Tag Archive for: MPNs

Advancing MPN Research: How Clinical Trials Work

Advancing MPN Research: How Clinical Trials Work from Patient Empowerment Network on Vimeo.

How do clinical trials advance MPN research? Dr. Angela Fleischman shares insight about the clinical trial process and the significance of clinical trials in moving MPN research forward.

Dr. Angela Fleischman is a physician scientist and assistant professor in the Department of Medicine at the University of California, Irvine. Learn more about Dr. Fleischman.

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Transcript:

Dr. Fleischman:

Well, there are multiple stages of clinical trials. One needs to have some rationale for testing a specific drug in patients. You just can’t say, I just want to take something off the shelf and see if it works for myeloproliferative neoplasms. 

There could be different ways that things sort of enter into clinical trials, either preclinical data from in vitro, meaning, in the lab, in the liquid media, with cells, that makes somebody think that it might work in humans, or that it works in a similar disease to myeloproliferative neoplasm. So, it’s a little bit of a stretch, but a very rational stretch, to then test it in a new population. 

First and foremost, safety needs to be evaluated, because as physicians, one of our primary objectives is to do no harm to patients. So, at very early stages of clinical trials, the primary objective is to see what the appropriate doses, what’s tolerated, what the side effect profile is. 

And then, moving on to efficacy. So, maybe it’s tolerated, but does it actually work at the next stage of clinical trials. Then, a much larger clinical trial would be to do a head-to-head comparison between, in most cases, standard of care versus drug X. 

And I think, for clinical trials, in particular, for myeloproliferative neoplasm, it’s very important to understand what the stated, primary end point is, in particular, for myelofibrosis patients, that myelofibrosis patients may have different problems. Some myelofibrosis patients, their primary issue may be anemia. And so, if they’re looking for a clinical trial to address their anemia, they would probably want to be looking for one whose primary end point is transfusion, freedom from transfusions, or improving the anemia, not necessarily – there was another trial that’s primarily looked at spleen reduction, but they didn’t have an enlarged spleen, that, necessarily, wouldn’t be appropriate for the patient. 

So, I think it is particularly important in myeloproliferative neoplasm to identify what the primary end point is, and whether what you’re going for is that primary end point. 

Katherine:

Mm-hmm. Any advances that are being done in MPN research require MPN patients to participate in clinical trials, right? 

Dr. Fleischman:

Of course. 

Katherine:

But what if they don’t? Why is it crucial that patients participate in trials? 

Dr. Fleischman:

Because without participation in clinical trials, we are not going to further our understanding of myeloproliferative neoplasm. Many of the drugs that we use today in myeloproliferative neoplasms, as well as other diseases, the reason why we use them today is because people 10, 20 years ago participated in the clinical trial and demonstrated a benefit of these medications. So, people don’t participate, we’re not going to have new drugs for myeloproliferative neoplasms. 

What Patients Should Know About Developing MPN Treatments and Research

What Patients Should Know About Developing MPN Treatments and Research from Patient Empowerment Network on Vimeo.

MPN expert Dr. Gabriela Hobbs provides an update on developments in myeloproliferative neoplasm (MPN) treatment and research. Dr. Hobbs explains how clinical trials and global research collaborations advance MPN care.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Gaby Hobbs.

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Transcript:

Katherine:

Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today we’re going to discuss the advancements in MPN research through clinical trials. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you. Well, let’s meet our guest today. Joining me is Dr. Gabby Hobbs. Dr. Hobbs, welcome. Would you please introduce yourself? 

Dr. Hobbs:

Hi, how are you? Thank you so much for having me. My name is Gabby Hobbs. I’m the clinical director of the Adult Leukemia Service at the Massachusetts General Hospital in Boston. And I dedicate my clinical time and research efforts to the care of patients with Myeloproliferative Neoplasms.  

Katherine:

Thank you so much for taking the time to join us today.  

Dr. Hobbs:

Thank you.  

Katherine:

I’d like to start by discussing your role as an MPN researcher. You’re on the front lines for advancements in the field. What led you to there and why is it so important to you?  

Dr. Hobbs:

Many things in my life led me to becoming an MPN clinician. First, I wanted to be a clinical investigator since I was very little, and I read a Louis Pasteur book about – you know. And I was fascinated by the fact that you could be both a scientist and a clinician. And after that, I had phenomenal teachers and mentors. And I was really always drawn to patients with hematologic malignancies. I thought that that interaction was very intense and intimate.  

And I was honored to be a part of that interaction. And then from a research perspective and from a scientific perspective, I very clearly remember seeing when the first targeted therapy, Imatinib, was approved when I was an undergrad. And I just thought that was the most fascinating thing. And so, I’ve basically continued to feel that way as I’ve gone through my training and I’m thrilled to be able to have actually become an MPN clinician so many years later.  

Katherine:

With the American Society of Hematology or ASH meeting taking place this month, it demonstrates how researchers work together around the world to advance care.   

Can you share with the audience how this collaboration works?  

Dr. Hobbs:

Yeah. So, the American Society of Hematology meeting – or the ASH meeting – is really one of my favorite events of the year.  

And it really highlights what you said. It is such a positive environment, and it’s so exciting to use that opportunity to talk to my collaborators from across the globe. And I really think that that’s where the scientific community shines because really all of us are actually trying to figure out how to work together and overcome sometimes a lot of obstacles – bureaucratic obstacles, regulatory obstacles – to make sure that we can share data, do it the right way. But really we always have one thing in mind.  

And that is to be able to advance the care that we give our patients. And so, that collaboration and really that collaborative environment is always very positive. And I always come back home very energized from that. And then just seeing all my colleagues presenting all the wonderful things that they are working on and getting updates on their research is just an exciting environment.   

Katherine:

In your view, why is it essential to present and share data at these larger conferences like ASH? 

 Dr. Hobbs:

So, for many different reasons. I mean, there are many different ways of presenting data that can be done through just publishing a paper. But the nice thing about conferences – and especially large conferences – is that you really get an opportunity to present work in progress. And some of these research projects may not end up turning into bigger projects or they may not become bigger trials. But all of them have at least an opportunity to learn something from them, whether or not they worked or they didn’t work.  

Oftentimes when things are published in journals, especially the high-impact journals, we are seeing trials that had positive results. But sometimes we don’t see those smaller trials that never went anywhere. And so, having a forum when we can discuss work that’s ongoing, discuss about projects that are maybe having issues, all those things actually really help us to change our research questions or develop new research questions based on what’s working and also really what’s not working. And so, having this large forum to present all of that data, I think, is really, really important to helping us design future clinical trials and projects.  

Katherine:

Yeah. Well, this is a great way to begin our clinical trial discussion, Dr. Hobbs. This research all requires MPN patients to participate in clinical trials. So, what should be considered when deciding whether to join a trial? 

Dr. Hobbs:

What a great question. Many things need to be considered when joining a trial. And I think some patients are really eager to join a trial, and they just need to be aware that they may be either too healthy, or they may have other things going on that may not make them eligible.  

And that’s okay. There are actually many ways of participating in research, even if it’s not a clinical trial that requires a medicine. For example, we often can send patients to what’s called a tissue bank where they have patients just give a sample of blood.  

So, patients can participate in research in many different ways. When considering whether or not a patient should enroll in an actual clinical trial with a new medicine, I think it’s really important for the patients to be informed and to not be afraid to ask questions. First, what is a clinical trial? Second, what will this trial involve? Is this a drug that has never been given to people before, or is this a drug that has already undergone many different clinical trials? And this trial that’s being offered is a Phase III trial where the purpose of the study is to get the drug to be approved.  

So, I think learning about the risk of the study, how it’s been utilized. And also the other more practical things. What is the time commitment of this clinical trial? How often are you going to have to be going to the office because of the clinical trial? Because there’s certainly a big investment in the part of the patients in terms of their time. Participating in a clinical trial most of the time requires more time than not participating in a clinical trial. That’s not always the case. There are some studies that definitely don’t require that many visits.  

But most clinical trials will require at least something extra from the patient. And I think it’s really important to ask about that, to read the consent that’s given to the patients. Oftentimes these consents are very long.  

And so, they can be overwhelming. I personally find them overwhelming. And I review a lot of those consents. And so, I think taking a minute to really ask those questions, speaking to the research staff, and getting the clarification on that is really important.  

Like you said, it is impossible to approve new therapies and improve the care that we offer our patients without patients participating in the clinical trial. But that doesn’t mean that absolutely every single patient needs to participate in a clinical trial if it just doesn’t make sense for them. [14:17]  

Katherine:

There have been huge developments in the last 10 to 15 years in the field of MPN. So, I’d like to dig a little deeper. We hear about the common driver mutations in MPNs like JAK2, CALR, and MPL. How are these being studied , and what is being discovered? 

Dr. Hobbs:

Yeah. So, it’s amazing how in the last 15 years really so much has been discovered. You know. The JAK2 mutation was first published out in 2005 and calreticulin in 2013. So, those are relatively recent discoveries. And I think a lot of efforts has been put into learning about what these mutations are doing and how they lead to disease. And so, we have the JAK inhibitors, which block the signaling through a pathway called JAK-STAT. And all of these mutations will activate that pathway within cells.  

And so, many of the approved drugs, for example, ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo), work on blocking that pathway.  

But since then we’ve also learned that there are other mutations and other pathways that are likely involved in the development of myeloproliferative neoplasms and also their progression. And so, what we’re seeing now is that many of the clinical trials that are being conducted don’t just target the JAK-STAT pathway or the pathway that’s influenced by these main mutations.  

But also block other pathways to try to really block all the variant expression of signaling in the myeloproliferative neoplasms. And so, we’re trying to attack it by many different angles.  

Katherine:

Yeah. Is there a possibility of specific targeted therapies at MPNs similar to those in AML such as FLT3 inhibitors? 

Dr. Hobbs:

Absolutely. So, similarly to AML, we know that we have mutations in similar types of genes called tyrosine kinases. So, these are enzymes that are turned on and always active. And so, I think there is definitely hope that we can develop some targeted agents. For example, ruxolitinib or the other JAK inhibitors are similar. They’re tyrosine kinase inhibitors where they block an enzyme, specifically the JAK2 enzyme.  

But I think that we can definitely do better and develop more specific inhibitors, for example, a molecule that just blocks the JAK2 mutation and not just every JAK2 molecule in every cell. Similarly to AML, there are mutations, for example, in enzymes called IDH.  

And we have IDH inhibitors for AML. And there are some studies that are using IDH inhibitors for MPN. So, I think we’re going to continue to see more targeted therapies specific to the mutations that occur in MPN.  

Katherine:

Yeah. Let’s talk about ET for a moment. Is there any research being done to help better manage this condition? 

Dr. Hobbs:

Yeah. I would say that of the three MPNs, ET is certainly the one that has the least amount of drugs that are being currently studied for this group. But that doesn’t mean that there isn’t any research. Ropeginterferon (Besremi), which was recently approved in polycythemia vera, is now being studied in essential thrombocythemia.  

So, I would expect in the next couple of years, if those trials are successful, to have ropeginterferon as a therapy to offer patients. There is also a clinical trial that we have at our site.  

We’re using ruxolitinib or Jakafi for patients with ET that have symptoms of their disease to see if it can help them in the same way that it can help PV or myelofibrosis patients. So, there’s definitely some research going on in ET. But probably less than for PV and myelofibrosis.  

Katherine:

Mm-hmm. While ET is typically well-managed, what patient type might benefit from joining a trial? 

Dr. Hobbs:

It really depends on what the patient is experiencing. I think there are some patients that really are very asymptomatic and can expect to have an excellent outcome with their disease. But they can also participate in research, for example, by participating in a tissue bank and offering a sample of their blood or if they have a bone marrow by offering some bone marrow if there’s extra. Because that can really help to understand the disease biology, if a patient is going to progress from ET to myelofibrosis.  

So, we can learn a lot from that. But then there are maybe some ET patients that need to be on a medication to reduce their blood counts or a cytoreductive agent.  

And that’s a patient that could ask about participation in a clinical trial. For example, the ropeginterferon study or, like I mentioned, there may be some patients that maybe are already on a medication and their blood counts aren’t well controlled on the first drug that was used.  

So, before considering switching to a second-line agent or a second medication, that could inquire with their clinician if there’s a clinical trial available for second-line use. Or those patients that have a lot of symptoms with ET, they could potentially be eligible for a study that addresses just symptoms.  

Katherine:

Right. That’s really good news. I’m glad you talked about that.  

Dr. Hobbs:

Mm-hmm.  

Katherine:

There was recently an interferon approved for use in patients with PV. What other studies are showing promise for patients with PV?  

Dr. Hobbs:

Yeah. So, we as a community, there’s been a lot of excitement about this new interferon that was approved, the ropeginterferon study. And there are still some ongoing studies utilizing ropeginterferon to see if we can use it differently. Because currently the way that that drug is approved is that it has to be titrated up very slowly to get to the maximum dose. So, that’s something that is still ongoing. In addition, there’s a new drug that’s being studied called Rusfertide (PTG-300) from a company called Protagonist. And this drug has been very interesting. It acts through iron metabolism.   

And so far in preliminary results, it has shown that a lot of the participants that receive this medication no longer need phlebotomy. And I think what’s exciting about this is that phlebotomy is a very archaic way of treating patients.  

And I hope that we can stop utilizing it. So, it’s nice to have a compound that’s specifically asking that question. And the other thing to keep in mind is that this drug has been used in combination with other drugs, which is really reflective of how participants or patients show up to clinics.  

Some patients are not going to be on any medications. Some patients may be on hydroxyurea.  

Some patients may be on an interferon. Some patients may be on Jakafi. And these trials allow participants to be on a variety of different medications. So, that’s an exciting new compound.  

Katherine:

What about myelofibrosis, Dr. Hobbs? What advances are being made in the care of patients with this more advanced MPN?  

Dr. Hobbs:

Yeah. So, in myelofibrosis, I would say it is almost difficult to keep track of how many clinical trials are currently open. So, in 2011, we had ruxolitinib approved, or Jakafi. That was the first JAK inhibitor. Since then we’ve had two more JAK inhibitors approved, fedratinib and most recently pacritinib. And we’re currently awaiting the fourth JAK inhibitor to be approved, and that’s called momelotinib.   

And in addition to the JAK inhibitors, there are lots of other clinical trials underway right now that are either alone – a drug by itself or a drug in combination with ruxolitinib.  

So, there are several Phase III studies. And the reason why that’s important is that after Phase III we usually see a drug approval. So, we can expect, hopefully in the next couple of years, to see many more drugs available on the market to treat patients with myelofibrosis. Some of those include agents that block different pathways within a cell. And that includes a drug called parsaclisib. There’s a drug called pelabresib, which is a BET inhibitor.  

There’s another drug called navitoclax, which is a cousin of venetoclax (Venclexta), which is a drug that we’ve been using a lot in leukemia. So, there’s lots of different drugs that are being used in combination with Ruxolitinib. There’s also a drug called luspatercept (Reblozyl) that’s also been approved for myelodysplastic syndromes. And I suspect that that’ll be approved as well to help patients with anemia. So, really, there’s lots of drugs that are being studied right now. And I think the question that we’re all asking is, well, how are we going to use all of these different drugs? So, I look forward to seeing the results of those studies.  

Katherine:

Mm-hmm. Will some drugs work better for some patients and others not? 

Dr. Hobbs:

That is such a good question. And so, what I’m hoping to see is exactly that. I’m hoping to see that for patients, for example with anemia, perhaps we’re going to be using luspatercept and momelotinib. Perhaps we’re going to see that patients with certain mutations may respond better to certain medications like the BET inhibitors or navitoclax or the PI3 kinase inhibitor, parsaclisib. But as of now, we don’t have enough information.  

We haven’t seen enough results of these studies to start to be able to know, you know, what is the patient that’s going to do better with two drugs versus one drug? And so, I think that over the next couple of years we’re going to start to have answers to those questions.  

Katherine:

Yeah. I’d like to get specific about your research. What are you excited about right now? 

Dr. Hobbs:

A few different things. There’s a clinical trial that I’ve been leading for several years now that got somewhat delayed due to the pandemic that’s utilizing ruxolitinib before, during, and after transplantation for patients with Myelofibrosis.  

And that study is hopefully going to finish accrual in the next couple of months. So, I’m excited to see the results of that study. That study was presented at ASH of last year, the interim results of that study. And so far, we’ve seen exciting results. Patients have done well with transplant while receiving ruxolitinib.  

We’ve seen that patients that have undergone transplant and have received ruxolitinib have had very low rates of a complication of transplant called graft-versus-host disease.   

And that’s been very exciting, because we know that graft-versus-host disease is really very difficult to deal with after transplant. It can really impact quality of life. And so, that’s been exciting to see that we can help our patients to better tolerate this difficult treatment. On the complete opposite end of the spectrum, we’re treating patients that have low-risk essential thrombocythemia and polycythemia vera with ruxolitinib also to see if their quality of life can improve.  

We know that patients with ET and PV live with a lot of symptoms. And often times patients that are considered low-risk can still have a lot of symptoms. And therapies haven’t really specifically been studied just to improve symptoms. Really, therapies are usually used to reduce the risk of having blood clots.  

Katherine:

What about checkpoint inhibitors? You’ve done a study about that? Or it’s ongoing? 

Dr. Hobbs:

Yes. Great question. So, a few years ago we utilized a checkpoint inhibitor called Pembrolizumab for patients with advanced myeloproliferative neoplasms. And that study was open at Mass General and also at Mount Sinai. We were worried that it wouldn’t be well tolerated. But it was actually very well tolerated. But unfortunately patients didn’t have a response. And a group at MD Anderson utilized another checkpoint inhibitor, Nivolumab, for these patients. And similarly they also didn’t see a response.  

So, that was disappointing. However, I do think that there is a role for immunotherapy in patients with MPNs. I think that we probably need to think about utilizing the checkpoint inhibitors maybe earlier or maybe in combination with other agents. This has been done, for example, in solid tumors where two checkpoint inhibitors are sometimes utilized together. So, I think their area of investigation is still worth pursuing even though that was a disappointing result.  

Katherine:

Yeah. Yeah. Any other research that’s going on that you’re doing? 

Dr. Hobbs:

Yeah. We are looking forward to opening some clinical trials using different drugs in combination with ruxolitinib to offer different treatments to our patients up front. And so, instead of offering just single-agent JAK inhibitor, we can combine that with one of the new agents. And so, I’m looking forward to seeing how that’s going to work for my patients and to be able to offer them another treatment. I’m also thinking of developing a clinical trial for use in patients that have clonal hematopoiesis.  

So, patients that have this entity called CHIP where they have a JAK2 mutation but maybe don’t have overt disease. We know that they have a high rate of transformation to an actual MPN. So, we’re working to develop clinical trials for those patients with the hope of maybe preventing the MPN from ever happening. 

Katherine:

That’s great. We have some questions from the audience that were sent in prior to the program. Carl asks, “Are MPNs inherited? And why does one sibling develop an MPN and the other does not?”  

Dr. Hobbs:

Great question. So, historically, we’ve always said MPNs are very rarely inherited. Now that we’re able to test for JAK2 mutations more commonly, we have, I think over the last decades, probably found that there are more families where the MPNs kind of run in the family.  

Katherine:

Mm-hmm.  

Dr. Hobbs:

Generally speaking, it’s very rare for MPNs to run in the family. I would say less than 10 percent of the case. And this is why a sibling can have an MPN and one doesn’t, even if they’re identical twins.  

Katherine:

Is research being done to learn more about who may be at risk for developing an MPN? 

Dr. Hobbs:

So, over the list, there’s been a lot of attention placed on this entity called clonal hematopoiesis of indeterminate potential. And through those types of investigations, we’ve learned that people can actually live with a JAK2 mutation for many years, even decades, before they develop a myeloproliferative neoplasm. And so, indirectly, I think that type of research will help us understand why some people get the JAK2 mutation to begin with and what else needs to happen in a patient’s life for that person to develop an MPN.  

Because clearly there are many more people walking around with a JAK2 mutation than there are people with an actual MPN. So, there’s something else other than that JAK2 mutation that predisposes patients to then develop an MPN.  

Katherine:

Angela has another question. “What are the long-term effects of JAK inhibitors? And what happens when JAK inhibitors are no longer effective?” 

Dr. Hobbs:

Yeah. Great question. So, so far the patients that have been on JAK inhibitors for a long time don’t seem to have the development of additional toxicities that we didn’t know about. So, I’ll just comment on some of the things that we do know about. Weight gain is a common complaint that I have from patients, especially those that have polycythemia vera, because maybe they didn’t want to gain weight when they were put on a JAK inhibitor compared to the myelofibrosis patients who maybe had lost a lot of weight before being on a JAK inhibitor.  

There are certainly higher risk probably of developing infections with some of the JAK inhibitors. And we see, for example, shingles reactivation being a common one. And there’s the concern of development of skin cancers, which has been seen with some JAK inhibitors. But generally speaking, long-term use seems to be safe. That being said, ruxolitinib, which is the oldest one to be approved, has only been around since 2011, so we don’t have decades worth of experience to know.   

When JAK inhibitors stop working – to answer the second part of your question – until fairly recently we really didn’t have a whole lot to offer because there was only one JAK inhibitor. Now we have two others. We have fedratinib and also pacritinib. And we know from the studies that have been done with both of these agents that some patients that lose response to Jakafi, meaning that their spleen starts to grow or their symptoms start to come back, can be treated with these other JAK inhibitors.   

And many patients will, again, have control of their spleen and symptoms. Now losing response to a JAK inhibitor can come in many different ways. And so, some patients may also develop signs of having leukemia or progression of their disease to leukemia. And, unfortunately, for those patients, being on another JAK inhibitor doesn’t make sense. So, those patients may need to receive other types of medications or a stem cell transplant.   

Katherine:

Mm-hmm. Gary has two questions for you. The first is, “How useful is having a genetic panel done? Should all patients get molecular or genetic testing?” 

Dr. Hobbs:

Great question. And I think that it is very important to have genetic testing.  

And genetic testing involves more than just testing the JAK2 mutation. So, we know that the JAK2 mutation is the most common mutation in patients with MPN. But that being said, there are other mutations that also occur such as the calreticulin mutation and the MPL mutation. And so, I think having genetic testing that at least tests for those three mutations is very important so that we can actually help a patient know that they have an MPN. In addition to those three main mutations, many clinicians now have access to what’s called extended next-generation sequencing, where there’s a panel that tests for many different genes at the same time and can test for a variety of other mutations.  

And this is particularly relevant for patients with myelofibrosis. As we know that having other mutations, like, for example, mutations in IDH or ASXL1 and others, can increase the risk of that disease in terms of its risk of transforming to leukemia or how long a patient may live with their myelofibrosis. 

And so, I do recommend having extended next-generation sequencing done at least at diagnosis.  

When I generally think about repeating that, if there’s something that looks like it’s changing within the patient’s disease, to be honest, also on the flipside of that argument, sometimes this next-generation sequencing will mostly contribute to adding anxiety and will not necessarily directly impact how a patient is treated. And this is particularly true in patients with PV and ET, where we’ll sometimes order these tests, and we get a bunch of mutations back, but we don’t know what to do with that information yet.   

And so, as a researcher – not a clinician – as a researcher, I think it’s very important to have that information so that we can then do studies and understand the patterns of mutations and how that affects outcome. But as a clinician, and you as a patient, you need to really be aware of how that’s going to impact the patient in front of you and how that may impact you as a patient. Do you want to know if you have these mutations if nothing can be done about it? So, I would say, take a moment to reflect upon what I said and also to ask your clinician, how is this information going to help me? Do I need to have this information?  

Maybe you want to have it done so that it’s in your record. But maybe you don’t necessarily want to know those results. And everybody’s very different. And I think it’s absolutely wonderful to talk to my patients about all the information. But there may be some patients that really are just, like, do the test but don’t tell me the results, because I know that I’m just going to be very anxious knowing that I have something that I can’t do anything about. So, just take a minute to talk about it with your doctors. I think that’s really important.  

Katherine:

Yeah. Yeah. Here’s Gary’s second question. “Is allele burden a key predictor of progression?” And before you answer that, Dr. Hobbs, what does “allele burden” mean, and how does it impact progression? 

Dr. Hobbs:

Great questions. And I hope that in the next couple years I have a much better answer for you. So, maybe I’ll come back again and maybe we can talk about this again. So, allele burden – just simply put – is basically, like, how many of the stem cells in your bone marrow have that JAK2 mutation. And that’s a concept that’s not obvious. So, not all of a patient’s blood with an MPN has that JAK2 mutation. There are some stem cells that have the JAK2 mutation and produce JAK2-mutated blood. And then there are some stem cells that are normal that just make normal blood and don’t have a JAK2 mutation.  

And so, we can measure, what is a proportion of cells in the blood that has that JAK2 mutation? Now the next question should be very obvious and straightforward. But it really is not. So, what do we do with allele burden, and how do we measure that, and what does it mean if the allele burden goes up or it goes down? At this moment, we don’t necessarily know that. There have been some studies showing that maybe higher JAK2 mutation burden is maybe associated with progression or more with PV as opposed to ET.  

And we’d all like to think that lowering that JAK2 mutation level or that JAK2 allele burden has to be good and maybe will decrease progression or improve survival. We haven’t seen that yet. And so, I think we’re all really waiting to see, what does it mean to lower that JAK2 allele burden? And then how often should we be measuring that? But right now we really don’t know.  

Katherine:

Yeah. One more question for you. This one from Joseph. “I have PV and had adverse side effects from peginterferon alfa-2a (Pegasys). Is it likely that similar side effects would be experienced with Besremi?” 

Dr. Hobbs:

Good question. It’s hard to know. And it really depends on the severity of the side effects that you had and the type of side effect that you had. In my experience, ropeginterferon or Besremii is very well-tolerated compared to the other interferons that were available. But if you really had a severe side effect it may be difficult to consider trying it. But it’s worth considering it. I’ve definitely had patients that have gone from Pegasys to ropeginterferon without any difficulty. But just because you had a bad side effect to one doesn’t mean that you’ll have a bad side effect to the other.  

Katherine:

This is from Paul who lives in the United Kingdom. “How important is it to see an MPN specialist rather than a general hematologist? Right now I’m currently seeing a general hematologist who makes a note of my side effects but offers no coping strategies or solutions.” 

Dr. Hobbs:

Yeah. That is a great question. And one with not one answer. I would say that if you’re an MPN patient and you have a clinician that treats you that feels comfortable treating you or you feel heard and you’re being offered different ways of dealing with symptoms or side effects, etc., then perhaps you don’t have to go out of your way to find an MPN clinician. And participating in webinars like this or learning online may be sufficient to know how to advocate for yourself and how to monitor your disease. That being said, I do think that it’s nice for patients to at least have a one-time opinion with a specialist.  

And I would say that with the advent of virtual care, that has become increasingly more accessible. And so, if that’s something that’s available to you, that’s something you should consider. You know. Sometimes it’s very difficult to travel a long distance to meet with a specialist. But if you can avoid the travel by having a virtual visit, that often times can be very helpful in just knowing that you’ve met with somebody once. And then you can meet with that person periodically throughout your care can be very helpful. And I’ll tell you personally I see patients in the neighboring states to where I live.  

And I like to see those patients periodically or communicate with their local providers. And so, it just helps to offer care that’s very specialized in maybe areas of the country that don’t necessarily have access to specialized care. So, I would encourage patients to seek that out if that’s something that they’re interested in because it’s really become, I think, easier to access the specialists.  

Katherine:

Thank you for your thoughtful responses. And viewers please continue to send in your questions to question@powerfulpatients.org. Before we end the program, Dr. Hobbs, I’d like to hear why you’re hopeful about the future MPN care.   

Dr. Hobbs:

Thank you so much. Those are great questions. I feel very hopeful about the future of MPN. As we mentioned at the beginning of this webinar, the scientific community and the MPN community of clinicians and investigators, it’s such a nice example of how scientists can work together to improve the care of patients. That I always feel very inspired by my colleagues. And now that ASH is around the corner, I can tell you that I feel very hopeful for the future of MPNs because I know that we’re going to learn about a variety of different clinical trials that are showing promising results that are going to ultimately impact the way that we are able to treat our patients with MPN.   

And lastly, I feel very hopeful for the future of MPN because I know that the MPN community is very active. Patients participate in webinars like this, belong to different online groups, and are excellent advocates for themselves. I’ve seen firsthand in my clinic how when a drug gets approved, patients learn about new treatments online and come and ask for them. And so, I just feel very honored to be a clinician that is able to treat a group of patients that can advocate so well for themselves. And so, I definitely see lots of changes in the next couple years.  

Katherine:

This is from Paul who lives in the United Kingdom. “How important is it to see an MPN specialist rather than a general hematologist? Right now I’m currently seeing a general hematologist who makes a note of my side effects but offers no coping strategies or solutions.” 

Dr. Hobbs:

Yeah. That is a great question. And one with not one answer. I would say that if you’re an MPN patient and you have a clinician that treats you that feels comfortable treating you or you feel heard and you’re being offered different ways of dealing with symptoms or side effects, etc., then perhaps you don’t have to go out of your way to find an MPN clinician. And participating in webinars like this or learning online may be sufficient to know how to advocate for yourself and how to monitor your disease. That being said, I do think that it’s nice for patients to at least have a one-time opinion with a specialist.  

And I would say that with the advent of virtual care, that has become increasingly more accessible. And so, if that’s something that’s available to you, that’s something you should consider. You know. Sometimes it’s very difficult to travel a long distance to meet with a specialist. But if you can avoid the travel by having a virtual visit, that often times can be very helpful in just knowing that you’ve met with somebody once. And then you can meet with that person periodically throughout your care can be very helpful. And I’ll tell you personally I see patients in the neighboring states to where I live.  

And I like to see those patients periodically or communicate with their local providers. And so, it just helps to offer care that’s very specialized in maybe areas of the country that don’t necessarily have access to specialized care. So, I would encourage patients to seek that out if that’s something that they’re interested in because it’s really become, I think, easier to access the specialists.   

Katherine:

Mm-hmm. Dr. Hobbs, thank you so much for joining us today.  

Dr. Hobbs:

Thank you so much for having me.  

Katherine:

And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today. 

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What Is a JAK2 Mutation?

Editor’s Note: This resource, What is a JAK2 Mutation?, was originally published by MyHealthTeam.


One of the most commonly mutated proteins found in myeloproliferative neoplasms (MPNs) is the protein Janus kinase 2 (JAK2). This important discovery has changed how doctors diagnose and treat people with MPNs. We will be discussing both the JAK protein and the JAK gene.

MPNs are blood cancers caused by the overproduction of blood cells in the bone marrow. Mutations in the gene controlling JAK2 protein production occur most often in the three classic types of MPNs:

The V617F mutation in the JAK2 gene is found in:

  • 96 percent of polycythemia vera cases
  • 50 percent to 60 percent of primary myelofibrosis cases
  • 50 percent to 60 percent of essential thrombocythemia cases

Additionally, more than 50 different JAK2 mutations have been found in other parts of the JAK2 gene, primarily in PV cases.

What Is the JAK2 Gene?

The JAK2 protein plays an important role in controlling the production of blood cells from stem cells found in the bone marrow.

The JAK2 gene is responsible for genetically coding the JAK2 protein. This protein is part of the JAK/STAT pathway, which transmits signals to promote cell growth.

When the JAK2 protein is activated, it relays a signal to the protein STAT, which then binds to another STAT molecule in a process called dimerization. This group of molecules then moves into the cell’s nucleus, turning on genes that tell the cell to grow and proliferate.

What Causes JAK2 Mutations?

There are two main types of JAK2 mutations found in MPNs.

V617F Mutation

The V617F mutation is caused by a change in a single base in the genetic code. This simple change then switches the amino acid valine (V) to phenylalanine (F) at position 617 in the JAK2 protein, changing the shape of the protein. When this mutation is present, JAK2 signaling is turned on and cannot be turned off, leading to uncontrolled cell growth. In the case of MPNs, this causes an overproduction of blood cells, leading to blood cancers.

Multiple Mutations

Many different types of mutations can be found within multiple parts of the JAK2 gene. More than 50 different mutations have been identified in the gene, and almost all of these occur in people with PV.

One part of the JAK2 gene is particularly susceptible to mutations. This area genetically codes for a linker that connects two parts of the JAK2 protein. Common mutations here include deletions and insertions. A deletion is when entire pieces of the protein are lost. Insertions occur when incorrect pieces are put into the protein. Insertions and deletions change the shape of the JAK2 protein, which can affect its function.

Do JAK2 Mutations Cause MPNs?

MPNs are caused by a mutation in a single stem cell found in the bone marrow. These mutations cause the cell to rapidly divide, creating too many of one cell type. JAK2 gene mutations are involved in many cases of MPNs. In addition to JAK2 genesmutations found in CALR and MPL genes are also common contributors to the development of MPNs. These three mutations are usually mutually exclusive, meaning that if one mutation is present, then the others are not.

JAK2 Mutations and MPN Diagnosis and Prognosis

A number of tests are required to diagnose MPNs, each providing a different piece of information. The doctor will begin with a physical examination and health history. They may also order a complete blood count (CBC) with a differential, which assesses the number of red blood cells, platelets, and white blood cells.

Because most MPNs are associated with a specific genetic mutation, a pathologist may use blood samples to test for these. Two tests used to identify genetic abnormalities are quantitative polymerase chain reaction (qPCR) and fluorescent in situ hybridization (FISH). Typically, only one of the two tests is required for diagnosis. It is also an option to perform DNA sequencing to identify the driving mutation in an MPN case.

Quantitative Polymerase Chain Reaction

Quantitative polymerase chain reaction (qPCR) is the most commonly used method for diagnosing JAK2 mutations. qPCR is also the most sensitive test, and it can detect small amounts of mutation when other methods fail.

With qPCR, DNA obtained from a blood test is mixed with a fluorescent dye, which is run through a machine that amplifies the sequences containing the JAK2 mutation.

Fluorescent In Situ Hybridization

This test determines whether someone has chromosomal abnormalities contributing to a cancerous phenotype. For example, one type of MPN, chronic myeloid leukemia (CML), is characterized by the presence of a Philadelphia chromosome (named for where it was discovered). A Philadelphia chromosome forms when two pieces of broken chromosomes stick together. This is also called the BCR-ABL1 gene, because one broken piece contains the BCR gene, and the other contains the ABL1 gene.

Most people with MPNs who are Philadelphia chromosome-negative (Ph-) have the V617F mutation in JAK2. This important discovery revealed the driving mutation behind Ph- MPNs. Before the discovery of JAK2 mutation, the cause of these defects was unknown. This also led to the development of specific JAK2 inhibitors for treatment of myeloproliferative disorders.

In 2016, the World Health Organization (WHO) revised its document “WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.” This revision included new criteria for diagnosing MPNs by the three main driver mutations in JAK2, CALR, and MPL genes. PV is characterized by the presence of a JAK2 mutation. ET and MF are characterized by the presence of any of the three driver mutations.

JAK2 Mutations and MPN Treatments

Since the discovery of JAK2 mutations in MPNs, researchers have developed a number of inhibitors targeting the protein. There are currently two JAK2 inhibitors approved by the U.S. Food and Drug Administration (FDA) for the treatment of MPNs:

Jakafi

Jakafi (ruxolitinib) is approved for treatment of MF hydroxyurea-resistant PV. It is also being investigated for use in people with hydroxyurea-resistant ET. Additionally, some trials are investigating the effects of Jakafi in combination with the antimetabolite chemotherapies Vidaza (azacitidine) and Dacogen (decitabine). Antimetabolites are a special type of cancer drug that interfere with DNA by acting as a substitute for the normal building blocks of DNA.

Inrebic

Approved in 2019, Inrebic (fedratinib) is the newest MPN drug in almost a decade. It’s used to treat three forms: high-risk MF, post-polycythemia vera MF, and post-essential thrombocythemia MF with splenomegaly (enlarged spleen).

Other JAK2 inhibitors are currently in phase 3 clinical trials, including Pacritinib for the treatment of MF and severe thrombocytopenia, and Momelotinib for the treatment of MF. These promising new drugs are in final phases of testing.

Overall, the discovery of JAK2 mutations in MPNs has helped advance drug research, development, and MPN treatment. It has also helped combat uncontrolled proliferation of blood cells, improving the lives of people with MPNs. New medications continue to be developed and tested, providing a hopeful future for those affected by myeloproliferative diseases.

Finding Support With an MPN

You are not alone living with an MPN. When you join myMPNteam, you gain a community of others who know what it’s like to face a rare blood cancer diagnosis.

Do you know whether your MPN has tested positive for a JAK mutation? Did your doctor explain what the results of the test mean for your condition? Share your experiences on myMPNteam.

How Clinical Trials Advance MPN Treatment and Research

How Clinical Trials Advance MPN Treatment and Research from Patient Empowerment Network on Vimeo.

MPN expert Dr. Angela Fleischman provides a deeper understanding of how clinical trials advance myeloproliferative neoplasm (MPN) research and treatment, explains safety protocols in place for trials, and addresses common misconceptions associated with clinical trial participation. Dr. Fleischman also shares an update on emerging MPN research.

Dr. Angela Fleischman is a physician scientist and assistant professor in the Department of Medicine at the University of California, Irvine. Learn more about Dr. Fleischman.

See More From MPN Clinical Trials 201

Related Programs:

Understanding Common MPN Clinical Trial Terms

Understanding Common MPN Clinical Trial Terms

MPN Clinical Trial Safety, What Are the Protocols?

MPN Clinical Trial Safety, What Are the Protocols?

How Can You Access an MPN Clinical Trial?

How Can You Access an MPN Clinical Trial?


Transcript:

Katherine:

Hello, and welcome. I’m Katherine Banwell, your host for today’s program. Today, we’re going to discuss how clinical trials advance research for myeloproliferative neoplasms, or MPNs, and we’ll talk about what MPN patients should know about participation. 

Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you. 

Well, let’s meet our guest today. Joining me is Dr. Angela Fleischman. Dr. Fleischman, welcome. Would you please introduce yourself? 

Dr. Fleischman:

Thank you very much for the invitation. Hi, everyone. My name is Angela Fleischman. I’m what’s called a physician scientist, meaning, I do research as well as see patients, and my focus for my entire career thus far has been on myeloproliferative neoplasms, specifically their role of inflammation in MPN. And I am at the University of California, Irvine in Southern California. So, nice to be here today. 

Katherine:

Well, thank you so much for joining us and taking the time. Before we get into the discussion about clinical trials, because you’re so heavily involved in research, let’s talk about the latest developments in the field. What MPN clinical trials are you excited about right now? 

Dr. Fleischman:

So, I would say, there’s a lot of new clinical trials in the field for myelofibrosis, which is the most severe form of myeloproliferative neoplasm. 

There tend to be more clinical trials because that’s a patient population in – I don’t want to say in more need, but they do have more need in terms of necessitating better treatments. 

Drugs that are quite far along in clinical trials – and in order for a drug to make it to market, one needs to go through multiple clinical trials to demonstrate the safety, as well as efficacy. Things like a BET inhibitor are very, very promising in moving forward in clinical trials. Other medications for other diseases, such as polycythemia vera, not anymore in clinical trials, but excitingly, newly FDA-approved, was ropeginterferon for polycythemia vera. 

So, that’s a real exciting development for Polycythemia Vera patients. 

And now, we have – outside of the context of clinical trials, because I want to talk about what’s actually available to patients now, we now have three JAK inhibitors available for myelofibrosis patients. And really, since 2011, we had only had one, and then, more recently, a second JAK inhibitor, but now, we have three. So, now we’re moving into an era where we can tailor a specific JAK inhibitor for a specific myelofibrosis patient, depending on what their particular needs are. So, I think that that’s very promising. And then, there are lots of clinical trials combining JAK inhibitors with new drugs. 

Katherine:

So, how does it work? How do clinical trials advance MPN research and treatment? 

Dr. Fleischman:

Well, there are multiple stages of clinical trials. One needs to have some rationale for testing a specific drug in patients. You just can’t say, I just want to take something off the shelf and see if it works for myeloproliferative neoplasms. 

There could be different ways that things sort of enter into clinical trials, either preclinical data from in vitro, meaning, in the lab, in the liquid media, with cells, that makes somebody think that it might work in humans, or that it works in a similar disease to myeloproliferative neoplasm. So, it’s a little bit of a stretch, but a very rational stretch, to then test it in a new population. 

First and foremost, safety needs to be evaluated, because as physicians, one of our primary objectives is to do no harm to patients. So, at very early stages of clinical trials, the primary objective is to see what the appropriate doses, what’s tolerated, what the side effect profile is. 

And then, moving on to efficacy. So, maybe it’s tolerated, but does it actually work at the next stage of clinical trials. Then, a much larger clinical trial would be to do a head-to-head comparison between, in most cases, standard of care versus drug X. 

And I think, for clinical trials, in particular, for myeloproliferative neoplasm, it’s very important to understand what the stated, primary end point is, in particular, for myelofibrosis patients, that myelofibrosis patients may have different problems. Some myelofibrosis patients, their primary issue may be anemia. And so, if they’re looking for a clinical trial to address their anemia, they would probably want to be looking for one whose primary end point is transfusion, freedom from transfusions, or improving the anemia, not necessarily – there was another trial that’s primarily looked at spleen reduction, but they didn’t have an enlarged spleen, that, necessarily, wouldn’t be appropriate for the patient. 

So, I think it is particularly important in myeloproliferative neoplasm to identify what the primary end point is, and whether what you’re going for is that primary end point. 

Katherine:

Mm-hmm. Any advances that are being done in MPN research require MPN patients to participate in clinical trials, right? 

Dr. Fleischman:

Of course. 

Katherine:

So, to start, let’s talk about where clinical trials fit into the treatment plan for ET, PV, and MF patients. When should a patient consider participating in a clinical trial? 

Dr. Fleischman:

Okay, well, I guess a patient could really consider participating in a clinical trial at any point if they had a very altruistic philosophy, that understanding that their participation may not necessarily help them at this moment in time, but may help others in the future, and we’ll gain knowledge about myeloproliferative neoplasms. 

That’s one approach. 

Another approach, which is probably a more usual approach, is when a patient has already tried standard therapies and they haven’t quite worked for them, or they’re in a class where, maybe, we don’t have really great standard therapies for somebody. 

For example, a myelofibrosis who may not be doing too well and may not necessarily be a candidate for a transplant, I think that’s a very reasonable population to go out and seek clinical trials, because there’s really not necessarily a great standard of care treatments for that patient population, or ET or PV patients who have tried standard of care and, maybe, can’t tolerate standard medications, or they’re just not working for them. 

But really, anytime somebody can do a clinical trial, if that’s what they feel is important to them.  

Katherine:

What are the benefits and risks of a trial participation? 

Dr. Fleischman:

So, the benefits are that you’re getting a drug that, potentially, is better than standard of care, that could be standard of care five to 10 years from now, but you’re getting it early.  

As investigators, ethically, we can’t start a clinical trial if we believe that the drug that we’re testing might have negative side effects on the patient, or maybe worse than standard of care. I mean, ethically, that’s not appropriate. So, ethically, we believe that what we’re testing may be better than what we’re currently giving patients, but we don’t know that. So, that’s the purpose of a clinical trial. 

So, a clinical trial, it’s a new drug. So, could have side effects that are on unanticipated, including death. I mean, that’s just the reality. That would be a very uncommon scenario, but it’s an unknown, so it’s an unknown. 

Other things that I think are very important to discuss are the financial implications of a clinical trial. On the pros, one could be getting a free drug that is outside of standard of care, and many of the tests that are done for the purposes of the research are covered. However, drugs, say, if it’s a combination drug, standard of care plus a new drug, the standard of care drug is usually billed to insurance. And so, the patient would need to pay for that, or if there are studies that would be considered standard of care, the patient would need to cover them. 

So, I think it, really, is important to discuss the financial implications. What money is it going to save you by participating, and may there be extra costs, or hidden costs, potentially, involved by participating? 

Katherine:

Yeah. Let’s talk about safety in clinical trials. Would you review the safety protocols that are in place before a clinical trial even begins? 

Dr. Fleischman:

So, before a clinical trial begins, there, usually, needs to be safety information in animals. Also, a lot of drugs have been tried in other diseases first. Either, they’re, have been studied in clinical trials and maybe not found to be very efficacious, but at least we have the value of the safety data in another population. 

So, we’re entering, again, into clinical trials with the understanding that it would not be harmful to humans with the data that we have available in animals, or in liquid culture. But again, we just don’t know that. And then, also, for many clinical trials, starting off at lower doses, and then, increasing the dose slowly in different cohorts of patients, to see what’s the maximally tolerated dose. 

As well as, when somebody is on a clinical trial, safety and side effects are very closely monitored, and even small side effects that likely have nothing to do with the drug, really do need to be investigated fully, just to make sure that they’re not related to the drug. 

Katherine:

Yeah. How do you know if the medicine is safe prior to starting a human trial? 

Dr. Fleischman:

That’s a great question. 

Based on what the molecule looks like, as well as, many times, they’ve been tested in animals to see – for example, for myeloproliferative neoplasm, it would be important to know, does it change a healthy rat’s blood count? Does it harm their liver? Those sorts of things, and safety information is usually available for a new drug. 

Katherine:

Are patients monitored more closely when they’re in a trial? 

Dr. Fleischman:

Yes, definitely. And for the purposes, mainly, of paying very close attention to even small side effects that, if somebody was not watched closely, may be missed because they’re so subtle. 

Katherine:

What if a patient decides to leave a trial? Does that negatively impact their care? 

Dr. Fleischman:

No, and I think that’s a very important point, that, ethically, as investigators, we cannot – and we do need to make it a point to communicate this fully with the patient, that when we’re asking the patient, or informing them about a potential clinical trial, we need to inform them that whether or not they participate will have nothing to do with the way that we treat them. We will treat them equally, regardless of whether or not they participate, as well as, anytime during the clinical trial, a patient has the absolute right, for whatever reason, they can decide to leave the clinical trial. That’s the most – I don’t say that’s the law, but those are the rules of clinical trials, as well as, a patient cannot be treated differently if they decide to leave a clinical trial.  

We have to be fair. I mean, this is – you have to be fair to all patients, and all patients deserve excellent treatment, regardless of whether they participate in the clinical trial. 

Katherine:

Dr. Fleischman, we’ve been talking about what happens when people participate in trials. But what if they don’t? Why is it crucial that patients participate in trials? 

Dr. Fleischman:

Because without participation in clinical trials, we are not going to further our understanding of myeloproliferative neoplasm. Many of the drugs that we use today in myeloproliferative neoplasms, as well as other diseases, the reason why we use them today is because people 10, 20 years ago participated in the clinical trial and demonstrated a benefit of these medications. So, people don’t participate, we’re not going to have new drugs for myeloproliferative neoplasms.  

Katherine:

All right. We know that much of the reason that people don’t participate is because of various stigma associated with clinical trials, and I’d like to talk about that with you. 

Let’s start with the word “experiment.” Why does this word not pertain to clinical trials? 

Dr. Fleischman:

So, I think the word “experiment” may have a negative connotation, and making the patient think, maybe they’ll say, a guinea pig. The only way that we can identify whether a drug is going to be beneficial is to test it out in humans with a particular disease. 

So, I mean, on one hand, it is an experiment, because we don’t know what’s going to happen, but we’re doing the experiment for the benefit of people who are suffering from the same disease. 

Katherine:

Yeah. Yeah. That’s a good explanation. What would you tell patients who are worried that they will receive a placebo? 

Dr. Fleischman:

So, that is part of a clinical trial, and it is also important to look how your clinical trial that you’re interested in is structured.  

So, some clinical trials do receive, or split into placebo, or active drug, and double-blinded means that the patient doesn’t know, nor the physician knows. So, no one knows, and that’s important because we don’t want to sway any subconscious things that, if you know you’re getting the drugs, then you’re going to say your symptoms are getting better, things like that. 

Again, ethically, in a clinical trial, we cannot not give somebody treatment that they – we can’t keep treatment from somebody. So, for example, if a person with polycythemia vera was a, per guidelines, should be on a cytoreductive agent, we cannot, ethically, treat them without a cytoreductive agent. So, it would be – they would have standard of care plus placebo, or drug X. 

So, maybe I’m not explaining this correctly, but if a placebo study is done, the placebo can’t take the place of something that we know is good for the patient. 

We can’t leave them hanging without any treatment, unless, for their specific situation, there’s not, necessarily, a known standard treatment, that it would be very reasonable to treat them with nothing.  

Katherine:

Another myth we often hear is that trials should only be considered if you have no other options. Why is that false? 

Dr. Fleischman:

I think there is a place for patients with no other options that – they may be more inclined to participate in, I want to say, higher risk studies, in which there’s less data to support a particular medication. But that’s why we look at these drugs in patients with no other options, because there’s no other reasonable thing to give them. 

But the patients with no other options may not be an accurate representation of the patient population, as a whole. So, it is important for people who may have other options, but maybe they want to think about, well, I do have a standard option, but maybe there’s something better out there for me, to participate in clinical trials. 

Katherine:

What if an MPN trial isn’t offered at the center where a patient receives care? What can they do?  

Dr. Fleischman:

Many times, specific clinical trials are only open at specific universities. And so, it’s very likely that your university, or the place where you receive care, may have a few clinical trials, or maybe one, or maybe zero for MPNs, but may not necessarily fit your exact circumstances. 

So, what I would recommend is, doing searching on your own, either through clinicaltrials.gov, or the MPN Research Foundation also has some nice resources, but doing some research on your own to identify some potential clinical trials that you’re interested in, and then go to your primary oncologist and say, “Hey, I printed these out. I think these might look really interesting to me.” 

And usually, on clinicaltrials.gov, they would have where they are, and you can actually, also, search for your state. So, maybe bring some that are close to you, and discuss with your primary oncologist the pros and cons of them. And then, ask your primary oncologist to make a referral to the location where they offer that specific trial. 

And a lot of times, you can – there’s a phone number you can call and be pre-screened. Say, “Hi, I’m a 55-year-old man with myelofibrosis,” and there are specific inclusion, exclusion, criteria that they can ask you. And if you don’t meet the inclusion criteria, then it’s not worth your time to go and have an actual visit, but if you do meet the inclusion criteria, then you could go and have an actual visit, and learn a little bit more.  

Katherine:

Oh, that’s great information. Thank you. Here’s a question we received from an audience member, prior to the program. Susan wants to know, “How can I get my community oncologist on board with trial participation? I’m interested in participating in a clinical trial that’s based in Chicago, and I’ll need her help in coordinating care with the team from a distance. Any advice for how to talk to my local doctor about that?”  

Dr. Fleischman:

So, that may be a tough one. So, many times, if somebody has to travel for a clinical trial, it does require some coordination. There are specific – and it’s clinical trial specific. There may be specific things that actually need to be done at the study site. For example, specific labs that would be drawn, and say, need to be frozen within two hours, or specific tests, for example, MRIs, if you need to look at the spleen size, you would need to do it on the same machine for everyone. 

So, there are specific things that have to be done at the location, or if it’s written to the protocol, you have to come to the location for a physical exam on this day and this day, and if it’s not within a two-to-three-day window, then there’s a deviation, and the data is not valid. 

So, what I would say is – sorry, this is a long answer here, but where certain things, if they’re written in the protocol that say a CBC could be drawn at any institution at week four, then that would be reasonable to have your primary oncologist do. But in the context of clinical trials, certain things are really set in stone as to the exact dates that needs to be done, and the exact location. And if they’re not done exactly, to a tee, then your data will not be – your data cannot be used for the analysis. 

Katherine:

Mm-hmm. But then, there’s also the issue of patients being willing and able to travel a distance to a teaching university where a clinical trial might be happening.  

Dr. Fleischman:

Correct, yes. And I think that, for some clinical trials, when the protocol is made, understanding that trying to minimize the trips to the actual site, and working the protocols, working some sort of wiggle room in the protocol, such that lots of stuff, or hopefully, lots of stuff, can be done remotely. But sometimes, it’s just not possible.  

Katherine:

Yeah. I’d like to turn our conversation to health disparities, Dr. Fleischman. Based on American history, some people believe that they won’t receive equitable or safe care if they participate in a trial. 

How can you reassure those people who are concerned they’ll be treated fairly? 

Dr. Fleischman:

Now, I think that this is a very important point, and something that there’s been a lot of emphasis, to try to improve diversity in clinical trials, because our American population is quite diverse. However, the participants that, in general, participate in clinical trials are, unfortunately, still have not a very diverse population in our clinical trials. 

I think what we need to first start doing is education, to reach out to underrepresented communities, to start to build the trust amongst these communities, to tell them about the value of clinical trials. And I think it’s going to take some time to build trust first, because it does take quite a bit of trust to participate in the clinical trial. 

But I don’t have a great answer for that, other than, we need to work hard to, first, build trust, and then, I think the diversity will come. 

Katherine:

Mm-hmm. How does holding on to some of these beliefs lead to limitations in care and create disparities? 

Dr. Fleischman:

So, and rightfully so, if a patient is scared, or has some reservations of participating in a clinical trial, they may – that’s offered to them, that they provide them with, potentially, something better than standard of care. They may be missing out on a potential opportunity. 

Also, potentially, if a patient, if they’re asked about a clinical trial and they have a negative connotation about them, they may lose trust with their physician, if they say, oh, my physician is asking me to participate in a clinical trial. 

This means that they’re thinking of me as an experiment, and maybe they’re not really thinking of me as patient. And so, they may not have that trust with their physician, and so, may not be as open, in terms of communication, with their physician.  

I think it all boils down to trust, and as physicians, we need to demonstrate that we are worthy of the patient’s trust, and we really are ingrained in us to treat every patient the same. I mean, that’s what our oath is. That’s what we’re supposed to do, and I think that the vast majority of patients, they have, ethically, are treating patients exactly the same, regardless of their circumstances. 

Katherine:

Yeah. Health equity means that no matter what a patient’s circumstances, whether it be race, income issues, lack of education, that they should have access to the best care. What is being done by the medical community to address this issue? 

Dr. Fleischman:

So, yes, this is a significant issue, and in particular, with myeloproliferative neoplasms, in whom there are lots of oral drugs – or with interferons, it’s injectable, but you get the prescription, and you give it to yourself – that there can be quite high copays, in some cases, exorbitant amounts, which, really, are not able to be paid for by the vast majority of people. 

So, many companies do have copay assistance programs. Also, foundations have copay assistance programs. So, I think that is, at least, one step in trying to make things more equitable, to get people who need a drug, their drug, at a very reasonable cost. Again, it does take some time, some legwork on the part of the patient, to seek out these programs, or to find an advocate for themselves to seek out these programs for them. 

Katherine:

Yeah. Would a healthcare team be part of that process, though? Would they be able to help the patient? 

Dr. Fleischman:

They will be able to help the patient in terms of saying, “Hey, there’s this program for this drug. Why don’t we fill out the form together?” Or, “Why don’t you call this,” you know. Many times, the patient needs to initiate the process. So, I think the healthcare team can sort of guide the patient in saying, this is what’s available, we can help. We can fill out our portion of the form, you fill out your portion of the form. But no, it does need to be – the patient needs to be an active participant in seeking out the support. 

Katherine:

Mm-hmm. Before we end the program, Dr. Fleischman, I’d like to close with some advice from you. What do you want to leave MPN patients with, relating to clinical trial participation? 

Dr. Fleischman:

I would say that MPN patients today are the key to our future treatments. 

Without participation in clinical trials today, there’s going to be no new drugs for myeloproliferative neoplasms. They’re just not going to appear. We need to test them in patients before them actually coming to market, and before really knowing whether they work or not. So, I would say that the MPN patients today are the key to the future of MPN treatments.  

Katherine:

Dr. Fleischman, thank you so much for joining us today. 

Dr. Fleischman:

My pleasure. As always, I really enjoy connecting with MPN patients, and I think this was a very important topic to discuss.  

Katherine:

Yeah. And thank you to all of our partners. To learn more about MPNs, and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for being with us today. 

What Are Common MPN Symptoms?

What Are Common MPN Symptoms? from Patient Empowerment Network on Vimeo.

Dr. Jeanne Palmer, an MPN specialist, reviews the most common symptoms associated with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF).

Dr. Jeanne Palmer is a hematologist specializing in myeloproliferative neoplasms (MPNs) and bone marrow transplant at the Mayo Clinic in Arizona. Dr. Palmer also serves as Director of the Blood and Marrow Transplant Program and is Vice Chair and Section Chief for Hematology. Learn more about Dr. Palmer, here.

 

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Transcript:

Katherine Banwell:

Would you walk us through the common symptoms of each of the MPNs? Let’s start with essential thrombocythemia. 

Dr. Jeanne Palmer:

Right. So, there are a number of shared symptoms throughout all the diseases and when we start to figure out how to categorize them, they call into several different categories. The first one is inflammation-related symptoms. We know that the inherent pathway that’s dysregulated or that causes these diseases to happen can also result in significant inflammation in a person, that can result in things like fevers, night sweats, weight loss, and overall feeling really fatigued and poorly, which is something that it seems to be much more prevalent in patients with MPNs, all sorts of them, actually. 

The next set of symptoms is related to microvasculature, so all the little blood vessels. And sometimes we think, oh, maybe that’s because there’s too many red blood cells or platelets and the blood become viscous. It’s probably more related to the actual dysregulation of that JAK2 pathway, which is inherent to all the myeloproliferative diseases and as a result, the little blood vessels can clamp down and that can give people headaches, visual changes, numbness and tingling in the hands and feet, and even can cause sort of a painful rash called erythromelalgia in the body. 

So, these are things that can happen that are probably less appreciated side effects of the disease. And finally, there’s spleen-related symptoms. The spleen is in the left upper quadrant of the abdomen and it’s an organ that generally is about 12 centimeters in length, 10 to 12, but in patients with myeloproliferative diseases it can be enlarged. And as a result of an enlarged spleen people can have feeling like they get fuller early. So, if you’re eating a meal, all of the sudden you can only eat half of that meal versus the whole meal. 

Discomfort or pain in the left upper quadrant. Sometimes it’s much more noticeable when you like bend over to tie your shoes. And then sometimes people can actually, when the spleen gets really big, the blood flow can be impaired towards the end of it which can cause some of the spleen tissue to die, and that can be painful. So, these are things that if somebody does start to notice that they’re having fullness in the left upper quadrant, pain, stuff like that, that that may be related to spleen symptoms.  

Katherine Banwell:

What about PV or polycythemia vera, what are the symptoms? 

Dr. Jeanne Palmer:

So, all of these sorts of relate to all of the myeloproliferative diseases. So, one other one that I didn’t mention, and this is actually more in PV than others, is itching. Itching can be absolutely unbearable when somebody has PV. It’s particularly noticeable after taking a shower. So, a lot of times I’ve met patients who are like I haven’t been able to take a shower in years, because it causes such a high degree of itching. 

Katherine Banwell:

Why a shower? Is it different from having a bath?  

Dr. Jeanne Palmer:

Water on the body that can cause the problem. So, if people take hot showers, it’s even worse. Although I think that people sort of react to it differently. Usually what patients end up doing is more like sponge bath type of things, rather than actually being exposed to the water. 

 Taking colder showers or cooler showers can sometimes help mitigate that. But the itching, and even in the absence of a shower, people can have pretty severe itching, and that can also be one of the major side effects. 

Thriving With an MPN: Tips and Support for Navigating Care Resource Guide

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Three Reasons MPN Patients and Their Families Should Continue Telemedicine

What are some reasons why MPN patients and families should continue to use telemedicine visits? In the “Should MPN Patients and Their Families Continue Telemedicine?” program, expert Dr. Kristen Pettit from Rogel Cancer Center shares three ways myeloproliferative neoplasm (MPN) patients and families can benefit from continuing to use telemedicine for care.

1. Access to Care

One of the most impactful benefits to patients from the COVID-19 pandemic has been the emergence of telemedicine. Telemedicine has brought improved access to MPN experts, care teams, and specialty cancer centers via smartphone, tablet, or computer to broaden expert care for patients and care partners. Many family members or friends can now join telemedicine visits to help ask questions and to take notes for more engaged patient care.

2. Safety and Travel Benefits

The use of telemedicine has also brought safety and travel benefits. Patients and care partners have reduced the amount of time they spend in clinics and waiting rooms. Their risk of infection with viruses, bacteria, and other illnesses has been decreased when some of their MPN care appointments can be carried out remotely. And reduced travel to appointments helps patients and care partners in lowering  travel costs and stress related to commuting or scheduling rides.

3. Remote Monitoring

MPN patients must also empower themselves to keep track of their health concerns to ensure their remote monitoring is reported accurately. Patients and care partners can monitor any weight changes, enlargement or feeling of fullness with their spleen, feeling overly tired or fatigued, and other symptoms their care provider has mentioned as symptoms to be aware of. If you have any questions about symptoms, make sure to ask your doctor.

By continuing to take advantage of telemedicine, MPN patients and care partners can reap the benefits of remote care paired with in-person visits as advised by your doctor. If you’d like to expand your knowledge, check out our MPN information.

Thriving With an MPN: Your Role in Managing Your Treatment and Care Resource Guide

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Blood Cancer Awareness Month 2022

How Can MPN Patients Become More Proactive in Their Care?

How Can MPN Patients Become More Proactive in Their Care? from Patient Empowerment Network on Vimeo.

How can MPN patients become more empowered and active in their care? Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London shares advice for patients to gain confidence to become a more active participant for optimal care.

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Transcript:

Dr. Nicole Rochester: 

So what advice would you give for patients so that they can really take a proactive approach to their healthcare and feel more confident in talking about their concerns and communicating with their healthcare team, you’ve shared with us how important that is. Do you have maybe two or three specific tips or maybe questions that every MPN patient should ask their healthcare provider?

Dr. Claire Harrison: 

I think the first thing to say is, in my personal view is you do not have to be under an MPN expert to get the best care. I know some people differ with regard to that, but these are chronic conditions, there are national and international guidelines, clinicians are connected. We all talk about patients over time, as we like to do that, we like to get the best for our patients, so a local center with a clinician who you trust, who you get on with…where you can get there easily. You trust their team, you know their logistics work for you, maybe it’s a nurse who work who you get on with, well, who comes to the appointment with you, that is just as good as being under the best professor in the state, where you might not actually see them  when you turn up and go to the unit, so that’s really important, understanding your condition, and if you don’t understand being empowered to ask questions, and if you’re in a position where you can’t ask a question, something’s wrong. So don’t be afraid, take somebody with you, write it down. 

Sometimes it can be a mistake to do a troll on the Internet, so I wouldn’t always encourage that because what’s on the Internet is not always accurate, but go to a trusted website as the clinician…where can I go to find out more information? Some patient advocacy groups run buddy systems that can also be very helpful and it can be very empowering to meet another patient with the same or similar condition, so I think those are all helpful tips from my perspective, also don’t expect to get all the answers all the time, it can be really tricky as a clinician, maybe you get a patient who comes with a big long list of questions, and say What is your top question that you really want answers to. 

Dr. Nicole Rochester:

Those are awesome, awesome tips. I’m just going to repeat a few of them, just to highlight, you mentioned prioritizing your concerns which is incredibly important, and acknowledging that the clinician doesn’t have unlimited time, and so really focusing on the things that concern you the most, you mentioned bringing a buddy to appointments, which is something I fully endorse, so that there’s someone else that’s taking notes or…it can be your eyes and ears during that appointment, things that you may have missed either because of anxiety or stress, and you mentioned writing things down, taking notes, even as the patient asking questions, which is so incredibly important, and really the way that I feel patients demonstrate their involvement in their disease and being an active member of the team, so I really, really appreciate those tips, Dr. Harrison, I think that you have given us so information, so much information about how to empower MPN patients and their families so that they can really get the best care at the outset. 

Advice for Hesitant MPN Clinical Trial Participants

Advice for Hesitant MPN Clinical Trial Participants from Patient Empowerment Network on Vimeo.

What should MPN patients know about clinical trials? Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London shares information about the varying degrees of clinical trials and advice to those who are hesitant about clinical trials.

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Transcript:

Dr. Nicole Rochester: 

It’s said that clinical trials are tomorrow’s medicine today, and you’ve already kind of alluded to the importance of clinical trials as it relates to MPN. What would you say to an MPN patient who is on the fence or may be concerned or afraid of participating in a clinical trial?

Dr. Claire Harrison: 

It’s right to be cautious and, you know, careful because ultimately it’s a huge privilege as a clinician that involves patients in clinical trials that my patients trust me and trust my team to look after them with something that is experimental, but remember there are varying degrees of experimental. Most clinical trials are not first in man, you’re not a complete guinea pig, it may be a drug, for example, navitoclax is in clinical trials mainly for myelofibrosis also ET and PV but that is a drug that has been used for thousands of patients, for another indication so talk to your healthcare team, if you don’t find the answer from the primary person that you’re used to dealing with, find someone else, be linked to somebody you trust and that you have a good relationship with, take someone with you to the consultation, write down the questions I’m so sure you say this all the time, don’t you Nicole to the people that you talk to, but write down your questions, don’t be afraid to ask them again, there is no stupid question in this context, you will be given a 30-plus page booklet to read, and I lost count of the number of times, my patients go, yeah, I’ve got this, or I trust you.

Actually, you know, you need to read it…we are experimenting on you, and you need to read that and understand. And you need to understand, what happens if I go on the control arm, will I be able to cross over? How many visits will I have, will I have to pay for those visits, etcetera. It’s all really important. But ultimately the relationship with your healthcare provider is important, and using an advocate is really important too.

Dr. Nicole Rochester: 

I agree 100 percent. So important, these are things that I talk about all the time, so I really appreciate that you highlighted that, and just the importance of patients taking an active role in their medical care and also the trust that is required between the patient and their treating providers. So I really appreciate that. Do you have any examples, Dr. Harrison, in your own practice of successes with MPN patients who have participated in clinical trials? 

Dr. Claire Harrison: 

Oh yes, I think I started doing clinical trials, well golly, a long time ago. I think my first clinical trial, probably the records were written parchment to be honest, but we’ve still learned a lot from that, so that was an ET study. It was from that study we understood about the JAK2 mutation, and we understood how patients behave differently. I think probably the most gratifying thing for me was being involved in the JAK inhibitor studies in myelofibrosis and being involved in delivering ruxolitinib and Jakafi to patients and seeing the benefits for those patients. 

Big things, you know, there are patients who are alive because they took part in that trial today, I think, but there are also patients for whom small things were also really important, so as a patient, that’s important to define what is the benefit you want to get. So one of my first patients, you haven’t been able to have a bath or a shower for years, because he had terrible what we call aquagenic pruritus, itching induced by contact with water, we called him two days after he started ruxolitinib (Jakafi), and he was in tears, he could take…or you can take it out.

These things are really important. Like myself, I can imagine not being able to dig it out, I would either be very tough for another patient, it was, well, I looked really skinny because I’d lost loads of weight and I put weight on, and body image was really important as well, but then the small things like being able to be…participate more in family activities is really, really important too. 

What Are the Unmet Needs in Access to MPN Care?

What Are the Unmet Needs in Access to MPN Care? from Patient Empowerment Network on Vimeo.

Which areas of MPN care still need improvements to access? MPN expert Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London explains patients who still experience barriers to care and what can be done to reduce access issues.

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Transcript:

Dr. Nicole Rochester: 

What would you say are the unmet needs in access related to MPN and care, specifically as it relates to clinical trials, and what can we do to address those unmet needs?

Dr. Claire Harrison: 

Well, I think there is a problem with rare diseases in terms of geographical access to trials, and we often find patients have to travel a long way. I know that’s true in North America as well as in Europe. And we’re very lucky in our geographical locations, but in some parts of the world, some companies or doing not open clinical trials, so I think there’s an access issue. 

I think also there is something about patients have to meet rigid entry criteria for clinical trials, and so oftentimes in myelofibrosis, for example, commonly patients who fail ruxolitinib (Jakafi) have a lower platelet count, and that is often an exclusion criteria. Those criteria are there to try to get a uniform population of patients in a trial, but it can feel like you’re excluded as a patient, and it can feel very tough and for your health care team that we can’t include you in a clinical trial. We also have to remember that it is there for safety purposes, so if there is a lower limit for platelet count, that’s often because the drug might affect platelet count. It is really important that we have a broad spectrum of trials available and that we try to increase the availability of trials for patients. 

I also want to say a word about inequality of access and thinking about accessing some different ethnicity, so often non-white MPN patients are under-represented in clinical trials, and I know that a focus in the UK and also in North America as well. And it is really important that patients have access to a clinical trial if they need it, and also that we understand how investigational products will work in people of different backgrounds. So for example, we know that probably, Nicole, your blood count assuming it’s a healthy, normal blood count may well be different from mine for background, racial genetic differences, so drug metabolism might be different, so this is really important, and we need to work hard as a community, the clinical community and the patient community to raise awareness and improve access for patients. 

Dr. Nicole Rochester: 

Well, as someone who does a lot of work in health equity, Dr. Harrison, I really appreciate you pointing that out. It’s certainly an issue here in the United States, as you mentioned, differential access to clinical trials, and we’ve learned that not only our patients, often not aware, but often the providers, at least here in the U.S., are not offering clinical trials as an option for patients from marginalized and minoritized communities. So I really appreciate you bringing that up. 

MPN Treatment Strategies for Patients Who Have Failed Traditional Therapies

MPN Treatment Strategies for Patients Who Have Failed Traditional Therapies from Patient Empowerment Network on Vimeo.

What can be done for MPN patients who have failed on traditional therapies? MPN expert Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London explains some treatments under study as options for some patients.

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Transcript:

Dr. Nicole Rochester: 

What about for patients who have failed therapies, are there any treatment strategies for MPN patients who have failed traditional therapies?

Dr. Claire Harrison: 

Yes, in fact, actually, that’s where we’re evaluating new therapies across all of these entities, so if you’re a PV or an ET patient and you failed a therapy, then this is where, for example, in ET, we would be looking at bomedemstat or we’re looking at the bromodomain inhibitor pelabresib, and there’ll be other agents that we’ll be looking at, or we might be looking at vaccination. And for MF patients that while there are a bunch of different therapies for patients who you have not tolerated or progressed through standard therapy. So actually, there are a lot of options, some of them are already approved, and some of them are in clinical trials. 

How Are MPN Treatments Changing for Low-Risk vs High-Risk Patients?

How Are MPN Treatments Changing for Low-Risk vs High-Risk Patients? from Patient Empowerment Network on Vimeo.

How do MPN treatments vary for low-risk and high-risk patients? MPN expert Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London explains how treatment differs for these patients and changes that she would like to see for care of some patients. 

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Transcript:

Dr. Nicole Rochester: 

How are treatment strategies changing for low-risk and high-risk patients with MPN?

Dr. Claire Harrison: 

It’s complicated because we need to think across the entities, and we don’t have an answer to that for patients with MPN unclassified. And we don’t actually have a good answer to that for this entity called pre-fibrotic myelofibrosis, which does appear and is strongly recognized in the new diagnostic criteria. But for ET, for example, low-risk patients I mentioned triple-negative, calreticulin, M-positive, young patients, platelets less than 1500, not too much changing their queries about aspirin or not, and then for PV patients, we haven’t really changed all kind of high-risk criteria and for both ET and PV, the questionnaire is, should we use the treatment above aspirin or above aspirin and venesection. 

And for the most part, that would be hydroxycarbamide, hydroxyurea (Hydrea), which is the commonest treatment used worldwide or interferon, and these are the right treatment for some patients and not the right treatment for other patients, so some patients can be very fixated on interferon is the absolute best, but there is no clear evidence of that, and there are some patients who interferon is not the right treatment, but low versus high risk becomes even more important for myelofibrosis patients.

And here, we’re thinking about using a risky strategy like transplantation for those patients who have higher risk disease, and we’re using, as I mentioned to you, these molecular markers and newer prognostic tools to stratify patients. And it is important to remember as a patient if someone puts your data into a prognostic tool and that comes up with five years, but it doesn’t mean to say five years on the dot your time’s up, that’s an average. And if we put your data into a slightly different tool, we might get something else. So for the most part, we make decisions like transplants, we are learning more about transplantation and outcomes from that, and then in some countries, some treatments are used for patients who fall into intermediate or high-risk categories, and some clinical trials are based on that as well. I would want to say about myelofibrosis, and something I think I would really like to see changed, not changing yet, but changed, is that we should be able to intervene for patients with a low-risk disease. If my myelofibrosis patients have breast cancer, we would not be going there, then you’ve got low-risk disease, we’ll put you on watch and wait, watch and wait is really hard for our patients, we know that I can see you nodding.

You know that too, right? So if these were patients with breast cancer we would not say, we’ll just watch and wait. So I would really like to see in the next five to 10 years a treatment that we could use earlier in the disease course, but there is nothing at the moment, but we’re looking at that. The other thing we’re looking at, if we’ve got a minute or so is the different endpoint, so we’re trying to understand what does it mean if your allele burden, so the amount of abnormal genes you’ve got goes down, the amount of bone marrow fibrosis you’ve got goes down. And again, this is something we’ll collect in a clinical trial, but also from real-world data.