Bose: Well, yes, it is, in the sense that your goal is the same. You're trying to reduce the risk of blood clots. And one thing- I should maybe preface that by saying that the question comes up, "Well, why not focus on survival?" And that is [00:21:00] because of two things. One, survival is relatively good in PV and ET compared to myelofibrosis, it's way better. It's in fact close to normal in a lot of patients, particularly with ET, younger patients for sure. And then we don't really have drugs that are proven to change the biology or the trajectory of PV and ET and prevent complications like myelofibrosis or AML, which is why we focus on what we know we can modify, which is the thrombotic risk, risk of blood clots. As Srdan was saying, that is the unifying theme in treating PV and ET because blood clots can be a cause of significant complications and even death, so we're trying to reduce those, but like Aaron said, in PV, we have a more well established numerical goal, which is the less than 45% on the hematocrit, that is a bit nebulous in ET. We don't have a platelet number below which we must keep the patient, rather we go by things like have they had a clot in the past, do they have a JAK2 mutation, how old they are, and we try to give - assign their blood clotting risk and treat according.

Dr. Verstovsek: Very good summary, thank you very much for that. Now moving on to myelofibrosis, and Aaron, you were actually in charge of the national guidelines of - and you did really well in updating continuously with all the colleagues involved, Prithvi is a part of the committee as well, I know that we are up to date on the guidelines, what to do. Moving to myelofibrosis, what are the therapies, risk and benefits of the therapies that are currently approved therapies for myelofibrosis?

Dr. Gerds: Thanks, Srdan. Credit to the committee, my job is mostly to the herd the cats, but - and get everyone's opinion included. But it's - I think the guidelines for a while were pretty straightforward. There was no drugs and then one drug, now we have two drugs, and in the near future we're probably going to have more drugs. It's going to get really complicated very quick, so I'm kind of developing a small ulcer over that one. But really, as we've kind of discussed, quite simply we think about kind of two intersections. One is disease risk, of course. Primarily patients with high risk myelofibrosis who are young and fit, we might shuttle towards transplant sooner rather than later, I think that's a big piece of what the guidelines are trying to explain. The other thing is when to use JAK inhibitors. That's the major hammer we have in our toolbox right now, and so when do we apply those? And really it's kind of two veins, patients who are high risk, they have kind of disease where their risk may be improved by that, so if you think about the comfort studies that you led, [00:24:00] Srdan, the types of patients that were included in those studies, but really across the disease risk, symptoms. Symptoms are key, and I think we spent 15 minutes talking about that before and it's so important because symptoms really are driving your treatment decisions for the vast majority of patients with myelofibrosis, and especially when you're thinking about starting a JAK inhibitor. Other agents that we kind of focus on in the guidelines are drugs that can improve anemia. It's kind of a - it's so common in myelofibrosis. Well over half a percent - half of patients will present with anemia or develop it within the first year, and so we wanted to spend an entire page focused on things you can do for anemia, whether we're talking about erythropoiesis stimulating agents, newer agents like luspatercept, older agents like the IMIDs, such as lenalidomide and thalidomide, as well as other older drugs like danazol, and how you might think about those different drugs to improve a patient's anemia, particularly if they're on other medications that may interact with those. Lastly, we try to give some guidance on initiating JAK inhibitors with mind to platelet counts. One of the major downsides, as you mentioned, we should cover here is blood count suppression. JAK - the JAK inhibitors we have available, ruxolitinib, fedratinib, are associated with worsening of the blood counts, particularly if you're already starting out with low blood counts, they may become lower or dangerously low. Someone who's transfusion independent may become transfusion dependent on these drugs, and so we want to be mindful of that too and adjust before we start treatment. Really those are the main areas of guidance that we try to put into those guidelines.

Dr. Verstovsek: Quite the elaborate guidance, actually, because there are patients with different characteristics, and if I understood, the first question would be what is the risk of dying? That's the risk that we are talking about, and if it's short, and we usually say less than five years, that patient should seek possibly transplant. And then you look at the symptoms, they may be general systemic symptoms that we discuss, they may be symptoms related to the spleen, and then you look at the anemia. These are usually the three problems in JAK inhibitors, ruxolitinib and fedratinib are approved therapies for these patients as long as they don't have platelets below 50 because they suppress the blood cell count. They are good for the spleen and symptoms, but they're not good for anemia. You mentioned a lot about the anemia drugs that can possibly then be combined with those JAK inhibitors. Let's talk a little bit, David, can I ask you a question? Is it, and if it is, why is it important for patients to seek institutions that are well versed in treating NPNs [ph]? What's your take, is it important to seek institutions that are - that have expertise, and why is that?

Dr. Ricci: If at all possible, absolutely, yes. I think just listening to this conversation, [00:27:00] it is overwhelming, and we know of patients who have evolved from ET to PV to MF, so it's not like you're just in one of these three disease states. And the people at the major academic institutions see more patients, they're involved in more research, they have access to more clinical trials, so if it is at all possible to get on the airplane or make that three or four hour drive to go to a major institution, such as the ones that all three of you represent, you're going to have better care, we believe, and you're probably going to get better answers to your questions. And I will mention, on the - on our website, the, under the living with tab, there's a ten step checklist under just diagnosed for patients to be able to look at, and one of these steps is help in finding a specialist, and this would be - tell some ideas in exactly how to do that.

Dr. Verstovsek: Patients -

Dr. Bose: Just to add to that, there are about five people living with myelofibrosis per 100,000 US population, and for ET and PV it's around 50. This is the prevalence, as we call it. You can see right there that these are rare diseases, so I think some of it comes - some of what you just said, David, comes right from that, that unless you focus on these diseases, it might be a little harder to develop that comfort level.

Dr. Verstovsek: It is fair to say that one should seek a team, perhaps a local doctor and then the expert in the academic center with expertise, and of course be educated on his or her own through the help of a NPN Foundation here, in large part, but to become involved and to know what is happening and why and be able to discuss the goals of the cares and the therapies that are being used and for what purpose, I think that's fair to say. For myelofibrosis, if you go on to talk about therapies for myelofibrosis in much more detail, we have the spleen and the symptoms and we have JAK inhibitors. How does the dosage or management of JAK inhibitors in every practice for reducing the spleen and improving symptoms works out? What do you look for? Maybe Prithvi, you can tell us, what do you do here about the JAK inhibitors, dosing, and how do you go about it?

Dr. Bose: Sure, Srdan. I think it's particularly relevant to ruxolitinib, between the two approved agents, [00:30:00] the rux and fedratinib, I think the dosing question is perhaps more relevant to rux, which is the one we've had for a decade now, so we've gotten comfortable with it and learned how to use it. With rux, I think something we've learned is that it's really important to sort of push the dose, optimize the dose, try and get patients up to a higher dose in the range of 15 to 20 milligram twice a day to get that optimal spleen reduction, because that really translates to a benefit in survival. That's been shown, you've shown that, Srdan, and others have shown that. And that is really important, but it's easier said than done because it causes cytopenias, as Aaron was alluding to earlier, and what do you do about that? Patients are going to get anemic when you try to push the dose, so you have to develop maybe alternative dosing strategies, some - there is some evidence, for example, for doing ten milligram twice a day for three months and then trying to go up as tolerated, and also something we do a lot is we add other agents to support the low blood counts, particularly hemoglobin, sometimes platelets as well, to try and give the patient that optimal dose which we believe will do more for their spleen and really ultimately have an effect on survival. And with symptoms, it may be a little less important, ten milligram twice a day may suffice, everyone is different, though. But generally, ten milligram twice a day may suffice. But with fedratinib, from what we know so far, 400 a day seems to be the dose across the range of platelets. I should provide the background that with rux, we dose generally based on the platelet count, and that is not necessarily the case with fedratinib thus far.

Dr. Verstovsek: There are other side effects that are possible. They both lower the blood cell count, appears to be to the same degree. The dosing appears to be little bit different. I don't - we have some GI toxicity and some other maybe [INAUDIBLE] but important to say side effects on fedratinib and perhaps some side effects on the part of ruxolitinib after patients are on it for five or ten years, like a non-melanoma skin cancer, for example, or a typical infection. Tell us little bit about these differences.

Dr. Gerds: Immediately, you hit the nail on the head there. For fedratinib, we often think about the GI side effects. There are some - what we call off target effect on a molecule called FLT3 and that drug is a class - any drug that hits that molecule tends to cause GI toxicity, meaning diarrhea and nausea, and so often we have to deal with that early on. And [00:33:00] the other thing in addition to lowering blood counts that we can see over time is like you mentioned, increased risk of non-melanoma skin cancer. Someone who's had a lot of sun damage or sun exposure over their lifetime, if they don't have a dermatologist, may want to get them connected with a dermatologist so they can frequently get skin checks. Additionally, there's an increased risk with developing viral reactivations. Most commonly we talk about shingles being a viral reactivation, but there are also case reports of hepatitis reactivating in the study in ruxolitinib as well as a couple of cases of tuberculosis, which isn't a virus, but tuberculosis reactivating in - or becoming worse in the setting of this. Those things were previously undiagnosed in those patients. We kind of want to be mindful of that before we start ruxolitinib, is there something that could creep up on us there?

Dr. Verstovsek: I think it's important to discuss those issues, but on the other hand, the GI toxicity of fedratinib, which may be present maybe in two thirds of the patients, this is usually not interfering with the delivery of the drug, you can give them anti-nausea or anti-diarrhea medications, and people will adjust and tolerate the fedratinib and it will work. And then there was this possibility, distant possibility, of a central nervous system toxicity called encephalopathy which really is a remote possibility, but one needs to mention because patients should have a timing what - when we want level check the - to make sure it's normal because the efficiency of that vitamin can cause this issue of central nervous system toxicity. I actually give my patients advice to take thiamine while on fedratinib, why not? And that skin search or skin survey that you mentioned later on in the course of therapy with the ruxolitinib is important as well, something novel that is coming around here. But -

Dr. Ricci: Srdan -

Dr. Verstovsek: Yes?

Dr. Ricci: But the single biggest question we get from MF patients is when do I consider a transplant, and I know there's no easy answer to that, but I know that is a question on patients' minds if someone wants to opine on that.

Dr. Verstovsek: We can do this two ways. We can say what is the guideline, and let's start with Aaron, and then we will say later on what actually happens.

Dr. Gerds: I think the guidelines say consider it in anyone with high risk disease. Srdan pointed out astutely that no matter what model you look at to determine prognosis or predicted or estimated survival, that five year mark is kind of the magic number, if it's - predicted survival [00:36:00] is less than five years, you would consider funneling folks towards transplant. But that's not what we necessarily do either, and our daily practice is a little bit different, and we - I know we've talked about this before on other calls, Srdan, where there's never a time that's too early to discuss things with a transplanter. It's always good to get connected with a transplanter and at least get HLA typing or plugged in the system, if you will, and have that in your back pocket. It's almost better to have that and never use it than wish you would have had it and done already.

Dr. Verstovsek: That's a very good point because disease does change over time, despite the therapies for control of the spleen and symptoms or those therapies that Aaron briefly discussed for anemia, things do worsen, and there is a loss of control of the sinus symptoms. And Prithvi, really, let's talk about this, what is the benefit in terms of the durability of that benefit and how do we go about the patients that have a toxicity or show signs of a progression? What else can we do? One is to send the patients to the transplant sooner rather than later, not to wait for people to lose the benefit, do the transplant when you feel the best on the therapy that you have. We all endorse on that, but patients that feel so good on therapies, they don't want to do that. They usually wait for a signs of a loss of a control. I think that's more regularly what I see with my patients. Prithvi, what's your take on that loss of response, timing of the transplant? How do you manage that?

Dr. Bose: No, absolutely, Srdan, it is hard for patients to agree to go to transplant, which is a procedure with a significant risk, even in the best hands, when they're feeling so good. While the data suggests that you should go to transplant when you are in optimal response, that is practically sometimes hard to do. But again, some patients are motivated enough to do that, but it is difficult, and some are not, and eventually people will progress. With ruxolitinib, for example, we generally say that the average duration of it working, quote unquote, is around three years, and this can vary in studies, but somewhere in that ballpark. You start to see progression of the disease, which can take many forms. The spleen could enlarge, the white count could go up, blasts could go up, hemoglobin could go down, platelets could go down, so all of these, progression can take all of these forms. And that is where we need new drugs, where the second line drugs come in. Fedratinib is a welcome addition, the last - in the last two years. It's given us at least an option in patients [00:39:00] who failed ruxolitinib. But then also we're looking ahead to these newer JAK inhibitors, which may be more - easier to use in patients with falling counts. As we look ahead to the possible approvals of pacritinib and momelotinib, we hope that patients who are getting more cytopenic as the disease progresses will have some additional options. And then there are of course many others, we are in an unprecedented era in NPN. It feels like AML felt a few years ago. There's nine or ten phase three trials, there's lots of new agents which are very promising which are being developed in this failure setting.

Dr. Verstovsek: This is really good, very concise summary. No patient is the same patient, right? We have therapies that have helped with the symptoms and the spleen, there are patients that benefit to great degree, some don't benefit that much, so kind of a in between, sub-optimal response. We try to optimize the care by adjusting the dose, the dose needs to perhaps sometimes even be lowered because of anemia or thrombocytopenia, disease can change over time and spleen can start to grow, or blast baby cells in the blood can start to increase and there is risk for progression to acute myeloid leukemia or anemia worsens, and durability of the benefit has limits. We usually say these are really good therapies, but they don't last forever. And for some patients, like patients with low platelets, below 50, new therapies are necessary. Prithvi mentioned pacritinib, that's one of the new JAK inhibitors that is not suppressing counts much in - possibly can be given with patients low platelets. And momelotinib was mentioned, that's a JAK inhibitor that could possibly have additional benefits in improving the anemia and might be very useful in patients that are losing response to current JAK inhibitors and develop anemia and have bad symptoms. These are on the forefront on what we expect possibly to be approved in very near future. But how can patients look for clinical trials that are actively recruiting patients, and how can they work with their care team, local care team, to see if they are candidates? How do we go about that? Aaron, what's your take on that?

Dr. Gerds: There's a lot of online resources of course to look for clinical trials, everything from just Googling clinical trials to curated websites, like A lot of hospitals will list their clinical trials as well, so the Case Comprehensive Cancer Cert, for which I'm part of, we list all of our clinical trials that are available for patients on our website, as do many cancer centers. If you are in the area of a large, certainly NCIA designated cancer center, they will generally post them online, you could look there. Places like the NPN Research Foundation and their website have - lists trials, NPN Advocacy [00:42:00] and other advocacy groups list the trials on their website too, as well as a lot of patients, I find, find it on Facebook, or now what is called Meta, the family of social media platforms. There's a lot of closed groups and open groups for these diseases on social media platforms, and I find a lot of patients hear about trials through that - through those connections.

Dr. Verstovsek: And David, what information does the MPN Research Foundation have for patients like this that are particularly interested in clinical trials?

Dr. Ricci: I'm glad that Aaron mentioned that because if you go to the website,, it's kind of long, which is why [INAUDIBLE] living with tab, there is a listing for MPN clinical trials, and it's fairly comprehensive of all of the trials that are available and open today, listed by disease type, ET, PV, MF, and it is a brief summary of who this trial is for, which would give you some sense as a patient whether or not you would qualify based on what you know about your current disease. And then you can click on the drug and it'll take you to the website that Aaron mentioned and it will provide much, much more detail, including the list of centers who might be participating to see if there's one that's relatively close to where you live.

Dr. Verstovsek: That's very good. Looking ahead, what are some things that are on the horizon that patients and their loved ones should keep an eye on, I would say particularly in the ballpark of new therapies? And perhaps we can first discuss therapies for ET and PV. Prithvi, give us a little summary on the what's going on with new drugs for ET and PV.

Dr. Bose: Sure. Like I said earlier, there's about ten phase three trials that I can think of right now in our field, just between ET, PV and myelofibrosis, and just for our audience, a phase three trial is generally a trial that would - that is - that will hopefully lead to FDA approval where you're comparing a new drug to a standard therapy. For ET and PV, I would say that after many slow years, shall we say, now we are having some excitement in that area, with several new agents looking good. In ET, there is a trial of a drug called ropeginterferon alfa-2b. It's a bit of a mouthful, trade name is Besremi in Europe. And in Europe, it is [00:45:00] licensed for PV, but in the US currently, it's being studied in a phase three trial for ET, which is really exciting. In the second line they're comparing it to anagrelide, so as the name suggests, ropeg is a form of interferon and will be really a paradigm shift in the way we treat it, if it were to get approved. Obviously depends on what the approval of it might be when it makes it in the US and we - and this is something that could work in both PV and ET. Like I said, it's already approved in PV in Europe. And then also in PV, there is a drug called rusfertide, which is, again, a very clever mechanism. It's what we call a hepcidin mimetic. Essentially deprives the bone marrow of iron. It stores the - it works on the body in a way that the iron gets trapped elsewhere and is not available to the bone marrow to make red blood cells. And so that's a really neat and clever mechanism and very nice results in the phase two, that's going into a phase three trial in PV. And then in ET as well, although this is early, there are some other therapies which are in earlier phases, like phases one and two, and there I think the data is too early at this point to really comment on how exciting they are. But it's good to see that there is movement in ET and interest in looking at new therapies like LSD1 inhibitors, BET inhibitors. These are being looked at in ET as well, but again, as a cautionary note, much earlier in development than say things like ropeg that I just talked about.

Dr. Verstovsek: And the myelofibrosis, the backbone of what we do, as we discussed, are JAK inhibitors. We control the spleen and symptoms, maybe use one after the other. We have a problem with anemia, we have a problem with the patient with low platelets, we talk about pacritinib already, but there is a drug that is being developed as quote unquote anemia drug, and then there are other drugs that are being combined with the JAK inhibitors to enhance what the JAK inhibitors should be doing, or after JAK inhibitors. I think we have areas here for different patient populations. Aaron, give us little breakdown on maybe focused on phase three studies in myelofibrosis.

Dr. Gerds: In myelofibrosis, I think there's kind of a couple of - you almost think about a two by two table for all the trials. On the one hand, you have front line therapies and then therapies after JAK inhibitors have already been used to a certain degree. And then on the other angle, you'll have new JAK inhibitors and then additional therapies, so in the new JAK inhibitors, we've already mentioned these drugs like pacritinib, that is being tested right now in a randomized phase three trial. It - for patients with very low platelet counts, platelet counts less than 50,000. Momelotinib being tested in patients with anemia, [00:48:00] transfusion dependent anemia in particular. And then where the pacritinib too is almost entirely front line in the PACIFICA trial, patients who haven't really had much JAK inhibitor before, and then momelotinib is kind of both, but mostly patients who have had some JAK inhibitor exposure. But really the - I think a lot of the excitement now too is in these combination therapies in myelofibrosis, both in the front line and in patients who have previously had a JAK inhibitor. As Prithvi mentioned, there are a number of phase three trials that are ongoing that are going to answer these really big questions. For example, is giving a BET inhibitor with ruxolitinib in front line setting better than ruxolitinib alone? Are we going to get more spleen responses, more symptom responses, and do something beyond what ruxolitinib can do to the disease? This whole mythic quest for disease modification, if you will. There are other drugs being developed like navitoclax, both in the front line and in patients who JAK inhibitors aren't doing very well for them. Other - outside the combinations with JAK inhibitors, there are other drugs like intellistat [ph], the telomerase inhibitor, which is going about treatment in a totally different fashion, different than any other drug that we have on the market as well, trying to improve the survival and really create deep responses in patients with myelofibrosis. Really the exciting part is we're attacking this disease from all different angles, not just hitting this JAK/STAT pathway, but all the other additional pathways that are activated in these cells, trying to really get a strong edge on the disease.

Dr. Verstovsek: Looks like the disease is biologically very complex. There is a lot to even learn much more, and that leads to implementation of different therapies. JAK inhibitors inhibit underlying uniform abnormality in all the patients, which is the activation of the cascade of proteins inside the cells in the bone marrow that leads to their growth and also that inflammation that we talk about it, this highway, as my patients call it, called JAK/STAT highway or pathway, inside the cells, and this is what the JAK inhibitors do. They inhibit that highway and make cells grow less, and inflammation decreases, so the spleen decreases. It can lower the blood cell count, right? Maybe not to all, but majority. And it does improve quality of life because of this anti-inflammatory benefit. And now you have other drugs targeting many other areas of the abnormal biology of the disease. And we have one question here from the audience which goes to the very beginning of what happens when you are newly diagnosed? Question is I was recently diagnosed with MPN. Unfortunately, I don't know which one, but MPN. What are some [00:51:00] of the questions I should ask my provider? That's the first visit, the patient is newly diagnosed. Prithvi, what would you suggest the patients to ask?

Dr. Bose: Certainly in the absence of information on which MPN, and perhaps the person asking the question is not yet clear on that, I think the natural history's very important to understand. PV and ET are far more indolent than myelofibrosis, so obviously with any malignancy, one is - the first question that pops into one's head is about natural history and what to expect and life expectancy, which is - which can be vastly different between these conditions, as we've been saying, and also what's the goal of therapy? What are we trying to achieve here? Somebody could be overtly symptomatic and somebody could be completely asymptomatic, and I think the goals of therapy will differ what the drugs can do, what are the different classes available, do I need a transplant, all these things are going to really depend on each individual scenario.

Dr. Verstovsek: We would say make sure that the diagnosis is correct, right? We don't even know in the question which one it is. Then you would say prognosis, what are we talking about? Is it a prognosis to decrease the thrombotic risk, like in ET and PV, or is it prognosis on the survival, like in myelofibrosis, then what are the goals of the therapy? That will determine what is the next step. And so in this aspect of the prognostication, perhaps, what role do genetic mutations such as, for example, TET2 mutation, play in MPN? Where do we stand with the significance of these other mutations? Because we usually talk about the JAK2 mutation, CALR [INAUDIBLE] mutation, or MPL mutations. These are the three ones that are usually present independent of each other and activated JAK/STAT highway, JAK2 mutation, CALR [INAUDIBLE] mutation, or MPL. Tough names, I know, but these are the three we usually test for. Some test for more. Why? Aaron, what's the significance of these other ones, like TET2?

Dr. Gerds: As we mentioned, this disease is complex. It's not just one mutation leading to this disease and you can target that mutation, it's all over, but these other mutations are important for understanding prognosis, and we know that certain mutations, when present, can predict for a more aggressive disease, things like P53 or ASXL1. Other ones may provide targets. We're starting to develop targeted therapies and there's an ongoing trial with an IDH2 inhibitor in patients with myelofibrosis. I think that's also an important thought. There's also increasing work showing that just the sheer number of mutations that we can detect too is prognostic in and of itself. [00:54:00] I - in kind of circling back to diagnosis too, again, looking for these mutations, whether we're talking about JAK, STAT, or other mutations, establishes clonality, that this truly is a malignancy, and can aid in diagnosis, first and foremost. And so I think for all those reasons, it makes sense to do these multi-gene panels, looking at the different mutations that might be in the disease.

Dr. Verstovsek: And they may particularly useful, not only at the beginning, to assess the prognosis and maybe sometimes guide to therapy, but also at the time of a change, if there is a loss of response to JAK inhibitors or a sign of progression to acute leukemia, you want to know whether there is something new or different. And some of these mutations can lead to specific therapies, like you said, you have a mutation in gene called IDH1 or IDH2, there are pills that you can prescribe. Now, disease can change from one to the other. That's interesting topic. We know that ET or PV patients, but not too many of them, can go to myelofibrosis, and they all can go to acute myeloid leukemia. I have also seen patients that go from ET to PV, like high platelets and then over time they have high red blood cells at the same time. It's not fixed forever. How can we address that in a simple way for the patients? That's one of the questions. Why does this happen? Prithvi, what do you think?

Dr. Bose: That's a tough question, Srdan, but of course we all know that this can happen and does happen, these diseases do transform into each other. ET goes to PV and of course they both go to MF and unfortunately, sometimes, to AML. But I like to think of them as a continuum. It is sort of the same type of molecular abnormalities, perhaps to varying extents, that are leading to these diseases. We are learning now, for example, that one can acquire the JAK2 mutation even in utero, like before birth or as a child, and then it shows up way later. And then somebody asked about the TET2. TET2 and such other epigenetic mutations sort of lay the ground for the JAK2, CALR and MPL to arrive later and drive the disease. It's complicated, but I think overall, they are probably all on a continuum, although there are some who disagree with that. But I think the general feeling in the field is that there's a lot of relatedness between the two. It's the same molecular drivers to greater or lesser extent, and that is why you sometimes see these phenotypic shifts, as we call them, as people go through the disease.

Dr. Verstovsek: But it's important to say that the presence, to complement what you really summarized well, the presence of the JAK2 mutation on its own does not mean a disease. That's very important, [00:57:00] that the genetic testing on its own does not mean the patient has the disease. If we talk about CHIP, what is CHIP, Aaron?

Dr. Gerds: CHIP is clonal hematopoiesis of indeterminate potential, or prognosis, some people say. It's basically we've identified a mutation in the bloodstream or in the blood cells of a patient who doesn't have an abnormal blood count, or - and I think that's the key there, abnormal blood counts. And when we look in the bone marrow of these folks, their bone marrows look normal as well. And run in this many times, patients say would have a high red cell count or hematocrits or hemoglobin, and we're thinking maybe polycythemia vera, and we check for mutations and we find a mutation at a really, really tiny level. But then they also have sleep apnea or are smokers and have other reasons for an elevated hematocrit, and then you're kind of battling yourself, is this truly polycythemia vera? Or is this just CHIP with secondary erythrocytosis? It can sometimes get very, very tricky for patients. But CHIP is this entity that was identified in large studies of sequencing lots of different people's bloods and is - can be a precursor to blood cancers. In fact, the risk of developing a blood cancer is about 1% per year if you have this CHIP thing.

Dr. Verstovsek: Very nice new development in the field, I don't think that too many patients understand that. It is something maybe a little bit difficult to explain, but people - older people walk around with mutations, not just JAK2 mutations, without disease. They may not, and almost a great majority will not develop any problem at all. It just something that happens through life. And let's do one more question here. What types of lifestyle or dietary changes should I make to help me both during and after treatment? That's really good, what the patients can do with the lifestyle changes and dietary changes. Prithvi, what do you think?

Dr. Bose: We don't have concrete data on this, but again, our colleagues [INAUDIBLE] and Robyn Scherber have done a lot of good work on this. Anti-inflammatory diets of various kinds, there is some general value to them. Yoga also has been looked at it and is beneficial. But I don't think we have concrete recommendations around this.

Dr. Ricci: One of my favorite sections on our website is patient stories. There are over 80 specific people with - often with their pictures, telling their stories, and you can read about what changes other patients have made. Now, as Prithvi pointed out, there's not hard data, but there's [01:00:00] a lot of data coming out of the benefits of diet and exercise and many, many people in these stories will tell you what changes they've made to help them deal with their own situation, and may not apply to everyone, but it helped someone. And so I think they're worth reading about.

Dr. Bose: Absolutely.

Dr. Verstovsek: This is a really good point. We are running out of time, so let's just hear from each of you perhaps a little bit more on the overall feeling of where we are heading and what's happening in MPN field, starting with Aaron. Give us your final thoughts, please.

Dr. Gerds: Thank you so much, thank you Srdan and Prithvi and David, this has been a great discussion. And thank you everyone in the audience for joining in. And I think the point I would like to make is it's a very exciting time for those of us who take care of patients with MPN. There is so much research going on under - to understand the disease, there are so many new treatments, and so the call that David made earlier to connect with someone who's in the field who kind of keeps up with what's going on in MPNs is so key because it's moving really fast right now. And I think it can be kind of hard to miss, kind of like Ferris Bueller said, "Life moves pretty fast. If you don't stop every once in a while, you might miss it." I really think that's what's happening for MPNs right now.

Dr. Verstovsek: That's really nice summary, thank you, Aaron. Prithvi, from you?

Dr. Bose: No, absolutely, I'll just echo our NCCN Chairman's thoughts here. His job is going to get harder with all the new drugs with where to position them in the guidelines. But this is a very exciting time. I've been a practicing hematologist now a little over 11 years, but these last couple of years in MPN, just it's an explosion of new therapies. There's so much more understanding of the biologic underpinnings, the pathways that matter. There's a lot of pharmaceutical company investment in research in the field, and I think that it's a very exciting future. I think as a drug developer, that's extremely satisfying.

Dr. Verstovsek: And David, from your perspective in the MPN Research Foundation?

Dr. Ricci: The foundation was founded in 1999 by Bob Rosen, who was a recently diagnosed PV patient, and there wasn't a lot back then. We have since put - funded [INAUDIBLE] million dollars, and there's so much more to be done, but I can tell you, because I joined the board in 2000. And we had to beg people to take our money to do some research. [01:03:00] There just - it was hard to find scientists and clinicians back then because it was - there was no iPhones, there was early days of the internet, and if you fast forward to today and the field has exploded. The number of researchers who are involved and the commitment of this group in working together and collaborating, just as evidenced by the fact that these three fine doctors are here tonight sharing their thoughts, and hopefully we're getting closer and closer, as is evidenced by all the drugs that are currently in trials.

Dr. Verstovsek: Thank you very much, David, and thank you Aaron and Prithvi. Unfortunately we are out of time. For our patients, if you would like to watch this webinar again, it will be available on the Webinars-On-Demand page of within the coming days. I want to thank our panelists and the audience for attending and participating in today’s event. I would also like to thank CURE and our partners, Bristol Myers Squibb and MPN Research Foundation, for making today’s educational webcast possible. Don’t forget to check your email tomorrow for the survey to be entered to win a gift card. Thanks to all for joining, we’ll see you next time. Good-bye and have a nice evening.