Watch our Myeloproliferative Neoplasms Webinar where an expert panel discussed topics highly relevant to patients, caregivers and advocates right now.
Topics for discussion included:
MS. KRISTIE KAHL:Hi, everyone.Welcome to today's live broadcast, a CURE Educated Patient Webinar in myeloproliferative neoplasms.I'm Kristie Kahl, Editorial Director of CURE Magazine.We're pleased to bring you this webcast presented by CURE and in partnership with BMS.
We have a few important announcements before we begin.We encourage you to ask questions during the event, which you can submit by typing them into the Q&A box.You will be receiving a survey via email tomorrow.As a thank you for watching the full webinar and completing our survey, you'll be entered to win one of three Visa gift cards.
We are pleased to be joined today by our moderator, Ruben Mesa, Director of Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center; Andrew Kuykendall, Assistant Member of the Department of Malignant Hematology, Moffitt Cancer Center; and Naveen Pemmaraju, Department of Leukemia, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center.Thank you all for joining us today, and I'll now pass it off to our moderator, Dr. Ruben Mesa.
RUBEN MESA, MD:Wonderful.Well, thank you so much, and very excited to be here today, particularly with my very good friends Naveen and Andrew, and for us to have a very open discussion regarding myeloproliferative neoplasms.A lot of things going on, how we assess the disease, potential new therapies, and even some lessons we've learned along the way about how to communicate with your healthcare team, what it's like to be a patient, and some other parts.
Then we're going to have some time for Q&A at the end, so certainly you can be kind of weaving those questions in.You could submit them at any time.If they're relevant we may tackle them kind of as they come in, or somewhat at the end.Before we start the discussion, why don't we have each of my friends introduce themselves a little further in terms of what their MPN practice looks like at their institution.Every institution is just a little bit different, and I thought that might be helpful.Andrew, why don't you kick us off?
ANDREW T. KUYKENDALL, MD:Yeah, so I'm Andrew Kuykendall.I'm at Moffitt Cancer Center in Tampa, Florida.At Moffitt we are a little bit different than Mays and MD Anderson in certain ways, but we're a comprehensive cancer center in Tampa, and we have a very specialized group of physicians that see malignant hematology patients, and I specifically focus on myeloproliferative neoplasm patients, so that's the majority of my practice.
I would say 80-90% of the patients that I see have some sort of an MPN, and by that I mean myelofibrosis, essential thrombocytopenia, polycythemia vera, and I do see patients with eosinophilic disorders and systemic mastocytosis as well.So, it's very specialized in that group.Obviously, we have a close-knit group, and I see other myeloid neoplasms as well, and we're very focused on running clinical trials and working with translational research, and also collaborating with our colleagues across the United States and outside the United States as well.
DR. MESA:Wonderful.Very helpful.Naveen?
NAVEEN PEMMARAJU, MD:Ruben, thank you so much.So great to see you, and thanks for having me here for this important venue.So, I'm Naveen Pemmaraju, Associate Professor of Leukemia here at MD Anderson in Houston.I believe that it's really an honor to take care of patients with super-rare or ultra-rare diseases; as you know, my career passion and focus.So, in addition to taking care of patients with myeloproliferative neoplasms, I also take care of patients with acute leukemias, and a very rare type of leukemia called BPDCN.
From my clinical trials focus, I really have become interested in novel agents beyond the traditional JAK inhibitors that are approved and available both as single agents and combining them.So, as you and Andrew know, we have multiple clinical trials for patients there, and we have a team approach here at MD Anderson led by our team leader Dr. Serg Verstovsek.And the last thing I would add is we work very closely with our stem cell transplant colleagues, Dr. Ude Pulpod [phonetic] in particular here at Anderson.
So, I think moving forward we have the chance and ability to offer patients clinical trials, stem cell transplant, novel therapies, and a focus on rare subtypes for our patients out there.Ruben?
DR. MESA:Wonderful.And I'm at the Mays Cancer Center at UT Health San Antonio, so we're part of the University of Texas, and we're a cancer center within a kind of comprehensive healthcare university.It also has things like cardiology, orthopedic surgery, et cetera.But I oversee all the efforts related to cancer, and Moffitt and MD Anderson being two of the world's finest comprehensive cancer centers, cancer is all they do.
Now, I think it's helpful as we kick of the conversation, sometimes it's a little confusing for folks as to what sort of doctors see what.So, if you look at Naveen, Andrew, and I, we are very subspecialized physicians, meaning we have research focus in a fairly narrow area, and a little bit different between the three of us, but basically the same.
But we might see patients in a little broader area, but again of related disorders that are very similar to MPNs, if not MPNs.MPN specialists, many of whom you might have heard of that are good friends of ours, again, a group of individuals, but probably under 50 in the United States that that's primarily what they do and really focus on.
There are centers where people see--they're at academic centers but they see a range of heme malignancies.So, they might see MPNs, lymphomas, myelomas, and some other things.Out in non-academic centers there are more than one spectrum of focus.There are some large private practice groups, US Oncology, others, where again there may be a large group of hematologists and medical oncologists in a place, and one individual might focus on hematology.Rarely would they focus just on MPNs, but they may focus on hematology or an aspect of hematology.
Finally, you have others that truly see the entire gamut of blood diseases and solid tumors.So, their level of engagement with MPN is probably kind of the least in that group.Doesn't necessarily mean that they don't know a lot about it, that they don't take good care of you.None of that is necessarily the case, but it's just about how much are you trying to keep track of at a time.I'm mindful even overseeing a cancer center that there's no way I could keep track of what's going on in breast cancer, even though it's a major area of my institution.
So, that's just a bit of how the teamwork of these things work, and when you have less-common diseases, sometimes having a team that has somebody who really focuses on MPNs working with people who have a connection to heme malignancies or in general practice sometimes is beneficial.
I want to cover a few key things to really kind of lay a foundation for our conversation, and the first is a bit regarding what do MPN patients experience.First, I'll show that MPN patients, and we'll start with patients with essential thrombocythemia, too many platelets, polycythemia vera, too many red cells, and there's more implications, of course.In myelofibrosis, this is a pretty heterogenous group.
So, first, Andrew, why don't you share with them a bit?If you are a patient with ET or PV, what sort of features of the disease likely have when patients are diagnosed, both in terms of what they might be feeling at a high level symptom-wise, but other features that clue people in that they might have ET or PV?
DR. KUYKENDALL:Yeah, thanks, Ruben.It's a great question.As you guys know, this really ranges a huge spectrum.We all have patients that are quite symptomatic from their disease, and other patients that aren't.I would say kind of leading into that, what leads to the diagnosis is always a question that we don't often talk about with patients because they already have the diagnosis most of the time when they see us.
But the vast majority of patients are getting the diagnosis based on some routine lab work, or maybe some lab work that wasn't expected to be abnormal but was done because there was a concern that was considered to be either mild or moderate or non-specific that led to these abnormalities on their blood counts, which would ultimately lead them to get a bone marrow biopsy or come see us.
I would say with essential thrombocythemia, with ET patients, many of them are relatively asymptomatic, but some of the symptoms that can indicate a potential of disease is what we consider to be microvascular symptoms, so things like ringing in the ears, headaches, and the one thing that I would say plays out through most of the MPN patients is fatigue, and that's just such a challenging symptom to either link with a diagnosis specifically because it could be present for so many different reasons.
Patients will attribute it to a variety of things, but fatigue is really something that I think all of our patients suffer from to some degree, and it may be only after we get the diagnosis that they start to link it with that diagnosis.With ET I would say headaches and ringing in the ears, some of these microvascular symptoms are probably the most common.With PV, at least in my experience, I would say headaches can be also common, but it's a different type of headache, in my experience, with PV than ET.
But I would say the fatigue tends to manifest pretty strongly as well, but some other symptoms can happen.In particular, you can have this itching that occurs that is quite unique to the disease, and can sometimes be associated with occurring after hot showers or something like that, and that has a fun name called aquagenic pruritis.You can also get some redness and some heat in the hands, and that's a little bit of an odd symptom that goes along with PV.
But once again, a lot of these symptoms can be quite mild and quite vague, and really ultimately leads to them getting some bloodwork done that points us in that direction.
DR. MESA:Wonderful, wonderful.Naveen, how might the experience be similar or different for the patient who has just been found to have myelofibrosis?
DR. PEMMARAJU:Yeah, thank you, Ruben and Andrew.So, as we move into the more advanced spectrums of myeloproliferative neoplasms, our patients with myelofibrosis can have what I would consider to be fairly heterogenous clinical manifestations, so meaning it can range a broad spectrum.Oftentimes with our "lower-risk" patients with myelofibrosis, they may have disease courses similar to what Andrew just described with ET and PV, but for the majority of our patients, intermediate-to-high-risk myelofibrosis, some patients can be very ill.
So, patients with MF can have things called extramedullary hematopoiesis, which means enlargement of the liver and spleen, because it turns out the liver and spleen know how to make blood cells since the time we were born, and they go into sort of reserve or secondary duty, so that's why some patients appear to have a very big abdomen area, and that can lead to symptoms of early satiety, getting full too fast.
Another component is, of course, unfortunately, bleeding and clotting.So, having both problems on those spectrums, that can occur in our patients with MF, and that's very difficult because that's one part of the same spectrum.Then I would also say another important part is that our patients can have increased infections in some of our patients, so it can be sort of what's called an immuno-compromised state.
One last point I would make, Ruben, is that our patients with myelofibrosis can also be at risk for going to outright cancer of the blood, that's called acute myeloid leukemia, and we and others have put together risk scores and ways to follow those patients.So, patients can be on the lower end having more like a PV/ET kind of a manifestation, or they can be quite ill, having cachexia, weight loss, early satiety, and these type of symptoms.But Ruben, back to you.
DR. MESA:Well, good.I think that gives us a great starting place.As I try to chat with patients, I share that there's in both groups, ET and PV, as well as MF, there's kind of short-term and long-term issues.And we've got a variety of different surveys and work with different patient groups to get a sense of this burden of symptoms.
But in the short-term, let's start with ET and PV.The risk of blood clots and bleeding, the potential of enlargement of the spleen, which is not very common, the impact of symptoms, and some risk of progression towards myelofibrosis.
Then in myelofibrosis patients, the spleen is much more likely to be an issue.They're much more likely to be symptomatic.The blood counts tend to have a different set of issues, frequently not uncommonly anemia or inadequate red blood cells.Sometimes the other counts are abnormal as well, and then the potential of progression toward acute leukemia.So, both groups have progression, both have symptoms, the profile of symptoms being a little different.
So, as Andrew had alluded to, in earlier disease, ET and PV, the high counts tend to drive a lot of the symptoms we see.There could be itching, there can be headaches, there can be difficulties with concentration, there can be fatigue.There sometimes can be night sweats, although less common.
As people move into myelofibrosis, they might have some of those features, but they tend to have, in general, more fatigue, they tend to have inadvertent weight loss, which is something that is clearly not something that happens normally in our society.If somebody loses weight without trying, one, if they have a secret, please tell me what it is, but two, it just does not happen.
So, somebody that sees patients, people do not lose weight without trying.So, frequently the story will be, boy, I've been trying to lose weight for 20 years and all of a sudden I lost 20 lbs. without trying.Boy, isn't that great?It's usually a sign that something is off.
So, that's a big of the burden that they face.Now, in addition to what they face, there is the issue of risk with the disease.With ET and PV having risks particularly as it relates to risk of blood clots or bleeding, or risk of progression, and then for myelofibrosis, risk that the disease could be life-threatening.So first, Andrew, why don't you share just a little bit, because I think it helps to frame our conversation around how we treat the disease, what do we think in terms of what gives a patient with ET or PV risk?
DR. KUYKENDALL:Yeah, I think that's an evolving topic too, and I think that you could ask various MPN specialists and we'll all kind of give you somewhat different answers, because I think it matters what perspective you're looking at it.Historically, our risk score for PV and ET is pretty rudimentary, and a lot of times we're talking about risk of thrombosis.
So, historically we've looked at--it's certainly not rocket science--but we've looked at age and prior history of thrombosis as risk factors for thrombotic events.If you're over the age of 60 or you've had a prior thrombotic event, we consider you to be on the higher-risk scale for thrombotic, and maybe we'll do a little bit more as far as treatment goes to protect you from that risk.Increasingly, and really with ET this has come into play, we know that mutations that drive the disease also impact that risk.
So, if you have a JAK2 mutation, we know that that is really a more thrombogenic or a mutation that drives a higher risk of having a blood clot than if you have maybe a calreticulin mutation which occurs in about 30% of ET patients.It doesn't really impact our risk scoring in PV that much, because pretty much everyone has that JAK2 mutation.
But I would as increasingly that's playing a role in my evaluation of ET patients, whether or not they're over the age of 60 or have a prior thrombotic event.I'm wondering are they a JAK2-mutated patient--not the patient is JAK2-mutated, their disease is.But do they have a JAK2 mutation driving their disease, or is that a calreticulin mutation?I think about those patients differently.
On the other hand, there's some other risk factors that we look at.When we think about very high platelet counts, which can happen in both ET and PV, those really, really high platelet counts, sometimes getting above 1 million, 1.5 million, 2 million, those can be associated with an increased risk of bleeding, which may be a little bit counterintuitive, but actually as the platelets get very high, this can lead to some platelet disfunction, which ultimately results in an increased risk of bleeding, so that's something we also take into account.
Then we could also talk about the other blood count that we haven't really talked about which is white blood cells.When those get high, there is some data that suggests that the risk of the disease is a little bit higher, maybe a higher risk of thrombosis, maybe a higher risk of progression.
So, with ET and PV, those are the factors we're looking at as far as risk go, and that's not to say that comorbidities don't play a roll too.Because if you have a lot of cardiovascular risks as well, diabetes, hypertension, hyperlipidemia, that's something that we have to take into account too, because certainly when we're talking about preventing thrombotic events, which includes heart attacks, strokes, those things, the disease is not the only risk factor.We have to think about the entire patient as well.
DR. MESA:Very helpful.Now, the situation is a little different for patients with myelofibrosis.So, Naveen, what features add risk or that we consider for patients with myelofibrosis?
DR. PEMMARAJU:Yeah, thank you, Ruben.Myelofibrosis, we have studied this now over the past decade, and there are number of different findings.
The first iteration was the so-called IPSS score, and this effort was now over a decade ago, and looked at sort of five basic features, and they were nice features at that point, including things such as age, the baseline white blood cell count of the patient, the baseline hemoglobin count of the patient, if someone had the constitutional symptoms that we mentioned earlier, the fatigue, weight loss, et cetera, and then if you had blasts, circulating blasts 1% or more.
So, those five features really constituted the first risk.It was a very nice risk score kind of with the natural history of myelofibrosis, and we still use it today.Subsequent to the IPSS, Ruben, now, as you know, we've developed in the field multiple, actually, so many risk scores that we can't even keep up with them.
Basically, the theme there with all of these subsequent ones, DIPS, MIPSS, et cetera, is the addition of the factors that you and Andrew were discussing.So, importantly, the patient's chromosomes or cytogenetics, the patient's molecular features, and clinical factors such as do you need transfusions or not, how low your platelets are, et cetera.
What I think I find to be amazing, even as we go into 2021, is each year we keep adding more and more information, really, to these risk scores, enough where it's almost difficult for people to keep up, and our European colleagues have even come out recently with a more personalized risk score that you can go online and click on that.
I think the them though for us is how can we marry and combine clinical factors that are easily ascertainable at the bedside, slightly more advanced factors that people can get from cytogenetics molecular, and then are there still a hint or two unknown on factors that we can combine to determine who's best for clinical trial therapy, who's best for transplant, who's best for new therapies.So, I think that's where we are.We have a lot of tools; we need to try to put them all together as we move forward.
DR. MESA:Wonderful.A couple questions that have come in that are relevant to this part of the discussion before we pivot to therapy; one that I'll answer and then one for each of you.So, first there was a question about the atypical headaches, and one of the things I think we've observed is, one, they can also be standard headaches if you're just getting it at a greater frequency.But they can include headaches where we think that the issues with blood flow are just really not what they should be.
So, that at the extreme can be a TIA; that's really the extreme where there's even a temporary loss of sensation or function in part of the body.Much less severe than that would be migraines or atypical migraines.Sometimes people have migraines where really there is a visual change or things of that nature.So again, things to be on the lookout for; they can be a sign.They sometimes can be a sign of somebody who has PV that needs a phlebotomy because their counts are too high, or things of that nature.
Now, Andrew, currently--and patients have asked me this many times--we talk about the risk of thrombosis, and people are always a bit scared, well, am I having thrombotic events and I don't realize that I am?What are the signs of having a blood clot?
DR. KUYKENDALL:Yeah, it really depends on where the blood clot is.Where did the blood stop flowing to, I guess is the question.When we talk about arterial blood clots, which we're not picking which one we're more concerned about, but certainly arterial blood clots have end results that could be life-threatening, to be honest.That could be atypical chest pain, it could be a manifestation of a heart attack, it could also be a TIA, temporary loss of blood flow to a part of the brain that's resulting in poor function, dysfunction, loss of sensation, loss of motor function.
I think those are the ones that we know about.You can also have a peripheral artery occlusion where you're losing blood flow to a toe or a foot, and you're getting a cold foot or a cold toe.I've had a few patients like that, that requires emergent intervention to open up blood flow to that part of the body.But with MPNs also we're worried about venous clotting as well, where the blood's coming back to the heart and is stopping.
With that, I think the most common venous clots we think about are DVTs and PE.So, DVT we always talk about a swollen leg, just one of the legs being swollen, and maybe you get a blood clot in the thigh that's leading to back-up of the blood and you get a swollen leg.Or a pulmonary embolism or a PE, that could be a blood clot in the lungs that's leading to shortness of breath, rapid heart rate, dyspnea, chest pain with inspiration.These are some symptoms that could happen that would be signs and symptoms of a pulmonary embolism.
But I'll say that the blood clots don't always occur in those two locations, that's just the most common.MPN patients also get weird blood clots, meaning that they present with abdominal pain and swelling, and you can find that they get blood clots in the veins that are draining the spleen, and these veins in the abdomen that we call visceral blood clots for the most part, or splenic vein thromboses.
You can also get headaches that ultimately persist and cause pressure, and we find that you can have blood clots in the veins that surround the brain.These cerebral sinus thromboses, they can lead to headaches.So, these are all different ways that these can present, but it just depends on where the blood stops flowing.
DR. MESA:Very helpful.Now, Naveen, a parallel but slightly different question.Someone asked what is the risk with triple-negative as it relates to myelofibrosis.What does that mean, and maybe explain a bit what we've learned about that.
DR. PEMMARAJU:Yeah.So, this term triple-negative, which is being used very frequently in the last few years is a borrowed term.Essentially we borrowed it from several other cancers, most notably in breast cancer where the term triple-negative really became famous.In breast cancer it means negative for the three most common or most important markers there, ERP and HER2.
So, this term is actually a very nice term to again describe in our patients with myelofibrosis who are really an ET as well, that you're "negative," you don't have showing up on the mutation analysis for the big three driver mutations; those are JAK2, V617F, CALR, and MPL.Interestingly, now that we're looking at this in 2020 and beyond, it does appear that maybe 80, 90% or more of our patients really should have one of those big three driver mutations.Of course, polycythemia vera almost 100% JAK2 B617F-driven.
The second point here of triple-negative is that not only it's a moniker or a term that can be used, but unfortunately it does have prognostic implications in that if you truly are negative for the big three driver mutations, likely the patients' overall survival should be worse, at least outcomes in survival, and also, now that we have the extended gene panels for most of us, ASXL1 and several other high-risk molecular mutations, this is becoming a very important factor.Likely you may have one of those that's driving your MPN, and those can be checked out with the doctor's office.
So, the constant here is that triple-negative not only means negative for those big three, but you may be positive for something else driving MPN, and it marks you, possibly, as someone who's higher risk to progress to leukemia, worse overall survivals, possibly maybe considered for a stem cell transplant in the appropriate or fit patient.Of course, consideration for clinical trials.
Ruben, I think the big question will be how to combine all of these data points, triple-negative, clinical factors into the latest scoring and risk stratification for our patients in 2021.
DR. MESA:Very helpful.Well, let's pivot to our treatment.First, let me frame a bit regarding what treatment looks like, meaning first we assess the disease burden, symptoms, blood counts, and risk, and then your hematologist, along with their team, develop a treatment plan.
Hopefully they communicate to you a bit about your disease, what you have, what potentially to expect, and with a plan, why that plan for you as an individual, what is the frequency of monitoring the disease in terms of either blood counts and/or visits?What does success look like?Is it controlling the blood counts?Is it shrinking the spleen?Is it having you feel better?Is it curing the disease?What is success?What does lack of success look like in terms of we're going to try this, we're going to try this for three months?If it doesn't work we're going to change gears.
Members of that team usually include their nurse or nurse practitioner or both, or their PA that may have different roles in terms of who you communicate with, how you send information to them or queries.Is it by phone?Is it increasingly through some sort of phone-based app that you can kind of communicate with the healthcare team?
Get feedback on the blood counts, should I have have a phlebotomy, and then if you have any additional members of that team, maybe it includes someone like one of us on this call, or some other part of the team.What is their role?There are some patients I see once a year and they see their physicians more frequently.
So, everyone has a different role, but it's a multidisciplinary team.There's even people behind the scenes: pharmacists, medical assistants, and others that are playing different roles.The pharmacist may see if you're prescribed a new MPN medicine what, if any, are the interactions with the medicines that you have, and should you have something different, or adjustment, or things of that nature.So, that's a bit of the team, but let's get into a bit more of the granularity in terms of how we approach each of the three diseases.
First on kind of a standard level, then we can talk a little bit about the drugs in development.There's tons of questions about interferon and Ropeg, but first let's frame a bit the broader question.Maybe, Andrew, why don't you start us off with the ET?I'll make a couple comments on PV and then have Naveen give us MF.But at a high level, before we start getting into the new drugs, just a bit of standard approach.
DR. KUYKENDALL:Yeah, standard approach to ET.Well, first I wanted to say I think Naveen took umbrage about your comment about us not knowing much about breast cancer, because he tried to prove that by his background on triple-negative [laughter], so very well done.
DR. PEMMARAJU:Hematology-oncology, okay?
DR. KUYKENDALL:Very good.Exactly, exactly.So, talking a little bit about ET, I think with ET at a high level, for most patients we're talking about recommending that they're going to be on a baby aspirin.Now, that's not for everyone.I think that when we look at the most recent risk scoring we're using the IPSET thrombosis, or the revised IPSET thrombosis, and we're looking at JAK2 mutation age greater than 60, and the presence of a prior thrombotic event.
Based on those factors we're either labeling you as high risk for thrombosis, intermediate risk, low risk, and very low risk.Patients that are high risk, meaning they're JAK2-mutated and have an age over 60, or they have aprior risk of thrombosis, we're typically saying that those patients should be on a baby aspirin at least once a day, and then we're recommending some sort of cytoreductive therapy.Typically by that we're meaning that they should either be on hydroxyurea, interferon formulation of some sort, or an anagrelide which is increasingly less utilized, I think, in the modern times.
For intermediate risk, most of those patients we treat as higher-risk patients, although it's a little bit more negotiable.Then for the lower-risk group of patients we're frequently not adding on cytoreductive therapy, although there are some special cases that we can get into.But we're usually saying a baby aspirin is reasonable.However, that may be negotiable as well in the very low-risk category where they're CALR-mutated, young, no history of thrombosis.We're not really sure if the value of a baby aspirin is really there, although many patients are on it if they tolerate it okay.
DR. MESA:Wonderful.And polycythemia vera, the situation is similar with a couple important variations.So first, almost everyone has the JAK2.There's no patients with the calreticulin mutation.Overall, and there clearly are exceptions, patients with PV may be a bit more symptomatic than patients with ET and have a bit more problems with the disease.But that's just in general.There are ET patients sometimes that have more burden of disease, and some patients with PV.They clearly can overlap to a significant degree.
The big difference is a propensity of having too many red blood cells, and the importance of controlling that part.So, one, as Andrew had alluded to, most patients with p-vera will receive a baby aspirin.There's some controversy whether there might be some individuals where we could skip that.
I myself, I think that the risk for the aspirin is really exceptionally low, a low-dose aspirin, 81 mg per day.And short of an aspirin allergy or some other reason, probably able to have most folks on an aspirin.There's some discussion whether a baby aspirin twice a day may have certain advantages in all or certain patients, so that's in the mix.
But there currently is an upper limit to how much aspirin can help, meaning don't go out and take 10 of them.More aspirin than less aspirin increases risk of bleeding or ulcers, but it doesn't necessarily make it more effective.So, short of other reasons for being on an adult aspirin of 325 or more, those are typically in people with cardiac or other conditions where that was recommended.
The second piece, as I mentioned, was the red blood cells.So, that regardless of anything else, we try to control the hematocrit.The hematocrit is the percent of red blood cells by volume of the overall blood.So, if that's 45 what that means is if the tube of blood spun down, 45% by volume are red blood cells.There's perhaps some slight variations in what that target is.Perhaps I'm generous; sometimes it's a little lower.Perhaps people who live at a high altitude.
But overall, for the sake of today, let's say 45.Now, one key thing that we have found is that 45 really needs to be the ceiling as opposed to the average.People above 45 probably have a higher risk of blood clots, bleeding, and may have more symptoms.So, we probably become stricter with that.So, everyone aspirin, everyone phlebotomy to control the hematocrit.
Now, based on risk, symptoms, how well someone is tolerating phlebotomy, and intermediate risk such as cardiovascular risk, et cetera, people then sometimes receive a medicine to control the blood counts, of which for our US-based guidelines, both hydroxyurea and interferon have been felt to be interchangeable first therapies that could be used.If you ask 100 people you're going to get a 100 different answers in terms of which one to use.They both have plusses, but they both have minuses.At a high level Hydrea is cheap, it's a pill, and many people take it easily.Its downsides, it may not delay progression in the disease.Is that a key or not?Again, an area of controversy.
It can be sometimes hard on the skin, mouth ulcers, things of this nature.It's probably the least-specific to the disease, but it is a good drug that has helped a lot of people over many years.Interferon; there's short-acting that people take daily, or the long-acting, and for the most part when we talk of interferons in these diseases, it's long-acting.There's the one that in the US people can obtain pegylated interferon alfa-2a, or Pegasys, Ropeg, which is going to available in Europe.
We'll talk about the medicines to come.Interferons can help to control the counts, maybe can help to slow down progression of the disease.It's an injection under the skin once-a-week-or-less frequency, but can cause issues, irritate the thyroid, liver, sometimes cause depression or mild flu-like symptoms.Very strong back-up options with ruxolitinib or Jakafi, particularly for people with a lot of symptoms or splenomegaly.There's other less commonly used back-up options.Busulfan, which is kind of a hydroxyurea cousin, and other therapies that are experimental we'll discuss in a moment.
Now, myelofibrosis, different set of options.Naveen, what are those?
DR. PEMMARAJU:So, for myelofibrosis, as we mentioned with the risk scores, we like to think about it in terms of the lower risk, intermediate 1 and 2 risk, and then higher risk.Lower risk for the sake of this general discussion, primarily in the clinic treated as in ET/PV, so the earlier forms of the MPN, either observation or the treatments both of you mentioned.
For my comments I'll focus on the treatment-ready intermediate to higher-risk myelofibrosis patients, the ones that we discussed here today.It really represents the history of modern medicine, the treatment.Initially the treatments just a couple of decades ago may have involved older drugs, including the interferons, the hydroxyurea that you both mentioned, a class of drugs known as the IMiDs, the immunomodulators, the old drug thalidomide and its later incarnations, lenalidomide.
Then, of course, now in the modern era, the first and really only approved targeted agent which are the JAK inhibitors, Ruben nicely mentioned the ruxolitinib drug, which was the first JAK inhibitor FDA approved for intermediate to high-risk myelofibrosis that Ruben and Serg and others helped to pioneer.
Now there's a second FDA-approved JAK inhibitor just one year ago now which is known as fedratinib.The fedratinib agent, also a JAK inhibitor, can be used in all lines of the disease for intermediate and high risk.So, that's what you have in terms of the approved pharmacologic agents.
In addition to that, for the patient with MF, as we mentioned, consideration for allogeneic stem cell transplant in the appropriate fit patient who can actually go, which may not be the majority of our patients out there.That's really the only curative modality for myelofibrosis in 2020, and then of course clinical trials in the appropriate patient, which we'll talk all about.
Then lastly, maybe outside of the scope of this discussion, our patients with even more advanced disease, so-called accelerated and blast-phase myelofibrosis, that really, Ruben, resemble more like a patient with acute leukemia and may be candidates for other stronger chemotherapies and combinations with their JAK inhibitor.But with those comments, I'll turn it back to you, Ruben, to continue the discussion.
DR. MESA:Wonderful.We're getting several questions.We're going to pivot to that area soon, and perhaps weave in some of our discussion around some of the therapies in development around that.But before we do, one last thing that CURE had asked us to touch base on which I think is key, and it's really regarding communication.Communication between yourself and your hematologist, between yourself and your healthcare team, between your caregiver and the team, or even kind of between your doctors.So, lots of different areas.
There's no better communicator I know that Naveen Pemmaraju.So, Naveen, why don't you share with me again some of your thoughts on how should patients be thinking about communication?Because as chronic diseases, you're talking about a long-standing relationship with individuals.So, having good communication is really quite crucial.Thoughts for patients?
DR. PEMMARAJU:That's right, Ruben.I would really--and this is definitely something that you and I and others are very passionate about--I would say there's really three categories of communication, particularly in rare disease or rare blood cancer fields like ours and MPN.The first category is the sacred patient-doctor, or really patient-healthcare team partnership.
I love how you mentioned all of the new factors, the PAs, the nurse practitioners, the nurses, everybody is so important.So, that sacred bond has eroded in some cases over time as practices become busier, insurance changes, all of that.
So, I just want to encourage our patients to continue to have faith in that hematologist-oncologist no matter how busy or light their schedules are, definitely want to and will pay att.But, definitely the in-between-the-visit communication is important, so take advantage of your electronic medical records such as EPIC has an in-basket, email, whatever the appropriate - - is, and don't be shy to communicate with your health team in between the visits.Number two, Ruben, is the communication between the patient and their caregivers.That category is something very important.
Our friend and colleague Mr. Andrew Shore at Patient Power, this modality with CURE and others, are trying to help focus on the caregiver or the healthcare hero that's really trying to provide the basics.So, I think as a patient sometimes, oh, my fatigue or my quality of life, that's due to aging.No, it may be due to the new medication you have, the disease itself.So, we want to promote our patients to communicate with their loved ones openly, if they can, if they have the ability to.
Then finally, the third bucket that I put in communication, is the patient to the general community, if they are comfortable and want to do that.There's a growing community for rare blood cancers, again, such as MPNs.Facebook, Google, Twitter, all of these places.Again, if someone's comfortable and feels okay to do it, there are not just in-person townhall support groups, but now virtually, and this was even before the pandemic, but with the COVID-19 pandemic has shed a light.
So, remember that you're not alone, that no matter how rare of a rare disease you may have, that likely now in 2021 and beyond there may be a support group out there, there may be a group on Twitter out there.All you have to do is, if you have the ability, to look.So, I would say patient-doctor, but patient-healthcare team communication, patient to caregiver, and then patient to the greater patient community as three forms of communication to focus on.Ruben?
DR. MESA:Very helpful.Let me pivot to some of our questions and weave in some of the rest of our discussion into that.But first, Andrew, there's a couple questions here, very timely, regarding the COVID-19 vaccines.For all of you on the call, Andrew's received his vaccine, I got mine two hours ago, and Naveen gets it after this call is done.So, we strongly all both endorse the vaccines and think they're important.
But Andrew, just want to flesh that out a bit regarding why we feel some confidence that patient overall probably should take the vaccine, obviously with the caveat, always check with your doctor, but don't see a lot of downside as the takeaway.Andrew?
DR. KUYKENDALL:Yeah, absolutely.I think that with the caveat that we were certainly not--and I'm not a vaccination doctor, I'm not an expert on immunizations--but I think what we know is the risk of this vaccine is that even in patients with heme malignancies the risk is that maybe you don't have the most robust response to a vaccine.
But even then, I think that our patients most likely will have a pretty good response to the vaccine, and the data looks incredible as far as its ability to prevent future COVID infections and allow us to presumably get back to our way of life.If there are a group of patients that may not respond or may not get it, that just furthermore makes it more important for us of us that can't get it, to get it, to protect those individuals that are unable to get the vaccine.
The reason that the three of us are getting it is because we are taking care of a very vulnerable population of patients.I know that I'm scheduled to be on the inpatient leukemia service in a couple weeks from now, and going to be going from room to room, and I don't think that the way to deal with this pandemic is to not go into the room and see patients anymore.
I certainly think that that's a poor way to approach this, and so I'd rather be protected and be able to be with patients while they're in long stays in the hospital in a very scary time point.So, I think that we can look at the FDA data and look at the curves and see how effective these vaccines are, but we were just reminiscing about if we were able to put curves like that for our treatments of myelofibrosis, well, we'd be head of the cancer center right now.
One of us, I guess, but--or we'd have a bunch of followers on Twitter, but one of us also has that.So, I think that certainly the vaccine is something that's shown incredible efficacy in a very short period of time, and that's not really that surprising to me given the amount of money and effort and scientific focus that has been placed on this single goal.I think that that's one thing that friends and family ask me, is that is a concern that something has come to fruition so quickly.Frankly, it's not surprising at all.
Now the question will be in a year or two from now when we're back to a normal world is how can we get the entire world to rally around myelofibrosis and myeloproliferative neoplasms, and then we can come up with a treatment in nine months, and then we can be done with this thing.
DR. MESA:Wonderful.Very, very helpful.There's a couple questions here on Ropeg.Maybe I'll try to tackle what that is for folks.
So, there are let's say two interferons that we're frequently discussing.They're very similar medicines; one is pegylated interferon alfa-2a, it's made by Genentech and Roche, it's approved for hepatitis C, although there now have been several studies that many of us have been involved with showing its benefit in PV in particular, but also in ET; it's part of the guidelines, but it's not approved for MPNs, so there are not infrequently challenges in terms of getting insurance approval and things of that nature.
There is ropegylated interferon; this is made by two companies that work together, AOP in Europe and PharmaEssentia in Taiwan.It is a bit longer-acting interferon.It's ropegylated interferon alfa-2b, and the biggest difference is that it's a drug that they specifically want to get approved for patients with MPNs.
So, that from your end is really the very biggest difference in that it will make it easier in terms of insurance approval.Its data looks very favorable.We think that it's probably as good as the data with the Pegasys.It's possible that it's better, but they've really never been tested directly.But for patients in the US, one, it is not approved in the US.
Unfortunately, none of us can prescribe it, there's no way for you to obtain it in PV.There is a trial for patients with ET that it's a randomized trial between two different treatments, but that is one possibility - - I lead.There are questions regarding switching from one drug to the other.I think eventually if it does become approved in the US, which is possible based on the European data, we'll navigate that part.There's not been a lot of experience yet in terms of how does one best switch from Pegasys to ropegylated interferon.Do you overlap them?How one does that, I don't think we're there yet.
But I think that it likely will be fine.They're similar-enough drugs I think we'll get it all worked out.I do expect at the end it becoming an option, but probably with a bit of a delay.But don't expect anyone to be able to prescribe that quite yet.Even in Europe it's approved, but most countries are not paying for the drug yet, so people are not really yet quite getting it off clinical trials.
Now, let's pivot to some of the questions that we're having here, and maybe, Andrew, you can weave in a little bit of some of how we're looking at new therapies in myelofibrosis.As Naveen had mentioned, we have both ruxolitinib, and now we have fedratinib.People can prescribe it, very good in the second line for people that have failed ruxolitinib, particularly if they don't go onto a clinical trial.
But, there's a couple questions in here, both regarding what do I do if I'm longer benefitting from ruxolitinib, as well as, are there any medicines that reduce fibrosis?So, just in a short way, Andrew, just perhaps frame for folks a bit kind of what areas we're looking at, and the pipeline's pretty robust, and probably not enough time to get into each of the drugs in great detail.
DR. KUYKENDALL:Yeah.I think in past years if you asked us to talk about the drugs in detail it could have been done over the course of a few minutes.I think now this is something that we could go on for hours about, talking about the different options there in the pipeline.But I think when we talk about areas of need I think that there's a few key areas of need within the treatment.First and foremost, we need disease modification, and that's something that we're always looking into.
We want to be able to actually impact this disease and prevent it from progressing, prevent it from going to acute leukemia, let people live longer and better.But that will always be our gold standard of what we're trying to attain, but also I think there's other key areas of unmet need that are being actively pursued.So, first off there's patients that have cytopenias or low blood counts.I think that our current therapies don't do a great job of addressing that.We're pretty good at shrinking spleens and making symptoms improve.
But with people that have low blood counts we're reaching for more archaic agents such as thalidomide and lenalidomide and danazol and things like that.There's an ongoing study looking at luspatercept, which is inhibits a member of the TGF-β super family, and basically this is a drug that allows red blood cells to really come to their potential.
Some blood cells in these diseases don't full mature, and this is a drug that allows them to do so.This is approved for the treatment of a certain subtype of low-risk myelodysplastic syndrome, and it's something that we'd like to co-opt and use for our patients that have myelofibrosis and significant anemia.So, that's being actively pursued.
Additional, a lot of the agents we're looking at are looking at patients with myelofibrosis that haven't had a perfect response to JAK inhibitors, such as ruxolitinib or fedratinib.There's a variety of agents.
I would say the optimism or the excitement right now relies around really two or three agents primarily.One is a drug called CPI-0610 which is a type of BET inhibitor, and really this acts on a different inflammatory pathway than JAK inhibitors do, and it seems that in combination with ruxolitinib they seem to have some synergistic effects, whereby it seems to be in combination a little bit better than maybe just ruxolitinib would be at improving symptoms and spleen size.
And it may in fact, and this is really intriguing, improve blood counts, the hemoglobin; that seems to be getting better as well in those patients.So, it would be nice to tell patients that have symptoms of spleen and anemia that we can treat all of those things and not say, oh, we're going to treat some of that, but we're going to make other parts of your disease worse.
So, that's kind of nice.Then there's another--so, I think the BET inhibitor people are looking at navitoclax, a BCL-XL inhibitor, and this is a very interesting agent that has shown some ability to in combination with ruxolitinib recapture some spleen responses, so people that had suboptimal response to ruxolitinib are able to take navitoclax and get a recapturing of that, and it's actually shown some improvement in other aspects of the disease, so people that have really high white blood cell counts, or proliferative aspects of their disease, this seems to be an agent that has some benefit as well.
Those are kind of the add-on or the combination strategies that are important, but that's not even going into the newer JAK inhibitors that are coming down the line that may serve some patient populations that to this point have been underserved.By those, I'm talking about momelitinib, which has been very highly studied over the past decade, but still has not gained an approval yet.
What it seems like is that there seems to be a niche for this drug with myelofibrosis patients because it seems to do a pretty good job of improving spleen and symptoms, but also has favorable impacts on anemia, as well.
So, similar to what I said with the ruxolitinib combination with a BET inhibitor, momelitinib may be an option for patients that are anemic that have these large spleen and symptoms.Lastly, I'll mention pacritinib, which has also been heavily studied within the field but has yet to gain an approval, and this seems to be a JAK inhibitor that can improve spleen and symptoms but is safe to give patients that have very low platelet counts, and that's where it's being looked at.
DR. MESA:Very helpful.There's a question here I'll tackle real quick, a couple questions regarding the supplement N-acetyl-cysteine.This is a supplement that potentially has anti-inflammatory properties.There's been a trial done by our colleague at the University of California Irvine, Angela Fleischman, who also has a lab, and she's been looking at both diet and anti-inflammatory approaches to MPNs.It's early; I think they're seeing some potential benefits, but it's early and I think premature for us to know is it helpful, is it something that we should recommend.
We clearly are very much in the hunt for additional things that patients could take in addition to the other medicines we've discussed that might help aspects of the disease or how they feel.So, that's just one approach, but glad to see that Dr. Fleischman is doing that great work, and I think more to come.
Naveen, there's a question here on PV, and maybe I'll have you mention about the hepcidin agonists, as well as a cytoreductive approach.But somebody said, what if we have zero irons stores, low iron, everything, and you have a hematocrit of 50 and still get phlebotomy?So, maybe talk about the role of either cytoreduction, or perhaps what a hepcidin mimetic might fit in that mix.
DR. PEMMARAJU:Right.Thanks, Ruben.Yeah, so as we mentioned with polycythemia vera for patients who need cytoreductive therapy, we mentioned hydroxyurea and interferon, and now with the ropegylated interferon being studied in Europe.But there is one other encouraging early preliminary dataset to discuss that we saw at ASH, which is the TTG-300, which is a hepcidin mimetic.I think the one-liner here is that the body's control of iron, the periodic table element Fe iron, has a lot of complicated regulation in terms of how to keep its homeostasis or balance, when it's in storage, when it's in the blood, et cetera.
In the healthier non-PV state, there's a kind of a thermostat there that functions as you would expect it would.But in MPN such as p-vera, the disease itself plus the phlebotomies with taking off the blood can cause a disruption of that iron balance.
So, the hepcidin mimetic, PTG-300, Ruben, it really seeks to restore that balance, and in that setting with people having too many red blood cells, it tries to bring it down and make the presence of a phlebotomy not necessary.What we saw, still early, I think less than 20 patients that we saw, that the majority, the vast majority of patients were able to achieve what's called phlebotomy-free existence.So, they did not need any more phlebotomies after a certain time period.
I think the second part of the question that our viewer is asking is so important, because a lot of our patients are iron-deficient, either on purpose because of the phlebotomies, or they become iron-deficient, and then that can have its own set of morbidities as well.So, we are looking at drugs like the PTG-300 and others to try to help restore that balance so people are neither too high nor too low with their iron levels.
So, I personally am really excited to see that ongoing trial move forward, and also just the concept of getting a venesection or a phlebotomy, sometimes that's difficult.Patients can have these vagal reactions to it, sometimes there's pain at the area, so this is a welcome addition; clinical trial is ongoing.
DR. MESA:Wonderful.Let me tackle one last one and then have our two panelists each give kind of just a 20-second thing that they're hopeful as it relates to MPNs.But someone asked, how long can one expect Jakafi to be effective?So, in each of the medicines we've discussed really sometimes can have a very long period of benefit.
Ruxolitinib, I'd say the average has likely been about three to four years, but there clearly can be exceptions where some individuals have been on over a decade with this medicine.Likewise, the medicines we've discussed, fedratinib, pomalidomide, pacritinib, interferon and others, there are circumstances where individuals have been on for long periods of time.
So, much to be hopeful regarding that, and talking with your doctor in terms of if you're on a therapy, what would no longer benefitting look like is a bit of an individualized question.But, Andrew, some final thoughts, things that you might leave people with that make them hopeful for future options in MPNs.
DR. KUYKENDALL:Yeah.So, my hope within this field says that things happen.Science is, as opposed to COVID vaccines, science typically occurs quite slowly, especially when folks have a disease and they're waiting for novel advancements to make.
But I would say they also happen in a sequence of events, and it takes us understanding the science to really create novel therapies.So, 2005, 2006, we discovered JAK2 MPL mutations; 2011, ruxolitinib and JAK inhibitors approved; 2013 we discovered CALR mutations; next generation sequencing and mutation panels become increasingly utilized inthe 2012-2017 range.
From that, there's a ton of basic science that was done in the middle of the 2010s, and I think what we're about to enter is--that was the basic science phase, and I think we're about to enter the clinical development phase.Before there were three or four clinical trials with myelofibrosis going on, and a lot of those were very small studies, and we're on the verge of having I think four that I can count Phase 3 clinical trials that are opening all about the same time, and that's massive for the field.And that's not withstanding the 15-20 exciting Phase 2 trials and the other Phase 1 trials that are on the way.
So, we just have this massive boom of novel agents and novel concepts that are going to be entering the clinics, that people are going to have the ability get on clinical trials and have access to these agents.And we're going to learn a ton, and hopefully we'll get a lot of meaningful drugs approved and better options for our patients.
DR. MESA:Wonderful.Very briefly, Naveen, we're at time, but things that make you hopeful?
DR. PEMMARAJU:Most hopeful thing for us heading into 2021 has to be the focus on the more ultra-rare and niche diseases.We talked about systemic mastocytosis with several drugs being investigated.There's even more rare diseases, MPNs with an FGFR mutation with the drug pemigatinib and other approaches, and so on and so forth.
So, I think that when you have a rare disease to remember it's not rare to you, it's the disease that you yourself, your family is facing; there's probably somebody out there that's researching on that and trying to make a breakthrough.So, I'm very heartened and encouraged to see that as we move forward, Ruben.
DR. MESA:Wonderful.And myself, I'm very hopeful really by the sense of community.There has never been a stronger sense of community amongst MPN patients.I think the MPN investigators, tremendous engagement from the pharmaceutical industry to really try to make a difference in MPNs and partner with patients and physicians.
I think very much of an open ear from the FDA, the EMA, and others, on the burden that patients face and new therapies.So, patients frequently come to me and say, boy, I don't want to be on this drug for 30 years.I don't think anything that we're prescribing today in clinic, anyone is going to be on for 30 years.I think are options are going to continue to evolve, they're going to continue to get better, and they'll continue to be more personalized.
So, unfortunately, we are out of time.If you'd like to watch this webinar again it will be available on webinars on demand page of CUREtoday.com within the coming days.
I want to thank Naveen and Andrew, and the audience for attending and participating in today's event.I would also like to thank CURE and their partner BMS 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.Thank you all for joining.We'll see you next time.Please be well, safe, and have a wonderful new year.Good bye.Thanks, everyone.