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MPN 101: Definitions, Gene Mutations and What to Expect

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Published on November 25, 2020

Doctors Share Essential Information on Myeloproliferative Neoplasms

What are myeloproliferative neoplasms (MPNs)? What are the similarities and differences between essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)? What are the most common gene mutations? And most of all, what should I expect during my MPN treatment journey? 
Many individuals who have been diagnosed with an MPN, or who are close to someone who has, might be seeking the answers to these questions. Dr. Michael Mauro, Leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center and Dr. Abdulraheem Yacoub, Associate Professor of Medicine at the University of Kansas Medical Center, are here to share their expert knowledge and advice!

This series is sponsored by Bristol Meyers Squibb. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.


Transcript | MPN 101: Definitions, Gene Mutations and What to Expect

Ruth Fein: Hi, and welcome to our MPN Answers Now program, sponsored today by Bristol Myers Squibb. I'm Ruth Fein. I'm a health writer and a patient advocate for Patient Power. I'm also someone who's had an MPN for, what, about 25 years, one kind or another. I'm joined today by two very special guests, both experts in MPNs. Dr. Michael Mauro is with Memorial Sloan Kettering, and Dr. Abdulraheem Yacoub is at the University of Kansas Medical Center.

Dr. Yacoub: Hello.

Ruth Fein: Welcome to you both and thanks so much for your time with us today.

Dr. Yacoub: Thank you for having us.

Dr. Mauro: Yes, absolutely. Thanks for having us.

What is Essential Thrombocytosis (ET)?

Dr. Yacoub: Essential thrombocytosis is a blood cancer, just like all the other MPNs we're going to discuss today. These are diseases that manifest with proliferative features of the bone marrow, where the bone marrow is producing excess blood elements and, with the case of essential thrombocytosis, it's predominantly excess of platelet production. Patients also, as a byproduct of producing excess blood, they also produce excess hormones and chemicals that result in increasing symptoms that can affect their quality of life. Each individual patient will have a unique experience with the degree of symptoms and the severity and the course of their symptoms.

And, inherently, all MPNs and essential thrombocytosis have a risk of complications. Complications can be either a clotting or a bleeding event or a disease transformation, which is a word we use when a low-risk cancer like essential thrombocytosis can change behavior and turn into a higher risk cancer like polycythemia vera or myelofibrosis or acute myeloid leukemia.

What is Polycythemia Vera (PV)?

Dr. Mauro: Polycythemia vera, if you just look at the name itself, you kind of get a sense for what we're talking about. We're talking about an excess of red blood cells that's a true excess, and that's probably the best place to start. We look at a patient's blood counts and say there's an excess number of red blood cells, erythrocytosis, and then we go from there.

We are dealing with an overactive bone marrow, as my colleague mentioned, producing various cell numbers. And polycythemia, much like the other MPNs, can present with an excess of all bloodlines, an increase in white blood cells, platelets and red blood cells, and can be confusing. But the hallmark and what we look for is, again, a threshold excess red blood cell increase that's not explained by other causes and is usually linked to other clear signs of that being the case, meaning the body is trying to not send the signals to bone marrow to make extra blood by turning off a hormone called erythropoietin. Generally, by the presence of a mutation in the blood and bone marrow, which we believe underlies the causality or the trigger that made the bone marrow behave this way, and there are other signs and symptoms which can be seen as well.

The spleen often can enlarge in polycythemia, as well as in other MPNs. We put all these together and are careful to say it's not a reactive or secondary cause, it's a primary disease, and does it meet threshold? And the last comment I'm going to make is that we need to be looking for this disorder, as patients and practitioners, because sometimes the numbers aren't very different than normal or actually can be just at upper limits and the patient may indeed have polycythemia vera and, again, not have what, historically, used to be a great excess, it could be a more trivial excess.

What Does it Mean When Myelofibrosis Presents With an Enlarged Spleen?

Dr. Yacoub: In myelofibrosis, it presents the higher end of these three diseases, and it has features of ET and PV, although, with more advanced forms, patients might lose their ability to produce the excess blood elements. Those patients, on the contrary, would have lower blood counts, low hemoglobin and low platelets. Spleen is a hallmark of the disease, spleen enlargement is a hallmark of the disease. There's many theories on why that is the case, but a big reason is that the blood elements that should exist in the bone marrow space are crowded and out of space because of the fibrosis and the scarring that occurs in the bone marrow environment and, subsequently, blood elements will exit the bone marrow biopsy and seed into the spleen and result in enlargement of the spleen.

And another theory for the spleen is enlarged is because of all the chemicals and cytokines produced by myelofibrosis, which also are a phenomenon shared by the other diseases. An enlarged spleen can also exist in ET and PV, but it's just more pronounced and more prominent in patients with myelofibrosis.

Spleen enlargement has been associated with the outcome of myelofibrosis, with patients who have the largest spleens are the ones who're going to have the least favorable course of their disease, and that treatments that are directed towards shrinking the spleen, that the more successful the treatment is, the more favorable the patient will behave. The spleen is definitely an integral part of the disease and it's important to the diagnosis and to the prognosis and into the treatment.

How Do Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis Relate to One Another?

Dr. Mauro: We have to step back and look at what the blood counts show us and what conditions may be present because, in reality, we're dealing with a family of disorders and there can be a lot of overlap and similarity. For example, a high platelet count is probably one of the more universal findings in polycythemia and ET and early on in myelofibrosis. It's hard to separate essential thrombocytosis from myelofibrosis sometimes because they can look similar in their initial presentation, and that's probably one of the most difficult clinical scenarios is to say this is an early form of myelofibrosis or a simple elevation of platelets like ET.

But with their similarities, there are families of mutations that drive these conditions, with the JAK2 kinase abnormality being probably the best described and the longest described. And, really, activation of the JAK/STAT pathway, which is essentially a switch that's been turned on that leads to proliferation of the cytokines, chemicals, which my colleague mentioned, and overproduction, and it manifests in subtly different ways in the different disorders with different risks. There's a commonality with thrombosis as a risk factor, especially in the early and the initial points of diagnosis. There's a common thread for a use of antiplatelet agents and medications which modify this JAK/STAT pathway, as well as simple cell-reducing agents.

Biologically, they're connected by the mutations that drive them and the blood count elevations that are seen. They branch off really with regards to maybe the speed with which they move and the problems that they can cause, although, again, there's commonalities with thrombosis being at the center. And myelofibrosis, just to point out, can be a consequence of having polycythemia or thrombocytosis with time because the overproduction of blood cancer in the bone marrow will trigger fibrosis. If it wasn't a primary problem, it can become a secondary or a resultant problem from having had one of the other disorders.

You can see the intertwining is quite extensive, and one of the most important things for someone to do if they're facing this question is to really have an accurate diagnosis, and that often is with a full set of tests, including, for example, a bone marrow study, the right molecular tests.

Dr. Yacoub: As Michael explained very eloquently, the three diseases have a lot more in common in terms of how they occur and the demographics and the natural course of the disease. So, it is very plausible that one patient will be diagnosed with ET and they will grow into a diagnosis of polycythemia vera and then transform into a myelofibrosis, and there's actually even a calculated risk of how much does that often happen. Again, the problem probably has two different levels. One is making a correct diagnosis. Again, sometimes it's very straightforward to make an ET or a PV diagnosis or a myelofibrosis diagnosis and that stems from the clinical presentation of the patient, their bone marrow biopsy findings, their laboratory results, and their symptoms. Sometimes it's straightforward and easy.

But a lot of patients are on the fence sometimes and, actually, their disease falls right in between two big domains, either PV or ET, right in the middle, or a pre-fibrotic myelofibrosis with features of ET or MF. So, that's the first challenge is making an accurate diagnosis and an accurate classification at the presentation.

And then the second challenge is that those diseases are, by definition, dynamic. They are progressive. They start at a certain presentation and they will continue their natural behavior or progression and they might switch. Patients could present with a clear and stereotypical diagnosis of one subtype and, with time, they could progress into a different phenotype or a different disease classification. And, also, the word transformation is when they transform from a low-risk disease like ET and PV to a higher risk form like myelofibrosis, and we call that secondary myelofibrosis. That's the other challenge is that the diseases do not stay still, and they actually change, and they move.

How Often Does One MPN Progress to Another MPN?

Dr. Mauro: Clinically, if they are what we see by looking at blood counts and by serial examinations and just following someone over time, we can see the signs of progression. For example, myelofibrosis, as Dr. Yacoub mentioned earlier, is a condition where now the reverse is true, now blood count deficits can develop. When we start to see the blood counts turn in an opposite direction, we know we may be facing some evolution towards fibrosis. Polycythemia vera all of a sudden becomes easier to manage because the hematocrit may not be so elevated. The platelets may not be so elevated any longer with ET.

And that's the natural history, but in basic terms, we know that ET can be a more indolent condition and has a fairly lower frequency and rapidity with which it can progress to myelofibrosis. And for myelofibrosis, we worry about other things, such as more higher-level myeloid or white blood cell diseases such as pre-leukemia or leukemia. Polycythemia vera, we worry a little bit more about the risk of complications and thrombosis. That's not necessarily a sign of progression. It's really just the risk of having the condition. But, in turn, now, that is probably in second place with regards to risk for transformation to myelofibrosis. Myelofibrosis itself moves at its own speed.

The key to judging the likelihood of progression probably comes from the fingerprints, again, which would be the type of mutation that's driving the disease, where there are predicted and good research has been done over the last decade since we've unraveled the genetic fingerprint of these conditions so much more eloquently. Some forms will have a lower speed of progression, some might have quite a rapid rate of progression, just simply based on what triggered the disease in the first place. In addition, we look more broadly at what's the totality of damage or change in the blood that's causing the condition, and not just what we call a driver mutation, such as JAK2 or CALR, which is calreticulin, or MPL, which is related to JAK2 in another way to activate the JAK/STAT pathway, or other versions of the JAK mutation. These are the things that we look for in the clinic and help us to predict how these will behave.

But secondary mutations, if it makes sense, if you have a primary switch that's turned on and if you then add other circuits downstream that are now also permissive in allowing for the condition to be more prone to error, allow it to move faster, allow it to cause more of the abnormalities that it's triggering, it will move faster. The genetic fingerprint helps us predict the risk of progression of MPNs, in addition to the way it started, the switch that was thrown, the driver mutation, so to speak, and then, of course, nothing replaces good clinical observation and to help patients understand, "What's happening to me? Why are my blood counts a bit better or different now? Why am I having these different symptoms?"

Can You Talk About the ASXL1 Mutation?

Dr. Yacoub: So, ASXL1 mutation is a common mutation that we identify in myeloid diseases and it's not specific to MPNs, but it does add a negative twist to any story. Patients who have the ASXL1 mutation probably should be followed more closely. They probably should be seeing a specialist and they probably should be more educated about the risk of transformation. But, again, it doesn't guarantee a risk of transformation, but it does put the patient at a higher risk and, whether it's MPN or other cancers, it's a mutation that is famous for adding additional negative information on the prognosis, on the natural course of diseases.

Ruth Fein: A lot of people with MPNs are misdiagnosed either initially or for a very long time, and what we learn today and anytime we talk about MPNs is that, once the diagnosis is made, that really isn't the end of the confusion, is it? It begins it all. Let's keep going trying to sort some of this out. I have a question that says, it says, "Does JAK2 V617 lead to poorer outcome or faster progression in PV and what can quickly reduce platelets?"

What Does the JAK2V617f Mutation Mean for Polycythemia Vera Patients?

Dr. Mauro: Well, that particular amino acid substitution is the primary thing we see that goes wrong the JAK2, the Janus 2 kinase, and it essentially makes that enzyme able to turn itself on rather than to be regulated. That V617F isn't a higher risk or bad form, that's what we generally see. The prognosis in PV, most patients with PV have that form of the JAK2 mutation. It's a rare patient with polycythemia that has a different mutation, honestly. So, I would say it's fairly mainstream.

And the other part of the question was what's a quick treatment to reduce platelets? Treating platelets can be a bit of a complicated issue. Obviously, some of the cell-reducing treatments we use, hydroxyurea (Hydrea). We still use a specific inhibitor of the megakaryocytes called anagrelide (Agrylin). We want to inhibit platelet function with aspirin. There's a variety of different things we do.

How Can Patients Track Their MPN Symptoms? 

I think it's important for patients, or anyone really, to know their medications, know their blood counts, and know their test results so they can correlate how they're feeling based on what the numbers or things look like at the time. Diaries are very important, including activity, food, other medications. Adding a new supplement or medication or something in the diet can make a big difference in certain people.

My colleague mentioned interferon treatment and one of the most important things I tell someone who's on interferon is, "I hope there's someone else I can talk to because I want to know from them that you're feeling good, your mood is good." We don't want to have side effects from interferon such as anxiety, depression. Those can develop and can be hard to self-report.

Why Is it Important to Find an MPN Specialist?

I just think, well, the comment might be that those of us that see and think about MPNs most often and take care of the most patients might have just the benefit of greater experience and great exposure, more familiarity with the science and the literature that is going to help guide decision-making, and really more of the rigor of following guidelines.

One of my favorite examples to mention is that polycythemia is somewhat of an art in addition to a practice of how to manage it. The control of the hematocrit is simply a function of how many times you ask for the blood to be checked because ignorance can be bliss and, if that hematocrit is not checked, it may be high and no one knows it and there may be thrombosis risk. We're often finding ourselves just tucking in the corners and adding to the knowledge base and redirecting back to what is good science and good knowledge.

We don't have answers that no one else has access to or special information. We just have the rigor, the experience, and the familiarity with all of the data. We often can extend the diagnostics. We often can clarify the diagnostics based on our pathology departments, our colleagues. We can avail patients to clinical trials as well. We can often take care of things from A to Z. If we're dealing with myelofibrosis, we're dealing with transformation or risk of transformation, we can often connect treatments as well as MPN specialists because we have done that over and over again. There's a lot we can add to the picture.

But I really want to give a shout-out to those that manage the MPNs around the country, around the world, in basic practice because they do good medicine and I always strive to partner with them and to just say, "How can I help? What can I add to the discussion?" I think I always encourage someone to seek a specialist for second opinions and, with luck, it could be that simple, just to say, "Well, here's my two cents, five cents, 10 bucks, 50,000," it depends on how much advice you have to give, to make sure things are being done right, and we can be there as a resource continually.

What Thoughts Would You Like to Share with Patients?

Ruth Fein: As we wrap up, I'd like to ask both of you, our two specialists, to share just a brief closing message of hope with our audience. Dr. Yacoub, would you like to begin?

Dr. Yacoub: Thank you very much. Again, this is a great time to practice medicine and to take care of patients with MPNs. We have had a lot of breakthroughs in terms of making a diagnosis, making a prediction of the future, making a treatment recommendation – and now there is multiple drugs that are FDA-approved for variable myeloproliferative neoplasms, many medications in the pipeline. It's very exciting, the wealth of agents in development for those patients. And the way we're going to be practicing the treatment for these diseases will continue to evolve and, in the next five years, we're going to have a much more wealth of understanding of the disease, ways to predict the future of the disease, and medical therapies that can change the disease behavior.

We're also making strides at improving bone marrow transplantation as a curative therapy for patients with myelofibrosis. For the patients who are having the most aggressive diseases, there's also that path forward, which is now a lot more understood, it's paid for by insurances, and it's helping a lot of people to get rid of their diseases once and for good. It's an exciting time to take care of those patients and it's an exciting time for new therapeutics, and the future of MPNs will not be anything close to the past of MPNs.

Ruth Fein: And Dr. Mauro?

Dr. Mauro: I'll keep my thoughts quite simple, not just because this is Patient Power, but I'll say that information is power. And, for patients, I think we don't want to be afraid of learning more about the condition, learning more about what the treatments look like, asking questions, and partnering with your providers, because we're in it together and, if it's done right, we're in a preventative mode and an anticipatory mode, not a reactive and a damage control mode. That's always the way we want to operate in medicine. With luck and with all the great treatments Dr. Yacoub just mentioned, we're going to be able to be way ahead of or maybe being able to treat this much differently, including when it gets tougher, with more information. So, don't be afraid of getting that information and using it.

Ruth Fein: Thanks so much for watching. I'm Ruth for Patient Power. Be well. Take time to be your very best self and remember that knowledge can be the very best medicine of all. Take care.

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