Understanding Treatments for MPNs: Are There New or Emerging Treatments That Could Be Right For Me?
Understanding Treatments for MPNs: Are There New or Emerging Treatments That Could Be Right For Me? from Patient Empowerment Network on Vimeo.
What new treatments are in development for myeloproliferative neoplasms (MPNs)? What are the considerations when choosing a treatment plan? In this LIVE webinar, Dr. Bart Scott from Seattle Cancer Care Alliance and Dr. David Snyder from City of Hope will help viewers to understand the various treatment options for those living with polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF).
Hello and welcome to our Patient Power webinar today. Our topic is “Understanding Treatments for MPNs; are there new or emerging treatments that could be right for me?”
I’m Beth Probert, and I’m coming to you from Oxnard, California which is just northwest of Los Angeles. I am a polycythemia vera patient and patient advocate. I was diagnosed in April, 2016 by my specialist at the University of Southern California Norris Cancer Center. I was treated with Pegasys, which is pegylated interferon and a few phlebotomies for about 12 months. And I am happy to say that I am in remission.
But like many of our patients and caregivers in the Patient Power community, I am very concerned about the future of my condition and very interested to hear today about some of these new and emerging treatments and clinical trials that will give us hope for our future and for all of is in the MPN community.
Before I introduce our panel today, I do want to remind everyone that you can submit your questions and we will try to address every question in today’s show. If we don’t get to it, we certainly will address those questions in future webinars. You can submit those questions to MPN@Patientpower.info.
All right, I’d like to introduce our panel today. Joining us today from Seattle we have Dr. Bart Scott. Dr. Scott is a medical oncologist at the Seattle Cancer Care Alliance and a research associate in the Clinical Research Division at Fred Hutchinson Cancer Research Center. Thank you so much for joining us today, Dr. Scott.
Thank you for having me. Hello, everyone.
Great. And I’d like to introduce our other doctor on the panel today, Dr. David Snyder. He is joining us from Duarte, California which is in Los Angeles County. Dr. Snyder is an Associate Chair in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. Dr. Snyder, I hope I said that correctly. Welcome.
Thank you, I’m happy to be here.
Thank you. Now I’d like to introduce you to our patient panelist. Today we have James from Lubbock, Texas and James was diagnosed quite a few nears ago with the central thrombocythemia. James, welcome to our show today.
Hello and thank you.
James, I’d like to start with you. How long ago were you diagnosed with ET?
In October of 1994, I was 47 years old. I had a heart attack. If it had not been Monday morning and I was in the hospital visiting my mother, I would be dead. I had a blockage right at the aorta. But they pulled me out of it.
I’ve been active all my life. Even back then, I was running more than I do now. It just happened to me, and so eventually we got around to essential thrombocythemia, whatever that meant.
Well James, that’s such an interesting story because you’ve been dealing with this for several years. And in 1994, if I’m correct, we didn’t really have too much internet access. How did you and your family deal with this? How did you get information and educate yourself?
Well, just so you know, I’m 545 miles from Houston, 325 miles from Dallas, in a town of 250,000. But luckily, we have a medical school. And so I went to the library at the medical school and I befriended one of the librarians whose husband was an oncologist, or is, and she was very helpful in trying to guide me. But back then, there really was very little information.
It wasn’t current. It was from the polycythemia vera study group, and that’s real old data and things like that. But when the internet came on, I started playing around on Yahoo, came across MPN – or back then it was MPD – Digest, and read that franticly every night.
I can certainly imagine what a revelation that was to all of a sudden have information at your fingertips. If I’m not mistaken, when we were speaking earlier you mentioned that you also through the years have attended conferences. Can you speak a little bit about that?
Yes, it’s literally empowering to go – and my first one was in 1999, but to go into a room and find other people who are dealing with some kind of MPN. I was like wow; I really am not quite so alone. And over the years the quality of the information has increased tremendously, as it has in the whole field.
It’s still empowering. I have friends I’ve made by going to the Scottsdale conferences; you just learn a lot. It’s just good.
That’s very inspirational. I kind of want to shift gears a little bit here and ask you a couple questions. Do you see a specialist?
I see a hematologist/oncologist in Lubbock and I have right from the start. He started me on hydrea and soon to be 23 years, I’m still on it. I’ve varied my dosages from time to time, but I’ve seen no need to see what you would consider an MPN specialist. While hydrea is working, I’m goin to stick with it and when it doesn’t, I’ll start looking around and doing other things. There’s no one I would consider an MPN specialist in Lubbock. I’ve talked to some oncologists and I had to alert them about anagrelide. I would say they don’t quite understand Pegasys versus the normal interferon and things like that.
But that’s really kind of been immaterial to me so far because hydrea is working.
And you do have that challenge of being a little bit more remote, and I can certainly see how that makes a difference. I want to ask you one last question. You’ve been on hydrea a very long time. Do you have any side effects?
None really. My wife says I’m just not quite as wired as I used to be. But the things I read about, the possibilities that could be occurring, I don’t have to. I don’t know why; I just don’t.
That is fabulous news.
As a matter of fact, the doctors don’t know why either. They’d like to know; I would too.
Sometimes there’s just no explanation. James, I really appreciate getting to understand your story and we’re certainly going to come back to you and learn a little bit more about your journey. I’d like to go over to our doctor panel now.
I’m going to start off with Dr. Scott. We’ve heard a little bit about James’ story, and for our viewers could you explain a bit about ET; just help us understand really what it is and more importantly, what are we treating it with and what are the goals of treatment for ET?
ET stands for central thrombocytosis or essential thrombocythemia, so it’s been called both of those names but the principle issue is overproduction of platelets. When you see the blood counts of the patient with essential thrombocytosis, their platelet counts are elevated. There can be a wide range of how elevated we’re talking about; it could be anywhere from 650 to even greater than 2 million.
When you have a platelet count that’s really high, like above a million, paradoxically there’s an increased risk of bleeding. That’s because the platelets have, on their cell surface, what’s called a von Willebrand factor cleaning protein. It actually cleans a portion of the blood that helps in clotting. So even though they have all of these platelets, and we associate platelets with preventing bleeding and bruising; when the platelets are extremely high like that, patients can have bleeding like nose bleeding, gum bleeding.
But the real problem with essential thrombocytosis is clotting. The No. 1 cause of death in people with ET is due to blood clots. And so James was just saying, he presented with this basically heart attack that he probably wouldn’t have survived if he hadn’t been in the hospital already. That can be a common presentation that you see with essential thrombocytosis blood clots.
So the reason to treat patients with essential thrombocytosis when they are treated is to lower their risk for blood clots; to lower the risk for thrombosis. The standard therapy for ET would be aspirin, a baby aspirin a day, and then you look at different types of risk factors to determine whether or not they need cytoreductive therapy. Cytoreductive therapy is basically given to lower the blood counts.
The risk factors that we would look at age, would be history of prior thrombosis, also white count is another risk factor that’s come out recently that can predispose people for risk of blood counts. But there is a prediction model; it’s called an IPSET prediction model and it’s an international prognostic model to determine the risk of thrombosis in patients with ET. You can look at that and you can see what risk factors this patient has.
Interestingly, JAK2 mutations, so having ET with a JAK2 mutation is another risk factor for thrombosis. But if they are high risk for thrombosis, either due to age or history of thrombosis, other risk factors like cardiovascular risk factors or due to the IPSET model, these are patients that are treated with cytoreductive therapy. There are many choices for cytoreductive therapy and two of them have already – actually, three of them have already mentioned.
That would be hydroxyurea, which is a common agenda that is used; another choice would be pegylated interferon or Pegasys; and then another choice would be anagrelide. There have been two randomized trials that I’m aware of comparing hydroxyurea to anagrelide. One showed a benefit with hydroxyurea over anagrelide; the other one was basically equivalent. But for me, my preference is hydrea unless they are a younger patient.
And in those patients I typically prefer Pegasys. I think there’s more data that’s needed to determine whether hydroxyurea or Pegasys would be the best first choice. There is a randomized trial that either has completed accrual or will soon complete accrual where they compared hydroxyurea to pegylated interferon; it’s frontline cytoreductive therapy for people with PV and ET. That will help us to answer the question which is better between hydroxyurea or pegylated interferon. But both of those would be choices for initial cytoreductive therapy.
Recently one of the big things that we’ve learned about with all myleoproliferative neoplasms is the underlying driver mutations. All of the myeloproliferative neoplasms share in common up regulation of the JAK-STAT pathway. And the same thing of course is true with ET.
And so there are three common mutations seen in ET: JAK2V617F would be the most common, and then calreticulin and then what’s called the MPL mutation. So you would test your patients for those mutations if you suspect a myeloproliferative neoplasm. They’re helpful not only from the standpoint of diagnosis but also prognosis. In regards to what’s coming out in the future, there’s a lot of understanding of other things that determine risks.
So as James was mentioning, he’s done well for such a long period of time. And then there are other patients who have more rapid progression to myelofibrosis, for instance, with a diagnosis of ET. We are looking at that and we’re starting to understand more about why that is the case. One of the things that have come out is what’s called secondary mutation that can develop in patients that potentially increases their risk of going into leukemia or myelofibrosis.
Wow, that’s been really helpful to understand. When you hear James has done so well for 23 years, the same medication, some fluctuation in his dosing, do you see that often? Do you have in your patient group; have you seen people have that same success as James? He kind of joked like nobody knows why I’m not having so many side effects and I’m doing well; what’s your take on that? Is that an anomaly or do you see that?
We do see it, for sure and I will admit I’m what we call a tertiary referral center, which means I tend to be referred cases that are more recalcitrant that have failed other types of therapies. Among the patients that I see, I do have somewhat of a swayed pool of patients that typically have more severe presentations, more severe problems, that don’t respond as well to initial treatments and have more of a prolonged course with side effects and things like that.
But that just has to do with the nature of my referral base. But certainly among MPNs itself, there are many patients who do quite well with hydrea for many years.
Great feedback; thank you, thank you. Dr. Snyder, I want to talk to you a little bit about myelofibrosis. As I mentioned earlier, I have polycythemia vera and I do from time to time get a little concerned about progression. We’ll talk a little bit more about progression in a bit, but could you talk to us about myelofibrosis and give our viewers a summary of it, and also address the treatments and the goals of the treatments through the different therapies?
Sure. So we’re talking about the family of myeloproliferative neoplasms, and we started with ET; P vera of course is the other.
The third type is myelofibrosis. What we call primary myelofibrosis is patients who are diagnosed right from the beginning with myelofibrosis. But we know that both P vera and ET have the potential to transform over time to what we would call secondary myelofibrosis, meaning that they started with one condition and over time it transformed into myelofibrosis.
We see certain changes when that happens. As the name implies, there’s increased scarring, scar tissue in the bone marrow; that’s what myelofibrosis means. We tend to see decrease in some of the blood counts, particularly the hemoglobin with anemia and often the platelet count. And at the same time, often the white count is normal or it can be very elevated.
One of the clues for a patient with P vera for example, is say a patient was requiring a certain frequency of phlebotomies to maintain control of hematocrit or a certain dose of hydroxyurea and after awhile the doctor notices gee, we haven’t done phlebotomy in about five, six months and still the hematocrit hasn’t gone up.
Or, we’ve been on a certain dose of hydrea for a long time and everything has been stable, but now it looks like the hemoglobin is starting to drop. That’s the kind of clue that maybe it’s beginning to transform towards myelofibrosis and the bone marrow no longer is over producing red cells, but instead there’s a decreased production of red cells.
So along with that comes a number of other features. The spleen often enlarges around that same time and people may become aware of that enlarging organ in their abdomen. It may impact their ability to eat. There are also a variety of systemic symptoms that can occur. Sometimes we see this in patients with P vera and less so with ET/, but most commonly in patients with myelofibrosis.
Those are things like fevers, weight loss, night seats, fatigue, itching, and others. That’s kind of the clinical picture that you see when a patient either starts right off at the beginning or is progressing. So in terms of goals of therapy, there are a few issues. One, just like with the discussion about ET, patients with myelofibrosis are at increased risk for blood clotting and sometimes bleeding, as well. But our main focus is to help prevent blood clots from occurring. And so the same kind of baby aspirin is needed, is used.
In addition, there is a treatment called ruxolitinib or Jakafi is another name, that is FDA approved for treatment of patients with myelofibrosis. I’ll say that’s the only drug currently that is approved by the FDA for myelofibrosis, despite the fact that there have been many clinical trials that we may talk about with other drugs. But ruxolitinib was approved based on two main endpoints. One was a significant reduction in the size of the spleen for patients whose spleen is enlarged, with relief of symptoms from that big spleen. And second was control of some of these systemic symptoms that I mentioned. Those are the two main benefits that people can achieve.
There may be some other benefits such as gain in weight for people who have maybe lost weight. There may be some prolongation in survival; that’s a little bit of a soft call but some patients may benefit that way.
So that’s the main treatment that we think about for patients with myelofibrosis.
It sounds like from what you’ve described and of course what Dr. Scott described is the symptom burden is a big driver in how you’re going to treat patients and the symptoms are also a big indication of if it’s progressing, if it’s doing what it should be doing. You’ve both mentioned a little bit about some of the mutation. In previous programming, you’ve both talked about genetic testing. My next question is when someone is diagnosed, and I know when I was diagnosed with polycythemia vera, one of the first things that was done is that I was sent to the lab to get some genetic testing.
How important is genetic testing in both of your views? I’ll hop over to Dr. Scott real quickly. At what point are you suggesting genetic testing? Is it something you regularly do?
Thanks for asking. So, it is part of the recommend workup now for myeloproliferative neoplasms; that all patients have this testing done. It’s important to realize that we’re talking about acquired mutations that occur in the vast majority of people. When the word “genetic testing” is thrown out, there’s this automatic misunderstanding that it means that it’s something that was inherited.
The reason why that’s important is because we don’t necessarily want to convey the false message that having a diagnosis of MPN means that your kids are going to get it, because that’s not what we’re talking about with this genetic testing.
These are acquired abnormalities in the vast majority of patients with MPN. There are very rare inherited cases of MPN that have been recorded, and in the vast majority it’s something that you acquire; it’s not something that you were born with. These mutations up regulate expression of a particular pathway in your body that’s called the JAK-STAT pathway.
There are three defied mutations to date, and they are JAK2. There are two different types; there’s the exon VC617F mutation, which most people with PV have, most people with MF have and most people with ET have. But there’s another mutation called the JAK2 exon 12, which is primarily only seen in PV.
That accounts for the small proportion of PV patients that don’t have the JAK2V617F. Those are the two mutations in JAK2. And then there’s an MPL mutation which can be seen in myelofibrosis, and in ET. Then the third mutation is what’s called the Calreticulin mutation, which is the newest one that’s been described. That’s seen in about a quarter of ET patients and about a quarter of myelofibrosis patients. Those are the three driver mutations that people acquire that’s been associated with myeloproliferative neoplasms. It is now part of the diagnostic workup for these diseases according to the revised World Health Organization criteria.
So that’s part of what we mean when we say genetic testing. That’s actually not the whole picture, because there are new types of mutations that have been described that I was talking about earlier that we believe are secondary events.
They have been associated with worst prognosis, higher risk of going into leukemia, and higher risk of going into myelofibrosis. One of those that has a negative prognosis connotation is what’s called the ASXL1 mutation. If you have that mutation, there’s data showing that these patients are at higher risk of complication like progression of myelofibrosis and like progression to leukemia.
So, I think that all patients should have mutational testing, what I’ll call mutational testing instead of genetic testing. And I think it’s important not only from the perspective of making the diagnosis but also in regards to prognosis. And honestly, it also helps a little bit with therapeutic decision-making. Because we know that ASXL1 mutations have a very bad prognosis, and that might be a patient that you would consider more aggressive interventions in, like stem cell transplant, for instance.
Thank you. Dr. Snyder, PV; we’ve talked about ET, we’ve talked about myelofibrosis and kind of flipping back to PV, when you find out that someone is positive and has a mutation, and let’s backtrack just a little bit. I realize I really didn’t delve into what PV is. Could you give our viewers a little background on PV, and then we’ll talk a little further about how the mutation plays a role with that and what we look for in that.
PV is polycythemia vera. It’s an over production of red blood cells. It shares the properties with its cousins, ET and myelofibrosis, the JAK-STAT pathway is over activated, usually because of the JAK2V617F mutation. So the cells in the bone marrow produce red blood cells become autonomous, if you will; they’re always turned on.
Normally the body regulates very well how many red cells are produced by the bone marrow. If the tissues in the body sense that there’s not enough oxygen coming and the message gets sent through a hormone called erythropoietin goes back to the bone marrow, stimulates more red cell production. More red cells bring more hemoglobin, brings more oxygen to the tissues and then erythropoietin production is turned off.
In P vera, that production of red blood cells becomes independent of the erythropoietin signal so those precursors are always churning out red blood cells, even though the body doesn’t need them. So the hemoglobin hematocrit can go very high, and that gets people into problems with risk of thrombosis as the main issue. Also, there are systemic symptoms that we talked about in myelofibrosis can also be seen in polycythemia vera.
So the treatment goals there are to again control the risk of thrombosis by keeping the hematocrit at a safe level, and there have been some well designed trials now showing that keeping the hematocrit under 45 percent is the desired goal. Some hematologists would even be a little more blasé about it and say well, it’s under 50 percent; that’s okay. But there are now clear data to show that you’re doing a disservice to your patient by allowing hematocrits to get over 45 percent. And frankly for women, it may even be better to shoot for 42 percent as the target.
And so the question is how do you get there, and phlebotomy is certainly the most direct mechanical way, if you will, of doing that. But cytoreduction with interferon is one option; hydroxyurea is probably the most common drug used in that setting.
And now for the last few years, ruxolitinib is also FDA approved as a treatment for patients with polycythemia vera who have become intolerant to hydroxyurea or resistant to it.
Great. A couple of questions here, Dr. Snyder; how do you decide who gets what? For polycythemia vera, and I myself have seen this; I’m a member on so many different focus groups and such, and I see that there are people, one is getting Pegasys, one’s getting ruxolitinib, one’s getting hydrea; how do you decide who gets what?
The first question is does the patient need any of those drugs? We stratify patients with P vera into risk groups depending on age and the presence of other traditional cardiovascular risk factors or history of stroke.
But for a young person, say someone under 60 without risk factors, they can be maintained with baby aspirin and an occasional phlebotomy from time to time to maintain hematocrit under 45 percent. And they could go potentially for many years with that approach very comfortably.
The times that we say the cytoreduction is needed, there are a few things. One if it’s a higher risk patient, say over 60 with history of a stroke, other cardiovascular risk factors for example, or a patient who has other change sin their blood, not just the high hemoglobin but now maybe the white blood cells and the platelets are going higher, and also maybe the spleen is starting to get big. Phlebotomy is not going to help those features. That’s the time where you would start considering cytoreductive therapy.
We mentioned interferon, and Pegasys is the form of it that we now use. I do consider that more in younger patients because it’s a drug that may be harder for older patients to tolerate, so that’s the starting population. As Dr. Scott mentioned, there are trials going on to kind of compare head to head hydrea and interferon to see is one maybe better than the other. There are some suggestions that interferon may accomplish more than hydrea could in terms of some of the disease parameters. That’s not clear yet from the studies.
So that’s an option in a younger person. Hydrea really still is the main go-to drug for most patients who need cytoreduction. And then ruxolitinib, as I mentioned, it’s only FDA approved or indicated for patients who have already been on hydrea and have been either resistant to it or intolerant to that drug. So you can’t use ruxolitinib as frontline therapy.
The insurance companies won’t pay for it, and as we all know it’s a very expensive drug.
That’s a very, very common thing that we do here. We talked a few minutes ago about the mutations and doing some testing. Dr. Scott, I want to go back to you. How often do you suggest that patients have the initial genetic testing? I have found out that I’m a little unique compared to some of the other people I’ve been talking to about the frequency of genetic testing. So, how often do you suggest your patients get the genetic testing, Dr. Scott?
I’m going to be honest with you; that’s a very difficult question to answer in a definitive way, because there’s really a lack of data to address the question that you ask.
And so, I think it’s a personal decision that I assist my patients in making in conversations with them. There are a lot of different factors that go into answering that question. So, first I’ll say that everyone should have it at diagnosis, and I think most people would agree everybody should have an extensive panel sent at diagnosis to not only include the three driver mutations, but also the associated mutational changes that can be seen like ASXL1 and EVH2.
Almost all patients now are having that done at diagnosis. In regards to how frequently, it depends on a lot of factors. One of the biggest ones would be what’s the underlying health of the patient? So, would there be a utility in knowing are things changing? One of the reasons why you would want to know that, for instance, would be maybe their disease is bad enough at this time to say okay, a transplant is warranted, but you’re going to follow the patient closely
And if there’s new mutational changes or there are other signs or symptoms, then you might consider transplant at a later time. So when those patients are candidates for stem cell transplant, then I think one could argue that more frequent monitoring would be warranted. And so I might monitor those patients every six months to a year with mutational profiles.
I do think it should be done if there’s a change in symptomatology; if it looks like the disease is changing. So let’s say for instance you have an ET patient who’s been doing well on treatment for a long period of time, but they come in and they have low blood count now. And for the first time, they maybe need a red cell transfusion or maybe even a platelet transfusion. You’ve decreased their hydrea doses and their spleen has started to increase. You see immature cells in their blood smear. All of these are signs that maybe they’re going into myelofibrosis.
So if that were happening, that would be another reason that I would say okay, maybe we should do this mutational testing. So, I think it’s hard to be definitive; I think it’s an individual decision made after a consultation with the patient. And I think there’s a lack of data that we have to address your question, and that’s why you’re going to hear a lot of different opinions about when they should be done.
Absolutely. And James, I just want to go back to you for a few moments. Have you had genetic testing?
I think we all had it just to be sure about the Philadelphia chromosome. And I’m JAK2 positive, but other than that, no. I would like to interject sometimes the conversation has been once we find the right treatment; you’re going to stay on it. But if you get around a lot of patients, you’ll find that this drug works great for me for three years and now, for whatever reason I’m transforming; it isn’t working. Maybe I’m not transforming but it doesn’t work. But that’s the only thing I’ve had done.
Clinical trials and CALR and MPL I’m not sure right now what I’d change about my treatment. I haven’t gotten excited about that yet. But I’m aware of them through the conferences and through the Listserv.
Very, very interesting. You’re very connected and I know that when you and I talked before and we got to know each other, that you are very connected to what is out there and still kind of figuring out what do I need; things are going well. But James, you brought up a very good point. I’d like to ask Dr. Snyder; resistance. We hear the word so often, but could you talk to our viewers a little bit about what is drug resistance and what happens at that point?
Usually if you’re talking about resistance, say to hydroxyurea, a patient with P vera resistant to ruxolitinib, it usually implies – often implies that there is something new that’s occurred within those abnormal cells. We were talking about mutations, and that’s probably the main mechanism for the development of resistance; that a patient had a certain profile, let’s say they had the JAK2 mutation but no other secondary mutations.
Sometimes another mutation will develop in the course of the disease, and now even though for example with ruxolitinib, you may be inhibiting the JAK2 pathway pretty effectively; if a mutation has occurred that activates another pathway inside the cell, it may be able to bypass that blockade that the ruxolitinib was establishing and now the patient clinically becomes resistant. So it’s a time to wonder what’s happening at the molecular level and should we be looking at that.
If this fits into resistance and the whole issue, and we heard earlier from Dr. Scott talking about stem cell transplantation and I know that’s something that’s your area of focus. When you see resistance happening and you’re not finding another therapy that’s working, is that when stem cell transplantation is a viable option?
That’s a very good question, and not an easy one to answer.
I’m on a roll!
That’s the biggest question, really; well there are two. Who is the right candidate for stem cell translation, and when; when is the right time? We don’t want to compromise or jeopardize good quality of life that a patient may be experiencing with their current situation.
Stem cell transplantation, yes on the one hand it is a curative treatment potentially; that’s the goal of therapy with stem cell transplantation. But on the other hand, it’s a high risk approach as well, and there are risks of early death after transplant and if not death, then significant morbidity of complications that may affect the quality of life. So we certainly don’t want to rush into that approach. That’s the nuance of when is that right time.
I’ll just step back for a minute. We haven’t talked about DIPS or DIPS Plus, which I’m sure people are familiar with. That’s the Dynamic International Prognostic Scoring System for myelofibrosis that stratifies patients into low, intermediate one, intermediate two, and high risk. It helps to predict expected survival or average survival for a large group of patients with that category.
Generally speaking, once you get to intermediate two, the average predicted survival is under five years. That is to me sort of the minimum criteria to say we should be thinking about a transplant. But it’s not sufficient, because many people may be in intermediate two or even high risk and still have good quality of life. So I look for additional factors. One would be that a patient starts increasingly requiring red cell transfusion because of severe anemia; that’s one trigger. Because that would indicate that survival may be shorter.
The other is to look at the blasts in the blood. Patients may have none, or they may have a low number, say 1 to 3 or 4 percent; that hovers in that range. And then over time, something happens and now it’s 8 to 10 or 8 to 12 percent. Again, it may be one of those mutations that’s come along.
That gives you a sense that the patient is on the way towards transformation, so that’s another trigger to say this is the time to think about a transplant.
So definitely not a decision that is taken lightly; it is sort of a last sort of therapy, so to speak, a strategy to take because of the serious effects it could have on the quality of life, if I understand you correctly?
Again, in a sense it is. I like to say that I don’t like to take patients too early, nor too late to transplant. Because we want patients who are potentially going to benefit from it to have that chance. So too early means that a patient is doing well in their current therapy, they have a good quality of life, they’re doing the things that they need to do, that they want to do; we don’t want to interfere. Too late, that’s a relevant term because it’s hard to say that it’s ever absolutely too late.
But someone who’s transformed to leukemia, that’s a much more difficult situation. It’s not that we can’t transplant a patient in that situation; you need to go through treatments first to get the leukemia back into the more chronic stage. It complicates the whole picture; outcomes are not quite as good.
The other besides leukemia is the general organ function of patients as they get older and they have other issues. Their heart function, their kidneys, their liver, their lungs; those need to be in pretty good shape to be able to withstand the impact of a transplant.
So it’s a very intricate decision making process and highly specific, is what I hear you’re saying.
It is. I’d just like to get back a minute to what we’ve been talking about mutations.
As we’re learning more about what secondary mutations can be found and what their clinical impact is, they’re being incorporated into prognostic scoring systems so not just DIPSS, but there are things like MIPSS, molecular scoring.
So, incorporating those data along with the clinical parameters. We’re not ready yet, but there may be a time where we can define a patient’s risk through the genetic profile and allow us to say okay, this patient, even though clinically they’re doing well, we know that their risk for not doing well in the short term is X or it’s a much shorter timeframe, and we better not wait – or it would be better not to wait – to move to transplant since we had said that this patient is a candidate and they have a donor.
So we’re not going to wait and risk the chance that they would lose the benefit. We’re not there yet, but I think that’s the direction we’re hoping to head to in the coming years.
That’s great to hear about where we’re going with this; what we can expect in the coming years. It sounds like it’s going to get highly specific and very useful. Now I’d like to take the time to talk about some clinical trials. Dr. Scott, I’d like to have you start off with us. What’s new and promising? If you could talk about a few clinical trials that maybe are going on at SCCA, or that you’d like to share with us and then Dr. Snyder, we’ll go back to you and you can give us your feedback. So Dr. Scott, can you lead us into that subject?
Sure. We have a trial with a drug called imetelstat for patients with myelofibrosis. The accrual is currently on hold. A single center phase II result was published in the New England Journal of Medicine showing there were some patients who were able to retain a remission] of their myelofibrosis with treatment with imetelstat.
This includes both molecular remission and morphologic remission. Molecular remission would mean that their abnormal mutations went away and it responded, and morphologic remission would mean that visually the fibrosis had improved significantly. The phase II trial is currently on hold and they’re evaluating data. I’m helpful that the drug will continue to be explored in clinical settings. It does have a novel mechanism of action; it’s what’s called a telomerase inhibitor.
As I said, the drug is known as imetelstat. There are many centers that were participating in that phase II study. We just opened a trial with pactritinib. Pactritinib is also a JAK inhibitor, and actually I think it’s probably better to call these drugs JAK-STAT pathway inhibitors, because not all of them actually work directly on the JAK receptor, so I think that’s important to know.
These basically inhibit the JAK-STAT signally cascade. This drug, pactritinib, is in clinical testing. It is not yet FDA approved. It’s somewhat similar to ruxolitinib but it does appear to cause less cytopenias, so less toxicities with lowering of the blood count. It could be potentially useful in patients with low platelets. That’s one of the chief toxicities that can be seen with ruxolitinib are Jakafi is lowering of the platelet counts.
So, I’m hopefully that this drug will be approved in the near future. It was put on hold for the FDA for a brief period of time, but as I said the drug is now being studied again in a phase II trial, looking at different dosings. There are many centers participating in that study.
And then we also have a transplant study that’s looking at giving JAK inhibitors before transplant in an effort to improve the overall condition of patients before they go into transplant.
This is specifically for myelofibrosis patients. Patients with myelofibrosis can have a higher treatment-related mortality with transplantation because of other things that are going on with their body like malnutrition, the fact that they have a very big spleen, and other factors such as organ involvement with fibrosis can lead to a higher treatment-related mortality. They also have a slightly higher risk of graft failure in comparison to patients with other types of myeloid malignancies.
So, we’re hopeful that giving a JAK inhibitor before transplant can help improve the post transplant outcomes. So those are the three major trials that we currently have open. Of course there are other centers with really exciting drugs in development, as well.
Wow, that sounds very exciting. I know that I can say just hearing that there’s such a focus with MPNs and these trials.
And Dr. Snyder, what is going on in your neck of the woods at City of Hope and other trials that you’d like to tell us about?
Yes, we have a number of trials. We have the pacritinib and the imetelstat trial as well. We have two other trials that are for patients who have failed or progressed on ruxolitinib that have totally different mechanisms of action sort of outside of the pathways we’re talking about. One is called SL401, Stem Line 401. It’s an interesting sort of an immuno toxin; it’s a dual functional molecule that has an IL3, interleukin 3 portion that’s linked to a diphtheria toxin. It’s somewhat like a Trojan horse type of thing.
The cells in myelofibrosis and other hematological malignancies have an interleukin 3 receptor on their surface, and this IL3 molecule will bind to that interleukin receptor. That complex is taken inside the cells and then the diphtheria toxin is released and is able to kill the cell from the inside. So that’s one mechanism.
There’s another approach; there’s a molecule called CD47 which has been referred to as the “don’t eat me” signal. So, macrophages which are big cells in the body and in the blood and tissues, their name means big eaters. They like to eat foreign cells, tumor cells, bacteria, etc.
But some of the tumor cells or the malignancies become very clever and they have this protein called CD47 on their surface that sends a signal to the macrophage: don’t eat me, stay away and helps the cells to survive. So there is an antibody against the CD47 that binds to the CD47 and interrupts that pathway and then allows the macrophages to do their jobs, which is to eat these abnormal cells.
So that’s another approach that’s being tested not just in myelofibrosis but in other conditions as well. There is some data, sort of preclinical, that this approach may actually reverse fibrosis in some models, so it’s kind of intriguing particularly for patients with myelofibrosis.
The thing I will mention, we know that ruxolitinib is the only FDA approved drug so far; there have been several others unfortunately that have gotten just so far and then because of toxicities have been taken off of the table. But to me, I think another approach is combination therapy that is taking ruxolitinib as the base and then combining it with the second drug that has a totally different mechanism of action, and the two of them then perhaps can synergize and kill off the cells.
Those are trials, a quite a few of them going on around the country and I think those have a lot of promise.
And when you mention combination therapy, you both have mentioned it; are we looking at more of a personalized medicine? What’s your feeling on that, Dr. Snyder? Is it at that point we’re getting more personalized and we’re looking at that one person and saying this is going to work more specifically for you?
I think that’s a very good point, and I think as we learn more about mechanisms of action of some of these drugs and we talk about targeted therapy, it is something that can be very individualized potentially.
We talked about the genetic profile of what mutation someone might have. And so there may be a second drug beyond ruxolitinib that targets one of these secondary mutations that a patient might have. And so for that person with that particular combination of mutations, ruxolitinib plus this second targeted therapy may be just the right thing for them.
Even a drug like imetelstat, at least on data based on small numbers from Dr. Tefferi’s work suggested that there may be a mutational profile that defines the best responder type of patient, and conversely, patients who are unlikely to respond at all to that drug. That would be terrific to be able to say okay, don’t waste your time with this drug for this patient, but go in this direction because this is much more likely to be effective.
It could be life saving; it could get to the result much quicker than going through another therapy that just is not going to do it.
Very interesting. So, quick question for you James, before we move one. We’ve talked about a little bit about clinical trials. James, have you considered a clinical trial? Or you’ve been stable; would you consider one in the future if your condition changed?
Very definitely. But you know one thing we haven’t touched on and what drives the doctors crazy, probably, is the psychology of the diagnosis. We as patients quite often tend to think if I just took thing X or had therapy Y, I would be okay. And as these doctors know, it’s not that simple. But yeah, if I thought I would benefit from it and I needed to, of course.
You bring up an excellence point, James, because it is the psychology behind really how we… you’ve been doing this for 23 years and you obviously have educated yourself which helps you to understand what’s going on, which balances everything out. I know that I, as I mentioned, I’m in some support groups and I see people doing combination therapy. And it’s the old adage: he’s doing two things and I’m doing one, and I’m sure doctors don’t want to hear that.
There are other patients; the last thing they want to know is anything about the technical side. Just: I’ll go to the doctor and the doctor says this, and I do that.
There is, indeed.
I think even I’m on one extreme and they’re on the other.
Definitely. We have a little bit of time, and Dr. Scott, I’d like to go to you.
We have a question from Pauline, and she asks: is there any way to determine declining blood counts such as anemia and thrombocytopenias are due to drug side effects or the disease process? And she goes on to say: my husband has been on Jakafi for just over a year, and these declining cell counts began a couple of months ago. So let me know if you need to repeat that. Could you comment?
No, I’ve got it. There are things that are helpful to distinguish between drug toxicity and to these progressions, and one is timing. The cytopenias that are experienced with ruxolitinib, as long as the dose has remained the same are usually early side effects. So, most of the cytopenias are during the first eight weeks of therapy. So if you see early cytopenias, it’s more likely to be a drug effect. If you see later cytopenias, it makes you more concerned about disease progression. And to know definitively of course, you could repeat a marrow aspirate or a biopsy and that can be helpful.
And then other co-associated symptoms or size like increasing spleen size, or return of puritis can all be signs that the ruxolitinib is no longer working. But as I said, the side effects of drug-related are usually early events within the first eight weeks when treated with ruxolitinib.
Great. I think that’s going to be some good feedback for Pauline and some talking points that she can bring back to her specialist. We are coming to a close, and what I’d like to do now is ask each of our panelists just for some final thoughts or comments. You know, I’m feeling very optimistic from this discussion this evening to know that there’s just constant thought on these rare diseases, and there are clinical trials and research. But Dr. Snyder, let me start with you and if you could just give us some thoughts you’d like to share with us that you think would be meaningful?
Sure. These are obviously difficult diseases because they’re hard to cure. But I will focus first on the role of stem cell transplantation as the only current only curative approach. We are trying to improve both the efficacy and the safety of that approach, and Dr. Scott mentioned studying the role of JAK2 inhibitors in the peritransplant time, for example, as one. It turns out that ruxolitinib also is an effective drug to treat one of the main complications, which is graft versus host disease. We have a trial actually looking at it as a prophylactic way to prevent graft versus host disease.
So just to say that there’s a lot of work being done on that front to try to improve outcome for patients with the transplant approach. But of course we’d all love to have – we all think about CML, that was mentioned; the Philadelphia chromosome. The Gleevec story is kind of the model that we wish we could duplicate with many of the diseases that we treat, recognizing at the same time that it’s very unlikely.
Because in a way, patients and doctors were lucky with CML because it’s a very simple biology. And if you come up with a drug like Gleevec that targets really the definitive driver of that disease, you can have dramatic clinical benefit.
Not quite the case with the myeloproliferative neoplasms; more complicated. Ruxolitinib, we all hoped this is going to target the JAK-STAT pathway; it’s going to shut it down and restore normal hematopoiesis. It’s not quite that simple.
But we certainly have hope and optimism that with many of these trials that are going on, particularly as I said clinical trials with combination therapy, that that is going to get us closer to that point. I’m a transplanter but I would love to be put out of business because we have drugs or a drug that is so effective, transplant is just a thing of the past. Hopefully, one day that will be the case.
Wow, and that is very powerful. I will always remember those words; that’s really great. Dr. Scott, can you give us some final thoughts on just anything to let us know again what we should be looking for, what’s in the future, some optimism; whatever you feel is meaningful?
I think there is a lot of hope. When you compare what we know about myeloproliferative neoplasms now with what we knew about them six years ago, it is really remarkable. It was in 2005 that the first publications were published about JAK2, and we began our understanding of the underlying mechanisms of myeloproliferative neoplasms.
And over those 11 years there have been a lot of advances. So, I’m very encouraged by not only the clinical trial work that has been done, but also the basic science and the expansion of our understanding of these diseases. So when you compare what we have now with what we had ten years ago, it is really remarkable. I also do transplants but I do non transplant as well and I hope to be driven out of business. I would be okay with that.
That’s wonderful to hear; again very optimistic. James, you and I were chatting a little bit before our show started. James was commenting how even from 2014 to 2017, that there have been so many changes in progression and therapies. And James, I’ve got to say you’re like an MPN warrior.
You’ve been dealing with this for 23 years, you’ve been not only optimistic; you’ve been so resourceful, you are a born researcher. I would love to turn the stage over to you right now. And if you could give us some of your thoughts, some things you’d like us to know and help us feel more optimistic as we go forward.
Well, I’m very optimistic; I mean it’s just amazing compared to 1994. Actually, I was one of the data points in some of those 2005 studies. But there’s the MPN Research Foundation – let me throw in a plug for them, patients; they have funded some really specific studies. If you can’t go to conferences nearby or Scottsdale or New York – Dr. Silver runs one in New York; I know they’re in Seattle and all over now, get involved in a focus group. I drive to Dallas just to be around a focus group of those people. It’s tremendously empowering to talk to other people. Because your friends are like, you don’t really have a problem; you don’t look sick or anything, you know?
That is something that MPN patients hear quite a lot. But go ahead, James.
I’m just excited. When I have to get more knowledgeable and detailed about these things, I will but I’m not there yet. My goal is like the physicians here; I intend to die of something else. It didn’t get me the first time; I’m planning on no second time.
I think that is wonderful. You know, I would like to say that optimism is what is going to get us through this condition. I don’t tell too many people because I’m very optimistic, but I do agree with you James; I really connect well with people in focus groups. I drive sometimes about two hours each way into Los Angeles to see my specialist because that’s of value to me. If I ever could give advice, it would be make sure you’re connecting well with your specialist.
And that they are, like Dr. Scott and Dr. Snyder, very well versed in their field and in their clinical trials and things like that. So, wrapping up, a big thank you to our panel; I really believe that this webinar this evening gave us a great deal of information. Dr. Scott, Dr. Snyder, you both have very busy schedules so appreciate it. And James, you too took time out tonight so thank you all.
We have an upcoming webinar I’d just like to talk about really quickly on September 20th, and it’s what you can do to advance MPN research so I hope everyone will join us then. We will also be showing this video again and again. So thank you for our panel and thank you all for taking the time to watch Patient Power. Good night.