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Disease Progression in Myeloproliferative Neoplasms

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Published on August 25, 2021

What Do We Know About MPN Progression?

In this Answers Now program, host and MPN patient advocate Ruth Fein is joined by renowned myeloproliferative neoplasm (MPN) expert Gabriela Hobbs, MD, Clinical Director of Leukemia Service at Mass General and an Assistant Professor at Harvard Medical School, for a discussion about progression. Ruth and Dr. Hobbs break down this intimidating concept. Who is at risk? What should MPN patients look for in themselves? How likely is progression?

This series is supported by an educational grant from Incyte. This organization has no editorial control. It is produced by Patient Power and Patient Power is solely responsible for program content.


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Transcript | Disease Progression in Myeloproliferative Neoplasms

Ruth Fein: Hi, everyone. Thanks for joining us for our newest series on myelofibrosis today, one of the myeloprolific neoplasms or MPNs. I'm Ruth Fein. I'm a health and science writer and a patient advocate for Patient Power. We're here today with the renowned myelofibrosis specialist, Dr. Gabriela Hobbs, affectionately known as Gaby. She's Clinical Director of the Leukemia Group at Mass General Hospital in Boston and Assistant Professor at Harvard Medical School. Welcome, Dr. Hobbs. Great to see you again.

Dr. Hobbs: Great to see you again, Ruth. Thank you so much.

Ruth Fein: Thanks for spending some time with us today. Just for the record, we are a really large audience tuned in right now from across the U.S., and a shout-out to Israel and the UK and as far away as Australia.

Dr. Hobbs: Wow, that's wonderful.

Ruth Fein: Yeah. We're all looking forward to your insight on progression, when an MPN progresses from one to another. For example, when essential thrombocythemia (ET) or polycythemia vera (PV) progresses to myelofibrosis (MF), or as it can happen to an acute leukemia. So, let's get started. There's a lot to talk about.

We're talking today about the scariest word to a person like myself and most of this audience, and that word is progression. So, Dr. Hobbs, would you help people put that in perspective? How many people living with ET or PV are likely to progress to myelofibrosis? And then, what percentage of people with MF are likely to progress to acute myeloid leukemia (AML)?

How Likely Is Progression for ET, PV, and MF Patients?

Dr. Hobbs: That's a great question and something that is definitely always on the mind of the providers as well as the patients. Progression depends on the subtype of disease. Patients with ET are the ones that are the least likely to progress and maybe will progress to myelofibrosis about 5-10% of the time and to acute leukemia less than 3% of the time.

Patients with polycythemia vera have a slightly higher tendency to progress to myelofibrosis, and that can happen somewhere between 10-20% of the time, with a progression to acute leukemia, which can sometimes occur without necessarily a step in myelofibrosis, in about five percent or less of the time.

For patients that have myelofibrosis, we worry, of course, about transformation to acute leukemia and really, depending on the subtype of myelofibrosis, that can vary. But about 20-30% of the time, over a patient's lifetime, patients can progress to acute leukemia.

Ruth Fein: So as you know, I've been through all three over the last 25 or 30 years, ET, then PV, now MF. But that too has not been as scary as some might think and as scary as it might sound, not for me at least. And I'm one of the lucky ones, of course. But I'm feeling great thanks to the hard work of scientists and clinicians like yourself and other people living with MPNs, who [are] willing and able to participate in clinical trials like the one I'm on that's been so successful. Researchers, like you and others, are working hard to understand why progression occurs sometimes and not other times. So, what have we learned in the laboratory and from clinical trials that might help us determine who is likely to progress and who isn't?

Dr. Hobbs: That is such a wonderful question, and I think that we have made a lot of progress in that area. But, definitely, a lot of progress remains to be made. There have been a lot of insights that have been very interesting in terms of when do patients pick up or develop these mutations that are the center of our conversation in patients with MPNs.

There was a research study that was presented at our annual hematology meeting last December that showed that some patients may have the JAK2 mutation even as early on as when they are babies in utero. So, there's a lot that we need to learn about, “Why do some people get these mutations, and some don't?” And then, like you said, Ruth, if you have a mutation, and you have a disease like ET or PV or myelofibrosis, what determines if that patient is going to then progress from ET to myelofibrosis, or from myelofibrosis to leukemia?

Some of the things that we know for sure contribute to progression have to do with other mutations. It's difficult to talk about MPN without talking about mutations. And so, I'm just going to divide it into two groups. We have the main MPN mutations, which are mutations like JAK2, which is the most common. And then we have two mutations that are slightly less common, one called calreticulin and another one called MPL. Most people will have a mutation in one of those.

But we've started to learn about other mutations. We know, especially true for patients with myelofibrosis, if they have other mutations and especially if they have several other mutations, that most definitely increases the risk of transformation. For PV and ET, we're just starting to learn about that and trying to figure out what it means to have those other mutations.

Ruth Fein: Yeah. We know that some people, myself included, can have fairly benign disease over the years, and then it can progress slowly. And then others have a very swift transformation. What do we understand about why that is, and how it plays into predicting outcomes, and maybe how aggressive to be with treatments, from the lab to the patient clinically?

Why and How Does Disease Progression Occur?

Dr. Hobbs: Right. That's a great question, and it relates a little bit to my last question, but also highlights what we don't know. We have some patients that may look for all the world on paper like they won't progress. And then we have them come back, and the next thing we know, the blood counts are very different, and we're very worried about progression. And then we have some patients with a lot of mutations, where we think that they would most definitely progress, and they don't.

One of the things I tell my patients is that mutations aren't promises. Mutations just help us understand a little bit about the disease process at a population level. But what does that mean for that individual patient? Sometimes it's hard to know.

But in general, patients that have several mutations in the genes that are called high molecular risk mutations are more likely to progress than patients that don't have those mutations. Patients that have myelofibrosis and present with very low blood counts and perhaps increased numbers of blasts, which are an indicator of leukemia, if you have a lot of them, those patients are more likely to progress more quickly. And then there are some patients that progress, and we really don't have a great explanation as to why they progressed.

Ruth Fein: Do we think that there's aggressive forms and less aggressive forms of MPNs, and particularly myelofibrosis? Are we getting any closer to understanding this or even to predicting an individual's expected disease journey over their lifetime?

Are Some Forms of Myeloproliferative Neoplasms More Aggressive Than Others?

Dr. Hobbs: Yeah. That's a great question, and there's definitely been progress in that regard. One of the tools that I utilize, whenever I meet a patient for the first time, is a risk stratification tool. For myelofibrosis in particular, over the course of many decades, there have been several iterations of these tools. What that means is that your clinician can plug in several different parameters, which include age and blood counts and symptoms and other things like that, to get a sense of “Does a patient have myelofibrosis?” They should be considered low risk, meaning it has a lower likelihood of progressing. Or should it be considered higher risk, meaning that it potentially has a higher likelihood of progression.

Over time, these scores have become more sophisticated and more detailed, based on what we've learned in the laboratory about how to think about and how to utilize genetic mutations. The most recent score is a score that's called the MIPSS70, and that M is for molecular because we utilize, “Does a patient have a JAK2 mutation?” Yes or no. “Does a patient have other mutations?” Yes or no. And, “Does a patient have many other mutations?” Yes or no. And so, the scores now integrate what has been learned about these genetic mutations, and that really helps us to better guide our patients in terms of what to expect. And it also helps us to determine how best to treat patients or not to treat patients.

Ruth Fein: Right. Right. That was one of my questions. How does that translate to treatment? Knowing what we now know, are you able to move away from that sort of early wait and see? I'm thinking about an early diagnosis of ET or PV, with no progression yet or at all to myelofibrosis. Is there less of a wait and see, and more of a reason to be more aggressive or different in your treatment options?

Dr. Hobbs: That's a great question. I hope to be able to give you a different answer in a few years. In the world of ET and PV, there's been a recent interest at perhaps starting treatment earlier than we would normally. In general, classically speaking, patients that have ET and PV receive treatment to normalize blood counts in order to prevent blood clots or bleeding and in order to ameliorate symptoms, but the treatment generally doesn't change the course of disease. I find it unsatisfying. I'd like to be able to give my patients a treatment that is going to actually modify what's happening in the bone marrow and prevent that progression from happening in the first place. I think this is a theme of all of medicine. It's much better to prevent something than to have to treat something later.

There is a new interferon, called Ropeginterferon, that was approved in Europe, and hopefully, it will be approved in the United States. Some of those studies have included some patients that would historically not meet the traditional criteria for starting a medication. Over time, some of these patients have seen a decline in the number and the level of their mutations. Although one would think intuitively that less is better and that if you have no mutations, that means you're not going to progress. One of the things of science that is interesting and sometimes frustrating is that just because something makes sense doesn't mean that it's true. So, we don't actually know that that's the case, but hopefully we'll have an answer to that question at some point. And perhaps, Ruth, like you said, some patients that are maybe earlier on in their disease will get medication with the hope of preventing that progression from happening. We just don't have a medicine for those patients that'll do that quite yet.

Ruth Fein: Right. But we're all very hopeful. It's a really hopeful time. There's so much research going on and molecular research and treatments. We know so much more than we did even two, three, five years ago. We're all very hopeful. There's a lot going on.

I'd like to switch gears just a little bit. I'd love to talk about the importance of participation in clinical trials. We know how much clinical trials, myself included being on one, we know how much they mean to the science and to the clinical understanding of MPNs, including progression. Particularly among women and representation from different racial and ethnic, socioeconomic, groups within the MPN patient community. What would you say to why that's important that we have a broader participation?

The Importance of Diversity and Inclusion in MPN Clinical Trials

Dr. Hobbs: I'm so glad you asked that question, and that sort of relates to the answer that I gave before, where just because something makes sense doesn't mean that it's true. And I'll tell you how that applies to this. If we only have participants of one gender or one ethnic group participate in trials, we don't actually know that the results of that study apply to every ethnic or racial group or to both genders in the same way. I think that it's really important to try to get a broader group of patients to participate in clinical trials in order to really make sure that the results of our studies are actually applicable to the patients that we really do treat.

Ruth Fein: I know you've done some work with that, which we appreciate, and we hope that more centers will do as good a job as you're doing in that work. Are you actually seeing biological differences in different communities when you do get a better representation? Is that something? Is it more about access, or is it more about physiological differences?

Dr. Hobbs: Yeah, no, that's a great question, and I wish I had a better answer. As far as I know, there have not been any documented differences in terms of the genetic makeup of each of the diseases in different communities. But we do know there's been some studies that women may have symptoms that are different than men with PV, for example. I think we can't learn about the different genetic makeup of different groups, men or women, or Hispanics or African Americans or Asian Americans, et cetera, if the only people that we're including in the study are Caucasian men or something like that. So, we haven't really been able to make that distinction because we just don't know.

Ruth Fein: I have a question that was typed in from Susan, who's participating today. It's a great question. Is pre-fibrotic myelofibrosis much different than ET?

What Is the Difference Between Prefibrotic Myelofibrosis and Essential Thrombocythemia?

Dr. Hobbs: That is a great question, and the short answer is it's not that different. The more difficult question is how different is it, and what should I do about that? We don't know yet. Just from looking at studies, and this relates a little bit to one of the answers I gave before, that a genetic mutation is not a promise, and same here. A little bit of fibrosis is not a promise that this is going to transform or get worse.

When we look at large studies, with lots of patients, those that have some scarring tend to do worse than those without any scarring. That doesn't necessarily mean that everybody with prefibrotic myelofibrosis is not going to do well. Clinically speaking, when I have a patient with prefibrotic myelofibrosis, and their blood counts look, for all the world, like they have ET, I'll treat that patient like they have ET.

It would be fantastic if we could do clinical trials specifically in that group of patients that have prefibrotic myelofibrosis to see if any treatments really do halt that progression. Unfortunately, because that group is small and difficult to identify, it is difficult, logistically speaking, to develop clinical trials that specifically target that group. So, I'll tell you most scientists that work in the lab are absolutely fascinated with the concept of pre-fibrotic myelofibrosis. But when you're in the clinic, treating patients, you realize that it's actually really hard to find patients, such as yourself, with prefibrotic myelofibrosis to put on trials. But I hope that we're able to overcome that, or at least include a group of patients with prefibrotic myelofibrosis in our studies because, really, that's the only way to learn.

Ruth Fein: Yeah. I'm wondering, again, as someone who has had all the different MPNs so far, over almost 30 years, I may have had prefibrotic myelofibrosis when it was thought that I had ET and PV. So, what that makes me think is, would you be testing people? Would people be having bone marrow biopsies earlier, sooner in their health journey, so that you knew who was and who wasn't?

Dr. Hobbs: This gets into a controversial issue, where people that treat MPNs feel very differently. So, take that with my own bias. I think that part of the reason why we identify prefibrotic myelofibrosis is because we do bone marrow biopsies. But not everybody that treats MPNs does bone marrow biopsies. Most people, I would say, that have a diagnosis of ET and PV, or maybe most is too much, but a lot of people that have a diagnosis of ET and PV don't have a bone marrow biopsy. And listen, for the most part, that's not necessarily the wrong thing, especially because we don't have a medication that can help that progression. But many people, if they present with blood counts that look like ET and PV, and a mutation is found, and there's nothing else in the blood work that looks concerning, it's not an unreasonable thing to not do that initial bone marrow biopsy. So that's why we sometimes don't pick up that prefibrotic myelofibrosis.

Ruth Fein: Yeah. Thanks. We have a few more questions I'd like to get to. Melissa asks, can Ropeg be given to ET patients as well?

Dr. Hobbs: Yeah, so Ropeg is not currently approved for ET patients, but it is most certainly being studied for ET patients. So, stay tuned.

Ruth Fein: The next one is related. It's from Kathy, and it's related to what we were just talking about, prefibrotic myelofibrosis. Her question is how would I know if my ET prefibrotic is progressing to myelofibrosis? I assume it's the bone marrow we were just talking about, but if you'll answer that, that'd be great.

Dr. Hobbs: That's a great question, and it actually applies to any patient that's living with ET and PV or with prefibrotic myelofibrosis. There are several hints that things are progressing. I would say that, although obviously the gold standard to assess progression is a bone marrow biopsy, I really don't recommend that patients with ET, PV, and prefibrotic MF have very regular bone marrow biopsies because we're not going to do that much with that information. We really should only do those bone marrow biopsies if we're going to do something with those results.

But one of the ways that it's important to know if the disease is progressing is what does the blood work look like? Oftentimes, a clinician that treats MPNs will be able to get a sense of progression just by looking at the blood work. Are the counts changing? Is a patient that previously had a really high hemoglobin or red blood cell levels, all of a sudden, very anemic or having low blood cells? Or are there cells that are floating around in the blood that maybe indicate that there is some progression occurring?

In addition to the blood work, if a patient, all of a sudden, starts to develop a large spleen, and that's associated with some symptoms like fevers, night sweats, weight loss, all that together can be an indicator that some progression is occurring. And that could occasionally prompt a clinician to recommend a bone marrow biopsy, but not always. Having regular checkups with MPN providers is important in order to identify that progression.

Ruth Fein: We have one more question from James, who says, as a male PV patient, who is using Hydrea, which is hydroxyurea, and having phlebotomies, you said this is only to manage the symptoms. What would be a more aggressive treatment? So, the question being, for PV, what do we have now as an option for more aggressive...?

Dr. Hobbs: Hydroxyurea and phlebotomy are utilized for two things: to manage symptoms, like you said, but also to prevent blood clots. And that's actually very important. Although it's not as attractive in that we're not preventing progression, really, for a patient that lives with PV, preventing blood clots is critical because a PV patient is much more likely to have a problem with a blood clot than with progression. And I think that's an important thing to remember. Although hydroxyurea will not prevent progression, it will prevent blood clots, and it will prevent symptoms, and not everybody, but in some patients.

In terms of more aggressive, I wish I could tell you, if you just take this really intense chemotherapy treatment, et cetera, then you won't progress. We don't have that right now. We are interested in the interferons, both the interferons that are currently available, like pegylated interferon and, potentially, in Ropeginterferon, but we don't actually know that those drugs will prevent progression. Right now, even if you're willing and able, et cetera, we don't have something that will actually prevent progression from happening.

Ruth Fein: I want to go back to research for a bit, before we close. I know you work with Dr. Ann Mullally at Dana-Farber and others on what we call translational research. Can you walk us through that? We've been asked about that before because the term is used broadly, and people don't necessarily know what it means. Perhaps use an example, how bringing research from the lab to the clinic has changed some of your treatment options or your treatment approach to a particular group of patients, which you did allude to.

What Is Translational Research?

Dr. Hobbs: Yeah, sure. There's a lot of different types of research, and translational research can mean several different things. But I'll give you an example, exactly like you said, from my research. I'm what's called a clinical investigator. What I do, when I'm not seeing patients, is I'm thinking about clinical trials for patients, what medications are available, and how can we use those to improve the care that's delivered to our MPN patients.

But we also know that there's a lot that we need to learn about the biology of these diseases, why some progress, why some don't progress, et cetera. One of the things that I built into my clinical trials is the translational piece. What that means is that, as a patient in a clinical trial, and this is not just with me, of course, it's in clinical trials in general, you may be asked to give samples of blood and samples from bone marrow biopsies, if they're done as part of the trial, to answer a specific biological question.

Those samples, in my case, will go to Dr. Mullally and some of my other collaborators to see if we can learn something outside of just the clinical trial. That may be, “Is there a better way to measure what we call remission, by doing more sophisticated testing in the lab?” That may be related to, “Can we understand what the immune status is of patients that are on treatment compared to when they weren't on treatment because the immune system may play a role in how patients respond?” Those kinds of questions.

Those questions don't necessarily answer a question directly about how to treat a patient, but the hope is that by better understanding the underlying mechanisms that lead to these diseases, that we will eventually be able to have better insights to develop better clinical trials and, ultimately, develop better treatments for patients.

Ruth Fein: I just got one more question in that I want to slip in. It's a good one. It's from Arnold. Is there a relationship between the JAK2 burden and progression?

Is There a Connection Between JAK2 Burden and Progression?

Dr. Hobbs: That's a great question, and as of right this moment, we don't actually know that. Some patients with ET have maybe a lower JAK2 burden. PV patients have maybe a higher JAK2 burden. And there's been some studies about the utility of JAK2 burden measurements. But as of now, that's not a marker that's reliable enough for us to know if a higher JAK2 level will lead to progression. But I'm sure that that's something that will change in the next couple of years.

Ruth Fein: Hopefully, lots of things will change in the next few years. There’re so many people working on it. Before we close, I'd like to end with a few words about how we might change the conversation around MPN.

Dr. Hobbs: Like you said, Ruth, really a lot has changed in the last couple of years and really in the last couple of decades, for sure. Where we sit right now in the world of MPN and myelofibrosis, in particular, is a really unique time, where we have so many clinical trials, and not just clinical trials that are starting, but really clinical trials that are in Phase 3, meaning that one could expect some of these drugs to be approved and given to patients, whether or not they participate in the clinical trial.

I think it's important for MPN patients to remember that, really, all of the research that has been done is actually translating into new treatment options. I think that it's a time to be hopeful that we will have a lot more treatment options available in the next couple of years.

Ruth Fein: Thanks to our very special guest today, Dr. Gaby Hobbs of Mass General. A pleasure to have you with us as always.

Dr. Hobbs: Thank you for inviting me.

Ruth Fein: Absolutely. To our audience, if you have new questions for your doctor, based on today's program, make a note to self-reminder or whatever works for you, in your phone or with a pen. It's those conversations that can help you with your healthcare decisions and, ultimately, improve your care.

One more note. Patient Power is piloting a new clinical trial finder tool. Details are in the MPN newsletters, which if you're not already receiving, you can subscribe at patientpower.info. You can keep up to date with Patient Power on Facebook, on Twitter, and on Instagram. And that's where also you find information about the next few webinars in this series. I hope you'll join us as we talk to other MPN experts in the next few weeks on stem cell transplants, on the reality of living with pain, which should be a unique and interesting session, and treatment advances on the horizon, which we're always talking about and want to continue that conversation. That's all from here today on this humid, rainy, frizzy summer day in Saratoga Springs, New York. Take care. Be well. And remember, knowledge can be the best medicine of all.