What should you know before deciding which treatment is best for YOUR MPN? MPN expert Dr. John Mascarenhas reviews key factors–including essential testing–that guide treatment decisions for essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Mascarenhas also provides an overview of available treatment types and why he’s hopeful about the future of MPN research.
Dr. John Mascarenhas is Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai. Learn more about Dr. Mascarenhas, here.
Hello, and welcome. I’m Katherine Banwell, your host for today’s program. Today, we’re going to discuss how to access the most personalized therapy for your MPN and how you might benefit from key testing. 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.
All right. Let’s meet our guest today. Joining me is Dr. Mascarenhas. Welcome. Would you please introduce yourself?
Thanks for having me. My name is John Mascarenhas. I am an associate professor at the Icahn School of Medicine here at Mount Sinai in New York City, and I am a clinical investigator in myeloproliferative neoplasms, and I direct the Adult Leukemia Program here.
Excellent. Thank you so much for taking the time out of your busy schedule to join us today. Before we delve into our discussion, let’s start with a term we’ve been hearing a lot about recently. How would you define “personalized medicine?”
So, it’s a good question because I think it’s poorly defined in many ways because it can mean different things I think to different people. And, it’s a definition that’s in evolution. So, I think at its core, personalized medicine tries to embody the concept of creating an evaluation and management plan that is specific of tailored to that patient on multiple levels.
On a personal level, on an objective level of what the patient’s objectives are with their therapy or their disease, and then on a biologic level in terms of the type of disease, and now increasingly, on a molecular level. So, in some cases, it may be personalized therapeutics that are specific or targeted to certain mutations that the patient may have. And, that’s kind of where things are evolving from a treatment perspective. And to me, personalized medicine should be the goal of any interaction with a patient that you have to personalize the approach. Because, every patient that we meet is quite different and distinct from the next patient, and their own sensitivities, understandings and desires can be quite different. So, you want to personalize that approach to that patient at the most basic level.
Yeah. Well, that’s really helpful as we move through today’s program, which is going to cover the three classic MPNs, polycythemia vera, essential thrombocythemia and myelofibrosis. So, for someone who has one of these conditions, can you help us understand how one may progress to the next?
So, these are a very heterogeneous or variable group of diseases that are under an umbrella called the myeloproliferative neoplasm. So, MPNs can really present and behave and have very different clinical courses. So, I think it’s very important for patients to realize that these are rare diseases, that that has a complexity to it, because they don’t always have the ability or the privilege to know other patients or people in their lives that may have these diseases. So, it could be very frightening from a level of feeling isolated or alone with a diagnosis like this and not having familiarity, but also, that these are vague diagnoses in the sense that when you have breast cancer, one can kind of conceptualize that there is a mass in the breast, for example, and that that can be staged. It can go to the lymph nodes in the armpit, it could spread below. And people can kind of understand that concept. I think it’s a little bit more challenging when you talk about MPNs, because it’s a little bit more abstract.
These diseases are within the bone marrows at diagnosis. So, they’re not staged in a physical way, and they are complex because they can lead to high blood counts, low blood counts, different types of symptoms, and the approaches really have to be personalized. They are all three interrelated because there are commonalities. So, there are certain clinical commonalities and also biologic commonalities. So, for example, the JAK2 mutation, the JAK2V617F mutation is seen in all three diseases. So, it’s not specific to one or the other.
It’s more common in polycythemia vera, but in about 50 percent of patients with ET, and 50 percent of patients with MF, you can see this mutation. So, the mutation alone doesn’t really tell us what the disease is. It just tells us you have one of these diseases. And, there are other mutations. So, a bone marrow biopsy then becomes integral in helping subtype the patient and then create that treatment plan and that outlook that’s specific for that disease.
And as you mentioned, to make it even more complicated, these diseases can overlap not just biologically, but in a continuum. So, patients with ET or polycythemia vera can progress in some cases to myelofibrosis. And, all three diseases in a minority of patients can progress or evolve into acute myeloid leukemia, which is a more aggressive form of bone marrow cancer.
Well, let’s turn to testing. And, you did just mention this. You touched on it a moment ago. What tests are necessary to help understand a patient’s specific disease at diagnosis?
Usually, the blood counts are the first opening door test that allows some understanding of, again, either an abnormal production of red blood cells, platelets or under production of these cells. And, that’s really where often the evaluation begins. And then, there are further blood tests that often are done.
And I would say almost indefinitely or almost definitely one should have a bone marrow biopsy that helps categorize the type of myeloproliferative neoplasm because there can be overlap in how the blood counts can look from one disease to the next and overlap in the mutations like the JAK2 mutation. So, sometimes, the blood counts and the molecular testing are not enough, and a bone marrow biopsy looking under the microscope at the different types of cells, the proportion of cells, whether there’s fibrosis where there’s others other types of cells that shouldn’t be there, and they’re looking at the chromosomes and the flow cytometry, these are associated tests. As well as almost probably anywhere anyone goes at this point, they’re going to get next-generation sequencing, which is looking at multiple genes and mutations, and that gives a more broader, deeper sense of the disease.
So, those really become the integral parts. In some cases, patients will end up getting imaging of their abdomen to see if they have an enlarged spleen or enlarged liver.
Although that’s not always necessary, that is often part of the workup. So, it’s bloodwork, it’s bone marrow biopsy, sometimes imaging is usually the cornerstone.
And, what is molecular or biomarker testing?
So, molecular testing today really means – at one point, it really meant looking at PCR for specific gene mutations.
So, for example, we would look at the JAK2 and we would say, “In a given person, is this gene mutated?” We all have JAK2 gene, but in patients with these diseases, they’re more commonly mutated which means altered in the blood cells. And, it’s very important for a patient to understand not in every cell in their bodies, but in their blood cell compartment. And, that helps us understand and start characterizing their disease, and sometimes that mutation can be measured. It can be at a low level. It could be a high level. And, that’s all put together in trying to understand the molecular basis of these diseases.
Today, next-generation sequencing has really taken over and that’s looking at more than just one gene.
Its sequencing could be 40 genes, it could be 200 genes, to get a sense of the complexity of the disease and looking for certain mutations which are considered biomarkers that can portend prognosis or I think increasingly, we’ll see may inform treatment decisions and may even be targets themselves of therapies.
Right. Should all patients diagnosed with ET, PV, or MF undergo biomarker testing? Is that necessary?
I would say it’s part of the modern evaluation and management of patients today. I don’t think that that was true 10 years ago. But I think the field has matured. I will say I’m the first person to acknowledge to patients that we get a lot of information back, and the truth is we don’t often know what to do with all of that information. So, sometimes we get information back that can cause anxiety because you can see mutations in genes. But they don’t always inform us on how to educate the patient about their disease or tell us what to do with the treatment.
So, there is still a lag as there normally would be between the testing of the results that we get, and then the actual knowledge of what to do with that. And, that’s still a process that’s in evolution.
Right. Some patients may not know if they’ve received these important tests. So, what key questions should they ask their physician about testing?
Well, I think it’s important that the patients feel empowered to understand sort of where the field is and what key questions you would ask a physician, hematologist who’s taking care of you. So, I think all patients should be aware of their diagnosis, the name of the diagnosis, the subtype, but also do they have any of the key driving mutations, the JAK2 mutation, the calreticulin mutation, the MPL mutation, and that’s usually done off of a bone marrow biopsy sample, but it can be done off peripheral blood. And, they may not always know that it’s done. So, I think having a discussion with the position to understand there are criteria that exist called the World Health Organization criteria that are updated frequently and should set a standard throughout the world of how you diagnose and establish these diagnoses.
So, I think it’s important for physicians to be able to convey to the patients with confidence, “We follow these criteria and you have these criteria and we’ve done this testing that shows that you have these mutations.” And not just regurgitate what they found, but help them understand and navigate with that means, which again, I will point out that sometimes we don’t know. But I think it’s important for physicians to convey sometimes that some of the findings that they may see, for example, patients look on portals these days and they can look at their labs and stuff like that. And, we don’t always have a terrific answer or an informed answer for everything that we get back. And, we will potentially in 10 years from now, but sometimes at the moment, we don’t. But I think a discussion about the meaning of the labs that are obtained is probably good for the patient to understand what’s being done.
Absolutely. It sounds like each person’s situation is unique and should be considered before making any treatment choices. Can you talk about how the results of these tests may affect prognosis and treatment?
So, we do have risk stratification systems that we use for essential thrombocythemia, polycythemia vera, and myelofibrosis. I’ll talk about myelofibrosis because that’s probably a little bit more of a complex and sophisticated model. It’s also changing, and we update it frequently. And, these models are imperfect, so I always warn patients to not put all of their money in one basket when we talk about risk stratification. They broadly help us understand where a patient is in their disease course. So, for example, in myelofibrosis, historically, the DIPSS, the Dynamic International Prognostic Scoring System is used, which considered five clinical variables that have been shown to be independently prognostic. So, at age over 65, the presence of blasts or circulating immature cells in the peripheral blood, anemia, hemoglobin less than 10, symptoms, fevers, night sweats, weight loss or a high white count over 25,000, you those points up.
And patients can do this online. There are calculators that you can calculate your DIPSS score. And, you’ll see that there are four different risk groups that range from low risk to high risk, and they are associated with median survivals. We now know that mutations influence those, have influence on prognosis. So, there are a group of high molecular risk mutations like ASXL1, SRSF2, IDH1/2. So, there are mutations that also have prognostic significance, and we incorporate them into the decision-making.
And, essentially, and this is where I think patients have to be very careful, physicians have to be very careful with conveying this. With these risk models whether they are clinical variable risk models or these integrated molecular risk models, each category is associated with a median survival, that’s based on retrospective studies. But that doesn’t tell the patient specifically what they should expect in terms of survival. And, I always fear that patients, when they look at these things, or even physicians when they convey them that they may inadvertently misrepresent or convey what those really mean.
And, I think the purpose of those risk stratifications is really to help guide a risk adapted treatment approach that’s reasonable and is weighted for benefit to risk of the disease. So, for example, if you have advanced disease with a high-risk score of intermediate to or higher, bone marrow transplant in certain patients may be a warranted therapy to consider. So, they really help inform treatment.
Right. You mentioned a couple of these already. But, outside of testing, what other factors should be considered when choosing treatment?
I think patient expectation. So, sometimes physicians and family will impose what they want for a patient, and that may not be what the patient really wants. So, I have learned over the years that it’s crucial to make sure that you understand the patient and what the patient’s expectations, desires, and that’s influenced by the life they’ve lead or the remaining life that they want to live and their own personal religious and spiritual beliefs.
] So, I think knowing your patient and understanding what their expectations are, it’s fundamental, and sometimes, it’s overlooked. So, understanding that, I think, is very crucial. And then, dividing what are the objectives of the treatment in a given patient? Is it really to improve anemia in some patient versus perhaps a different patient, it may be to improve their quality of life and reduce their symptom burden. And then in other patients, it may be purely trying to cure the disease with therapies that may be aggressive, which may not be appropriate for an older patient where toxicity could outweigh any potential benefit of survival or longevity. So, you really have to have a discussion with the patient or caregivers, and then define what are the goals in that individual to personalize that approach for that patient.
Right. Right. And, there’s the patient’s overall health, comorbidities, other things like that?
Yeah, because we are not treating a disease in isolation usually. So, patients come with baggage posed of past diseases, current diseases.
And sometimes patients are not “fit” for certain types of therapies because they may be sick or they may have organ dysfunction that would make certain types of treatment approaches ill-advised because the toxicity could be higher. So, absolutely, you need to know their comorbid index, how much comorbidities they have and also their performance status, how active and how well they are in general.
Right. Are there specific biomarkers that may affect prognosis or treatment?
So, yes and no. I mean, I think that’s an area of intense interest and research. So, we have identified certain biomarkers that have, as I mentioned, prognostic significance, and that may influence treatment decisions. So, patients who have, for example, as we discussed next-generation sequencing and we see their mutations that are present, if they have an accumulation of high molecular risk mutations, that may give us a sense that perhaps that patient may not enjoy the full benefit and duration of benefit of, for example, a JAK inhibitor as another patient that has a less complex disease.
And, that doesn’t necessarily mean that the therapy is not appropriate for the patient. But it may help us plan and be prepared to move on to the next therapy sooner or to be more vigilant for changes that would tell us it’s time to move on. So, I think they help us maybe get a general sense of things and put things into perspective. They don’t always necessarily inform us on a change in therapy immediately or the next or the most immediate therapy. But I do think that that will change because I would predict in the next five to 10 years, I think that the number of available drugs for myelofibrosis, for example, will likely double from what it is now. I think we will have an armamentarium to choose from, and what we will learn from trials that are ongoing is there may be certain profiles, mutations, chromosomal profiles, other clinical variable profiles that we will learn from these trials that will help us to find upfront, “Well, this profile really should go with his medication. That profile should go with that medication.”
An early of example that would be we’re learning that not all patients with the JAK2 mutation are created equal, that you can have different burdens of JAK2 mutation. And, patients with low burden JAK2 mutation, for example, may fare better with up a specific JAK to inhibitor like pacritinib than patients who get treated with other JAK inhibitors like ruxolitinib.
So, there are differences even within patient defined by mutation that may help us predict which of the JAK inhibitors, as an example, may be more appropriate as a first-line therapy. So, I think that will evolve more so over the next five to 10 years.
Dr. Mascarenhas, what is inhibitor therapy and how does that work?
So, inhibitor therapy in general are usually oral drugs for the most part, small molecule inhibitors that are geared and usually specific but not totally specific because then they can have off-target effects, but geared to inhibiting usually an enzyme that is overactive or is contributing to the pathophysiology of the disease.
I think in MF, probably one of the best examples is a JAK2 inhibitor. So, there are a number of JAK2 inhibitors that have been in clinical testing. There are two that are approved, ruxolitinib (Jakafi) and fedratinib (Inrebic), which are excellent drugs in inhibiting JAK2 protein itself in the cells that could be either upregulated or hyperactive in the signaling pathway, and it quiets down a signaling pathway in the hematopoietic cells that leads to a lot of the manifestations of the disease, namely symptoms and spleen.
So, one of the clear benefits of JAK inhibitors that was established many years ago and reinforced by multiple drugs that are either approved or in late-stage testing is these drugs are excellent in improving the symptom burden in the patients and reducing their spleen. Unfortunately, as a class, we’ve not seen these drugs induce remissions or cure patients. So, there’s still interest in developing, obviously, non-JAK inhibitor therapies. But inhibitors in general are inhibiting proteins that are either inappropriately activated or part of a cascade of signaling molecules that are contributing to the disease.
And they are not chemotherapeutic, which might be an important point to make. In past days, we’ve relied heavily in hematologic malignancies in using chemotherapies which are nonspecific and just kill dividing cells whereas inhibitors typically are targeted, and in some sense, it’s personalized to the disease with toxicity profiles that are usually quite distinct from the traditional chemotherapies that we use.
Well, outside of inhibitor therapy, let’s review other treatments for patients. Depending on the patient, it seems like ET or PV may be easily managed. So, how are they treated? Let’s start with essential thrombocythemia or ET.
So, ET is a disease in which first and foremost, we’re trying to reduce the risk of thrombosis, clotting, and/or hemorrhage bleeding. So, typically, ET patients are risk stratified by low risk or high risk.
It’s almost simply based on their age, whether they’ve had a clot in the past, and some systems now even incorporate other factors like mutation status. And, you tailor the treatment based on their risk score. So, low risk ET patients don’t necessarily need to be treated. They can be followed expectantly and watched. The height of the platelet count does not predict thrombotic risk. So, we don’t treat the platelet count per se. A high-risk patient is at high risk for clotting. So, these patients almost invariably are getting aspirin at a baseline, and they are often on cytoreductive therapy. And sometimes, that is chemotherapy like hydroxyurea (Hydrea). Sometimes it’s a non-chemotherapeutic option and like anagrelide, and sometimes it’s a biologic therapy like interferon alfa either 2a, PEGASYS, or 2b ropeginterferon. And, these are therapies that have rationale, that have clinical data, that have demonstrated reduction in risk of clotting, which again is the reason why we treat high-risk ET patients.
And, what about PV, polycythemia vera?
So, in polycythemia vera, it’s similar to ET. We risk stratify patients low and high risk based on age and clotting histories. And whether you’re low or high risk, we give PV patients aspirin or at least once daily, and we look to keep their hematocrit below a threshold of 45 percent. And sometimes in women, we even go lower, to 42 percent. But the idea is that controlling the hematocrit, which is one of the red blood cells indices, you reduce the risk of having clots, and that’s been shown actually many years ago and reinforced in a very well-known study called the CYTO-PV study in Italy documented that if you keep the hematocrit less than 45 percent, so, stringent control versus allowing for less stringent control between 45 to 50, that you reduce by fourfold the number of cardiovascular events that can occur.
So, we know that controlling the hematocrit is important, and that can be done, again, with hydroxyurea, interferon, and ruxolitinib. The JAK2 inhibitor has also proved specifically for patients who had an intolerance or refractory hydroxyurea, but also importantly as a drug that can address, probably better than most drugs in this field, the symptom burden that could be problematic for some of those patients. But it’s really about controlling the hematocrit.
Yeah. Since myelofibrosis is a progressive condition, I imagine that makes it more difficult to manage. So, what else is available for patients with myelofibrosis?
The first line of treatment is typically a JAK inhibitor, although I would say that there are a subset of patients – well, there are patients we sometimes meet that have very low risk disease. They don’t have those clinical variables we discussed before that could uptick their risk score, and some of those patients can be watched.
And interestingly, there are a subset of patients that can have an indolent or slow form of the disease where they don’t have aggressive changes in their disease, their blood counts, their symptoms, their spleen, and don’t need immediate treatment. Most patients would benefit from a JAK inhibitor, although there are a subset of patients where their issue is less simple in spleen burden and it’s more anemia.
So, we take those patients where anemia’s the focus, we look at their erythropoietin level, which is their endogenous hormone level that regulates red blood cell production. If it’s low, we give them a lab-based form of erythropoietin, something called PROCRIT or Aranesp. If it’s high, we will move on. We can use a drug called danazol, which is a synthetic male androgen which can improve hemoglobin levels in 20 to 40 percent of patients. Or, we can use a drug called lenalidomide, which is an immunomodulatory drug. And, more recently, there’s a drug in testing called to luspatercept, which is an active activin receptor ligand trap. So, there is a growing armamentarium of drugs that can be used to try to alleviate the anemia which is present and can be a significant issue in about a quarter of patients with myelofibrosis upfront at time of diagnosis or about 75 percent through the course of their disease. So, that’s an unmet need that still requires attention and may alter the treatment plan for a given patient.
What about stem cell transplants?
So, we relegate stem cell plant transplants for those patients as mentioned before that are higher risk because we think that the potential benefit-to-risk ratio is in favor of transplant.
Transplant is really a modality that is the only modality that offers the potential for cure, but it’s also a modality that poses a significant risk of morbidity and mortality associated with it. So, it has to really be taken very seriously. It can’t be the kind of treatment you would think of as a last resort at the last minute. Once you see a transplanter, if they’re interested in that therapy and see it early on in the disease course, in my opinion, to start that dialog and then figure out when is the optimal time to employ a bone marrow transplant, which is not a surgical procedure. It’s often thought to be surgical. It’s not a transplant of an organ. It’s a transplant of hematopoietic cells. So, it’s really an infusion of stem cells that then end up in the person’s bone marrow, and they create a whole new hematopoietic system and immune system. And with that, you can have an immune system that then goes after the myelofibrosis stem cells.
That’s called graft-versus-leukemia effect. But with that included graft-versus-host disease, which is when the new graft, the new immune system doesn’t always recognize well the person’s own tissues, whether it’s the liver, or the lung, or the skin, and you can have immunologic reactions to that.
So, that’s a complex discussion. But, transplant, typically for patients less than 70 years of age who have high-risk myelofibrosis or even up to 75 if they have a good performance status and as we said don’t have a lot of comorbid issues with a goal of cure. So, if you have someone where their goal is to try to maximize their time out of the hospital and they’re not focused on longevity, they’re focused on quality of life, that may not be an appropriate patient for transplantation. So, I think a very upfront, honest and a transparent discussion with the patient about what to expect with transplant, what are the pros and cons, what are the risks involved, and importantly does it match up with their expectations or their desires.
We have a question from Mike that we received prior to the program. He wants to know, “What does it mean to have high-risk myelofibrosis?”
So, high-risk can be defined different ways. For example, if you’re using the DIPSS score, it means that you have enough of those points to put you in a category that would suggest that your disease is more likely in a shorter time period to cause significant morbidity and mortality than someone who has low risk disease. So, it’s really, as we said before, we don’t stage myelofibrosis like stage I, II, III, and IV metastatic disease. But we risk stratify patients. We put them in these categories, and that helps to decide what treatments may be more appropriate. And as we were discussing, transplant is a therapy if you’re a high-risk patient and you’re inclined and you don’t have a lot of comorbidities, and you’re not very advanced in age. That may be a treatment that is appropriate for a high-risk patient, a high risk for having a bad outcome of the disease within a shorter period of time.
And we have another question from Craig that we received earlier. “I’m currently receiving regular phlebotomies for PV, but my doctor is considering switching me to inhibitor therapy. What can I expect and are there side effects that I should be concerned about?”
So, for some patients, therapeutic phlebotomy is all that they need, and they do very well with it, and they don’t need to take a therapeutic like a JAK inhibitor or hydroxyurea, which is a non-specific treatment.
But some patients do. So, some patients where if their risk score is higher and their risk for thrombosis, that may be an appropriate indication. And some patients have a lot of symptoms with their PV. So, not all PV patients present and behave the same way. Some patients have a very low symptom burden. Some patients have a very significant symptom burden. Itching, for example can be a very annoying and very troublesome symptom for patients with PV.
And, if you don’t have PV or you don’t know someone with PV, you may not understand or realize the negative impact of having intractable itching, often associated with taking a shower or warm water.
And, that can really detract from quality of life and cause a lot of anxiety. So, that’s an example of where sometimes a JAK inhibitor like ruxolitinib can be really lifesaving in terms of restoring quality-of-life and functionality to a patient.
Usually, drugs like ruxolitinib are very well-tolerated too, which we’re fortunate about. There’s not a lot of toxicity associated with them. So, for example, nausea, vomiting, diarrhea, hair falling out with chemotherapeutics, you really don’t see with ruxolitinib or Jakafi. Easy bruising, headaches and some dizziness up front sometimes may be seen. They’re usually low-grade and they’re usually fleeting. And usually, the benefit, the feel-good aspect of it outweighs toxicity that can be seen with the drugs. They are immunomodulatory drugs. So, ruxolitinib or Jakafi may increase, to some small extent, but likely, real extent, infectious complications like shingles, urinary tract infections, upper respiratory infections. So, sometimes there is this increased risk. It’s often outweighed by the benefit of the drug.
But, there are risks that are associated, and of course the results are not guaranteed. So, I always warn patients, be careful when you look at the package inserts or talk to the physicians. Risks are risks. They’re not guaranteed. So, most patients don’t have these toxicities, but one is at risk for toxicity whenever they take any medication.
Yeah. Before we close, Dr. Mascarenhas, let’s talk about research. Are there new developments that you’re excited about?
Absolutely. So, what I’m happily interested in and involved in is clinical investigation and moving the field forward, and there are many people out there that are similarly involved and they’re doing really excellent work. So, I am super jazzed and enthusiastic and optimistic, and it’s what gets me work every day and inspires me is all of the effort that is happening. And, it’s a continuum. So, it’s not just one person trying to try a different drug here and there. It’s really a bringing together of many different people because these are rare diseases.
Many different people from many different institutions that have different areas of expertise, but have a common goal of translating from laboratory informed data, so, not just taking a dart and throwing it at the dartboard and hoping it sticks. But actually taking data that we learned from the lab and leveraging that information to develop therapies that are informed, that are targeted, that are personalized and going through a process of evaluating them to get them into the clinic, with the goal of, and I would say ambitiously, our goal these days is moving beyond trying to make patients feel better, which is an important goal, but it’s really can we really target the disease in a more effective way to induce remissions, to, dare I say, cure patients. So, I think the ambitious goal of the clinical investigators and laboratory investigators that are active in MPN research today is really one looking for an understanding at the basis of the biology of the disease to develop curative therapies. And, I am optimistic that that will happen.
And, I don’t mean happen in a hundred years from now. I mean happen in our lifetime. So, that’s where we’re going. There’s a lot of very exciting drugs, oral and intravenous drugs and they target very different types of aspects of the disease, and I think patients and physicians will see that maybe those drugs are used best in combination. So, the idea of using one drug, waiting for it to fail and using another drug is really old news, and much of oncology is combination therapy. So, taking drugs that have different targets or mechanisms of action and non-overlapping toxicity to try to better target and delete what’s called the myelofibrosis stem cell that’s the basic issue here, which we don’t effectively delete other than transplant. So, our goal would be to put bone marrow transplanters out of business.
Well, that’s a great plan. I hope that that can happen one day. Thank you so much for joining us today, Dr. Mascarenhas. We appreciate you taking the time.
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. Thank you so much.
What is inhibitor therapy? Dr. Joseph Scandura reviews approved JAK inhibitor therapies and explains how they work to treat myelofibrosis.
Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.
How does inhibitor therapy work to treat myelofibrosis?
So, the therapies that we have now that are approved therapies that are in this class are ruxolitinib (Jakafi) and fedratinib (Inrebic).
Both of these agents act to block signaling through a protein called JAK2. You can think of JAK2 as being part of the antennae system that a cell uses to communicate with the rest of the body. And so, our blood-forming cells have a lot of input from the body saying, “Okay, we need some of these kinds of cells, we need some of those kinds of cells,” and it’s a very adaptive system. And JAK2 is involved in a lot of the signaling in this as part of the antennae system.
And what happens in the myeloproliferative neoplasms is that signaling is a bit excessive.
And so, it’s like the volume is turned up too loud and the signaling is causing the cells to do things, make too many cells, make the wrong kinds of cells, and JAK2 is part of that signaling system. So, these inhibitors kind of help turn down the volume of the signaling in these blood-forming cells. They are drugs that have good activity in improving symptoms, they have great success in reducing the size of the spleen, they can be useful for a few years to many years. They are not curative therapies. We don’t think of them as therapies that change the course of disease, but they certainly have an important role in helping people feel better. There are other inhibitor therapies that are in clinical development.
So, clinical trials of some of these drugs have really impressive activity, but none is approved yet by the FDA.
I hope and expect we’ll have a couple more drugs available in the coming years. And there’s a lot of excitement in clinical trials in terms of some of the activities that are being seen, and really quite tolerable therapies, so not a lot of side effects for patients. And so, I think it’s kind of an exciting time for physicians and for patients and a lot more options now and, I think, a lot more options coming down the line.
What are the essential tests that should follow a myelofibrosis diagnosis? Dr. Joseph Scandura reviews the necessary laboratory testing, along with a discussion of next generation sequencing, and explains how often bone marrow biopsies should take place.
Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.
What testing should take place following a myelofibrosis diagnosis?
So, a diagnosis of myelofibrosis always comes after a bone marrow exam and a physical examination. Often, patients have an enlarged spleen and blood count testing and a variety of other laboratory tests. So, after that and a diagnosis is made of myelofibrosis and, sort of, coincident with the diagnosis, we often look for molecular markers of myelofibrosis. So, these are malignancies of the bone marrow, cancers, if you will, on the bone marrow, although the term is scarier than or is different than what we think of for many malignancies in how it acts. But the myelofibrosis, this is a disease that’s characterized by, really, mutations in the malignant cells, the abnormal cells.
They’re really just one of three genes. And so, JAK2 being one of the genes, calreticulin or CALR being another one, and MPL one.
And more than 90 percent are people having mutation in just one of those three genes. And so, often at the time of diagnosis, tests for those mutations are done, and they help eliminate the possibilities of other causes of myelofibrosis – infections, rheumatological diseases. Sometimes, you can have marrow fibrosis but they don’t go along with mutations and the same clinical situation. And so, at the time of diagnosis, we usually know something about a mutation in JAK2, CALR, or MPL.
More commonly now, and it’s increasingly common over the past 10 years in, I would say, in New York City and many places across the country, we also look more broadly for other common mutations in the MPN cells. And these are what we refer in the batch as next generation sequencing or NGS panels, and we use the term panels because we’re looking at from a few tens to even 100 or a couple hundred genes for mutations that occur far less frequently than in JAK2 or MPL or CALR.
But they occur often enough that some of them we use to help guide treatment decision-making or approach to therapy. The reality of it is that that the technology to sequence and identify mutations has really outstripped our knowledge of what to do with all of that information.
And, for the vast majority of people, it comes down to do you have a marker, a genetic marker that tends to go along with higher risk, meaning a higher likelihood of something that we don’t want to have happen. And in that instance, although it may be looking at a hundred or so genes, it comes down to a binary thing – either you have or you don’t have.
Is there any other testing that you usually want to do?
Laboratory testing, for sure and, as I mentioned before, a bone marrow exam. But physical examination, some people might do imaging of the spleen size. Honestly, I don’t routinely do that outside of the setting of the clinical trial. I don’t really think it dictates therapy very often.
And if the spleen is so small that you can’t feel it on physical exam, it probably isn’t clinically meaningful anyway in terms of something to treat. It might be there, but it doesn’t really change things too much.
How often should patients have a bone marrow biopsy?
So, I’ll answer there is no standard in terms of monitoring for myelofibrosis with the marrow or otherwise. My personal approach is I do a marrow when I think it’s going to help medical decision-making. And so, for a patient who’s got early myelofibrosis, who’s been very stable, responding well to therapy, that could be three, five years between marrow exams.
For somebody who’s being considered for a clinical trial, oftentimes, a marrow exam is required before they start on the clinical trial and at various intervals afterwards. If there’s somebody who had been stable and something is changing, like the blood counts are changing or his symptoms are changing, or any of a number of clinical features, then I might look in the marrow to see what’s happening there, to see if explains and can help guide a treatment approach to help people feel better. So, there is no single standard, but my personal approach is to do a bone marrow exam when I think it’s going to help make a decision.
Dr. Laura Michaelis discusses how frequently patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) should visit their doctor.
Dr. Laura Michaelis is hematologist specializing in myeloproliferative neoplasms (MPNs) at Froedtert & the Medical College of Wisconsin, where she also serves as Associate Professor of Medicine. Learn more about Dr. Michaelis here.
So, the regular follow-up for myeloproliferative neoplasms, whether that is somebody with ET, PV, or myelofibrosis, is incredibly variable. It depends on the risk stratification. It depends on how frequently you’re needing intervention.
For example, somebody with low-risk polycythemia vera whose hematocrit is elevated and gets a phlebotomy – that person I follow relatively frequently.
Maybe every month or so until I know for sure that the phlebotomy frequency, the number of times we are removing blood, and the frequency, the rate at which that happens, is adequate to ensure that that person is not spending too much time with a hematocrit of over 45 percent.
We know that because randomized trials have shown that a hematocrit over 45 percent leads to an increased risk for bad clinical outcomes.
So, early on in that person’s trajectory, I might check their blood counts more often. Once I know that they are stable and can go longer periods of time, we can relax that out. And that may happen, for example, when they become iron deficient, and the need for phlebotomies decreases.
In somebody with essential thrombocythemia that’s well controlled, again, one might do blood counts every three months or maybe, if things are very stable, every six months.
This is something that I usually make sure that I’m following the national guidelines on and that I adjust from a patient standpoint. If somebody is seeing their PCP in three months and getting blood counts, and things have been stable, then there’s no reason to see more frequently.
Now, when do I see people more frequently? For example, if they’ve started a new treatment, and we want to make sure that their kidneys and liver are doing okay. If I’ve noticed a change in one of their organ functions on the basis of something and do a little tweaking of their medicines, then I might see them more frequently.
So, again, there’s no set-in stone. This is part of the art of medicine, and you wanna talk with your doctor about what you should expect and who’s gonna be following up on the tests that are drawn.
How do you distinguish MPN symptoms from side effects? Dr. Laura Michaelis explains the difference, and why it’s important to share any changes with your doctor.
Dr. Laura Michaelis is hematologist specializing in myeloproliferative neoplasms (MPNs) at Froedtert & the Medical College of Wisconsin, where she also serves as Associate Professor of Medicine. Learn more about Dr. Michaelis here.
So, symptoms and side effects are sort of different things. Symptoms are the characteristics of the disease process. And these are things that often can vary in intensity. They maybe accumulate over time. But those are things like, for example, uncontrolled itching, fatigue, night sweats, fevers at night, unintentional weight loss, discomfort in the abdomen, or feeling full shortly after eating. Those are symptoms that often bring patients to the doctor’s attention in the beginning. And those are symptoms that can tell us that the treatments that we’re using aren’t working very well.
Now, side effects is the term that we use for problems that evolve when somebody starts a treatment for a condition. So, for example, if somebody starts the treatment of ruxolitinib for myelofibrosis, it is known that one of the side effects of this treatment is a small but significant lowering in the red blood cell [count].
That is a side effect of the ruxolitinib and should be anticipated. So, before you start the ruxolitinib, your doctor should sit down with you and talk about some of the side effects. And that might be one that gets mentioned.
In addition, we know that there is uncommonly – but uncommonly, people can have, for example, shingles reactivation once they’re taking treatment for myelofibrosis. And that might be something for which you take a prophylactic antiviral treatment.
Hydroxyurea has side effects. Interferon has side effects. And those are things that you should think about before you start them. They shouldn’t be reasons not to start the treatment because most people who take medicines don’t have the side effects. But it is something to keep in mind. And when then occur, report them to your doctor.
So, rarely, there’s conditions that occur, and you’re not sure. Is this a side effect to the treatment? Or does this mean the disease is progressing in some way? That’s one of the reasons it’s important to report all of these conditions to your physician because they need to know.
One of the things that can be helpful is there’s a common tool called the MPN SAF, which is a symptom assessment form.
If, periodically, you and your doctor fill that out during a clinic visit, you can sort of understand are those symptoms that I had with my disease responding to the treatment? Can we really measure that things have gotten better since I started treatment X or treatment Y?
And in addition, when you sit down with your doctor at your regular checkups, it’s not just about going through your blood counts and doing a physical exam. It’s also about telling them what you’ve noticed in the last two to three months since you saw your doctor with regard to the treatments that you’re taking.
When choosing an MPN treatment, what’s right for you? Dr. Brady Stein from Lurie Cancer Center reviews key decision-making factors, current treatments for ET, PV and MF, and shares advice on advocating for yourself.
Dr. Brady Stein is a hematologist focusing on myeloproliferative neoplasms (MPNs) at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Learn more about Dr. Stein, here.
Hello, and welcome to the webinar. I’m Katherine Banwell, your host for today’s program. Today, we’ll discuss how you can be proactive in your understanding of MPNs and work with your healthcare team to find the best MPN treatment path for you. Joining me today is Dr. Brady Stein. Thank you for joining us. Would you please introduce yourself?
Hi, my name is Brady Stein. I’m a hematologist at Northwestern University in Chicago, and thanks very much for having me.
Before we begin, a reminder that this program is not a substitute for seeking medical advice. Please refer to your own healthcare team about what might be best for you. Dr. Stein, let’s start with the basics. The term “myeloproliferative neoplasms,” or MPNs, can be a bit confusing. Would you give us a brief overview of the classic types of MPNs?
Sure. So, there’s three classical types of MPNs that we focus on. These are the BCR-ABL-negative MPNs. So, what we’re referring to in this webinar is essential thrombocythemia, otherwise known as ET, polycythemia vera, often referred to as PV, and myelofibrosis, often referred to as MF, and myelofibrosis can exist on its own.
It can be primary, so a patient can start with that diagnosis, but it’s also important to note that patients who have ET or PV for long periods of time – they can head in the direction of myelofibrosis, so that’s kind of a secondary type of myelofibrosis, sometimes referred to as post-ET MF or post-PV MF. So, those are the three basic subtypes that we’re gonna speak about today.
Do symptoms vary for each type – ET, PV, and MF?
They do. They vary, but they can overlap. So, oftentimes, ET is thought of as the more indolent of the MPN subtypes, but I think it’s pretty clear that patients with ET can have a similar burden of symptoms compared to patients who have polycythemia vera and myelofibrosis, so they exist on a spectrum, I think most to a degree that symptoms can be the most pronounced in patients with myelofibrosis, but not to undermine the symptom burden that can occur in ET and polycythemia vera.
Once a patient is diagnosed with MPN, what sort of testing should take place?
So, the test that’s gonna lead to suspicion is gonna be a blood count, and that’s probably gonna be done in the primary care doctor’s office, so that’s gonna be the first suspicious test, and in general, there’s gonna be some abnormality. Myeloproliferative diseases are characterized in general by an overproduction of blood cells, so it’s going to be a higher white count, it’s going to be a high hemoglobin or hematocrit, or a high platelet count, or a combination of the three that’s generally gonna lead to suspicion.
Some patients may have pretty unremarkable blood counts and may present with a blood clot in an unusual location that could ultimately lead to the hematology referral. Some patients might have pretty unremarkable blood counts, but they might have palpation of their spleen, enlargement of their spleen in a physical examination. So, they’re generally the ways that patients are getting to the hematologist.
And, what about bone marrow biopsy?
So, a bone marrow biopsy is a diagnostic test, and it’s generally recommended for all patients who have a myeloproliferative neoplasm either confirmed or suspected.
It’s advised in WHO criteria – World Health Organization criteria. PV can be made without a bone marrow biopsy – a diagnosis of PV – because it’s the most unique of the MPN subtypes. It’s the one that presents with a high hemoglobin.
So, that diagnosis can be straightforward at times for a hematologist when the setting is right, when there’s a high hemoglobin – or, high enough hemoglobin, I should say, a JAK2 mutation, which all patients with PV have that, or a subnormal erythropoietin level.
Oftentimes, we can make that diagnosis without a bone marrow, and the bone marrow becomes more prognostic. ET, a bone marrow is necessary for diagnosis, and myelofibrosis, you can’t make a diagnosis without it.
What do the results of these tests tell us about prognosis and treatment choices?
That’s a good question. The bone marrow can be diagnostic in the setting of ET and myelofibrosis. In the setting of polycythemia vera, it can be more prognostic. In general, when a bone marrow is done, 1). To confirm diagnosis, 2). To assess prognosis, what we’re looking for as prognostic features are generally the degree of fibrosis or scarring.
So, each of the MPNs can have that. Of course, MF is characterized by the most pronounced scarring. It can happen to a more subtle degree in ET and PV. That’s gonna be prognostic in the setting of ET or PV. The pathologist will alert us about immature cells called blasts. We basically never see them at diagnosis in patients with ET or PV. We can see them rise in patients with myelofibrosis at diagnosis or through the course of follow-up. So, that’s prognostic.
All bone marrows generally have a chromosome analysis that’s called cytogenetics, and so, if there’s an abnormality, that can help place the patient’s prognosis into different risk categories. And then, nowadays, more so in myelofibrosis than any of the others, there are extended panels done. These are called NGS, or next-generation sequencing, kind of looking at mutations in a greater degree of detail.
So, not just what we call main mutations – JAK2, calreticulin, or MPL. These are looking at additional mutations that basically hold prognostic significance.
These are pretty well defined, and I think more important in MF compared to the other subtypes.
Would you explain the driver mutations in MPNs? What are they, and how they – or, what they mean for patients?
So, there’s three of what we call driver mutations, and the most common is JAK2V617F, the next most common is calreticulin, and the least common or most rare is a mutation of MPL, the thrombopoietin receptor. So, the driver gene mutations are the three that we assess to help with diagnosis, and the prevalence varies. In ET, about 60% have JAK2, 25% have calreticulin, 5-10% have MPL.
In PV, 99% have some type of JAK2 mutation, and in MF, the situation is a lot like ET – 60% JAK2, 25% calreticulin, about 5-10% MPL. So, the driver mutations – we think of those as the genetic abnormalities that really drive the disease. They’re the main ones we can test for in a diagnostic setting.
I refer to them as the – to a patient, what I’m describing is you have a car, and the driver mutation is the one that’s sort of driving the car, and it’s doing it somewhat recklessly. It’s in the front seat, driving. And, along the way, the driver can pick up hitchhikers, which we should never do. I refer to those other mutations that are found by NGS as hitchhiker mutations that sit in the back seat, cause trouble, and really shouldn’t be there. They’re not the driver, they’re not fully responsible for the disease, but they can make it a bit worse.
We have a question from the audience, Dr. Stein. “I was recently diagnosed with MF, and I’ve had a bone marrow biopsy. How often will I need to undergo this procedure?”
That’s a really good question. It’s a very important, very common question. So, the first bone marrow biopsy is diagnostic. The second bone marrow biopsy – or third – are generally reactive, meaning we don’t schedule them year to year unless there’s a change. We do them in a reactive way. If there’s something about the condition that’s changing – for example, if we suspect or worry about a progression – that’s when we would do the second bone marrow biopsy. So, we don’t set a determined frequency if the condition or the course is stable.
Dr. Stein, I understand that therapy is different for each of the MPNs. What do you take into consideration to help guide the treatment choice?
So, that’s a good question. It’s gonna require maybe a little bit of a longer answer. It’s fairly nuanced. The treatment of ET and PV – right now, the goals are – the treatment is largely based on a patient’s vascular risk. That’s largely what influences the choice of therapy. And so if a patient has a perceived high risk for vascular complication in ET or PV, that’s when we’re gonna be a little bit more aggressive – so, more aggressive than watchful waiting, more aggressive than using aspirin alone, more aggressive than using phlebotomy and aspirin alone in polycythemia vera.
So, if the patient has a higher vascular risk, in general, we’re gonna need to do something more than what we consider to be the standard, and that’s where we enter into the question of cytoreductive therapy – therapies designed to lower blood counts apart from phlebotomy.
Maybe that’s gonna change. I hope it will change. Right now, the therapy for ET and PV is generally reactive. We either predict high risk and react, or if a patient is lower risk, if something changes – God forbid there’s a blood clotting event – then we may react to it.
So, ET and PV treatment are generally more reactive. In myelofibrosis, certainly, there are patients who can have lower risk and minimal systems, and there are some patients who can be observed with watchful waiting for sure, but more patients are symptomatic, more patients are gonna need therapy in myelofibrosis, and there’s sort of two big categories of therapy.
One is the risk-adapted, deciding if the patient is eligible and should consider stem cell transplant versus thinking only about medical therapy in a patient that may be transplant-ineligible.
And, the medical therapy is based on the worst symptoms for the patient. Is the symptom that’s the worst the spleen enlargement? Is it excessive fatigue? Is it weight loss, or inflammation, or fevers? If it’s that category of symptoms, we have a set of therapies. If it’s really the anemia that is the most problematic issue, then we follow a paradigm to treat anemia.
What about considerations like the patient’s health, age, genetic markers, things like that?
So, of course. The comorbid illnesses can influence therapy choices, so if a patient is older and has other medical conditions, they’re not gonna be treated as aggressively.
So, in myelofibrosis, if a patient is older, with other medical illnesses, then it may be inappropriate to consider something like stem cell transplant, for sure. So, age and health comorbidities are highly influential. In terms of genetic features, if you’re asking about things like the type of mutation that a patient has, right now, we’re – in terms of vascular risk, for ET, the type of mutation matters for blood clotting risk, so if patients have different mutations, it could be treated differently. In other subtypes, like PV or myelofibrosis, in general, there’s – the mutation can be prognostic, but it may not be – it may not lead to a precise and distinct therapy just yet.
All right. What do you feel is the patient’s role in the decision for therapy?
I think it’s a really important role. I think historically – and, this is decades past; this era should be well over and behind us – this era of authoritative medicine is over.
You can’t just have a doctor walk in the room and say, “This is your treatment, this is what you should do, I’ll see you later.” It’s shared decision-making, and that can be troubling for some patients. But, the idea of shared decision-making is us explaining options informing the patient and making decisions together. That’s really the paradigm for modern contemporary medicine.
Some patients have a harder time with that. A lot of patients say, “Well, doc, this is too overwhelming for me. I just want you to decide for me.” And, we try not to do that. That’s a more uncomfortable type of visit for me when a patient is very deferential and says, “Whatever you say, I’ll do.” That’s not really what we wanna hear. I wanna know that you feel really informed, that you have a good understanding because each of these treatments – any treatment, any medication has its pros and cons.
There’s no real magic bullets, and each upside has an equal downside, so you have to engage and open a dialogue, and what that means is that patients need to read and learn. That’s hard, but patients need to become proactive in their approach to their own illness, and all the patients who are listening now are doing that, trying to get more education about your relatively rare illness that’s gonna give you a much better framework to help make decisions together.
Absolutely. If a patient isn’t feeling confident with their treatment plan or their care, do you recommend that they maybe consider a second opinion or seek a specialist?
Of course, yeah. These are rare diseases, and patients often – I would say that in my clinic, a lot of the patients direct their own second opinions. Oftentimes, it’s coming from the patient more so than their doctor. I think the patient community is very active, the patients are networking, and they’re finding the right specialist to get to.
I think it should be really a team approach. It’s never – it’s usually not very convenient to go to a university unless you live really close, so you wanna have someone close to home who can handle the routine, and then, someone who maybe is a little bit further away who can see you once a year, can help with the big decisions, can be part of the healthcare team. So, we generally recommend that you have someone near, and that maybe you have someone far who focuses only on MPNs as part of your team, and now, it’s a little different. Telemedicine is becoming a pretty ingrained part of medicine. It’s a little easier to have those visits with a physician who’s far away because of telemedicine.
So, now that we’ve discussed how a treatment path is determined, can you walk us through the currently available MPN treatment approaches and who they might be right for?
Let’s start with essential thrombocythemia, or ET.
So, I think the first thing is taking an inventory of symptoms, seeing how symptomatic the patient might be. Again, there are some patients who are asymptomatic or have few symptoms, and they were told of a high platelet count during a routine visit, so some patients can be observed if they have few symptoms, and especially if they fall into a lower vascular risk category.
So, symptom assessment first. Second, looking at vascular risk, and there’s four categories of risk in in ET in terms of predicting the likelihood of a future blood clotting event. There’s a very low, low, intermediate and high risk group, and that’s based on a patient’s age, whether they’ve had a blood clot before, and the type of mutation they have. JAK2 mutations increase the risk of clotting.
So, if a patient falls into a higher-risk group – say they’re older than 60 with a JAK2 mutation or they’ve had a prior blood clot – those are patients who are generally treated more aggressively with cytoreduction. And then, the other thing is aspirin. We often see aspirin given to all patients with ET, but not all patients with ET necessarily need it. The role of aspirin is actually a little less clear in ET. For a very low-risk patient, there’s a potential for more harm than benefit, especially if the patient lacks a JAK2 mutation. So, the evidence base to support aspirin for all ET patients is just not there; it’s evolving.
What about polycythemia vera, or PV?
So, there’s a few standards. It’s different – the aspirin question in PV is generally answered by randomized data from 16 years ago in 2004. It’s been shown that aspirin reduces the risk of clotting in PV patients, so, generally, we give low-dose aspirin to all patients.
And, hematocrit control is really important. At least, a goal of 45% is mandated in PV. And then, there are patients who might fall into a higher-risk category – older than 60 or have had a prior blood clot – they need something more. And then, I’d also emphasize that there are lower-risk patients who may not be traditional candidates for cytoreduction, but they could have symptoms that really interfere with quality of life, and symptoms alone can be the trigger to add something more to the phlebotomy and aspirin program.
What about things like interferon?
So, interferons have been used in MPNs for decades and decades. So, a longstanding history with interferons. The issue has been tolerability.
These days, there’s a class called pegylated interferon that’s longer acting, and I think there’s been a lot more use, at least in the last 10 years, still much more in an academic setting than a community practice.
But, interferons have a pretty established role in MPNs, especially polycythemia vera, for sure in ET, less so in myelofibrosis.
Dr. Stein, you mentioned high-risk versus low-risk patients quite a bit. How is that risk determined?
So, it’s different for each subtype. For ET and PV, when we talk about high versus low risk, we’re talking about vascular complications, risk of having a blood clot. We’re not really talking about risk of transformation. We don’t have, I think, wonderful, widely used toolkits to predict those things. We know they can happen, but our treatment is still really based on clotting for ET and PV.
And, MF – each couple of years, the tools that are available to assess prognosis become more and more. So, in MF, we’re using the most comprehensive approach – of course, taking into account things like age and demographics, but also, looking at symptoms, looking at the depth and severity of blood count changes, looking at bone marrow features like the degree of scarring, looking at the rise in blast counts, and then, looking at chromosomes and novel genetic markers. So, we’re definitely the most comprehensive in myelofibrosis at assessing prognosis.
How do clinical trials fit into treatment choices?
Clinical trials are always a treatment – always an option for patients with myeloproliferative neoplasms because while we have some standards, we can definitely improve upon those standards for certain. So, clinical trials are always a therapeutic option. I think the one thing is that it may not – it’s not always the most convenient option, but it could be a really important option if available to you.
So, clinical trials basically offer something new or novel that would not otherwise be available to other patients. So, ruxolitinib was approved around 2011, but the first clinical trials were in 2007, so that’s the example I give to a patient about the benefit of a clinical trial.
The patient can get access to a drug that’s effective perhaps three to four years before it’s commercially available.
That’s really the biggest advantage, is you can get early access to something that could really help you. The downsides are that clinical trials are not usually as convenient as regular care, there’s often more visits, and there’s a lot of unknowns – unknowns about whether it will work. Some side effects are known and expected; there are others that are unknown. So, it’s a lot to think about, but I think it’s always important to consider, especially if your first-line therapy has not been effective, if it’s losing its touch, it’s a good thing to think about for a second line.
Are there emerging approaches for treating MPNs that patients should know about?
Yeah, absolutely. I think the first question – I think patients are often worried that they have a really rare disease, and why would anyone do research in this area, and that’s – the research community is extremely engaged, the productivity is pretty impressive, and there’s a lot of clinical trials in the space, and I think what I try to explain is pharmaceutical companies aren’t just targeting the most common diseases.
They have interests in rare diseases, and findings in rare diseases can be extrapolated to other diseases that you might think are unrelated, but they can share features, so when you find something working in one space, it can have broad applicability. So, there’s an abundance of research in myeloproliferative neoplasms which are emerging?
In PV, I think there’s quite a possibility that there’ll be a drug approval in 2021, a novel type of interferon called ropeginterferon.
That is a drug that’s approved abroad; it’s approved in Europe, and I believe it’s approved in Taiwan, and the FDA is looking at it now. So, it’s a possibility that there’ll be a future option for patients with polycythemia vera. So, yes, it’s research now, but it could be available, and so, that’s the drug that I’m starting to talk more and more about for patients with PV.
In myelofibrosis, you have two JAK inhibitors that are approved, ruxolitinib and fedratinib, you have two others in clinical testing, momelotinib and pacritinib, and then you have a whole other class of what we call non-JAK2 type of therapies targeting the vast array of pathway abnormalities in myelofibrosis.
So, there’s a number of different clinical trial options, especially in myelofibrosis. I think that’s the disease area where there’s the most clinical trials.
Once a patient has started treatment, how do you know it’s working?
That’s a good question because this is a very unique area. Yes, of course, in some respects, it’s straightforward with ET or PV. If we’re starting a medication to control a blood count in hopes of having lowered the thrombosis risk, you can look objectively at blood counts.
Okay, your hematocrit is at this goal? Yes, therapy’s working. You have not had a blood clot? Yes, therapy’s working. So, there are some objective things. In myelofibrosis, there are some objective things like measuring the spleen and seeing it reduce. You can feel that with your hands, or you can do an ultrasound. So, there are some objective parameters of success. But, in this area, patient-reported outcomes are really important, and so, a measure of success is really just asking the patient, “Do you feel like your drug is working? Do you feel better?”
It’s kind of a simple question, but it’s really important, and it’s what we ask in patients who are on certain therapies. “Do you feel like the net effect of your therapy is still positive? Do you feel like it’s helping?” Seems like a straightforward type of question, but I think the answer is extremely informative. When a patient says, “Yes, definitely, my medication is still helping me,” then I know that I don’t need to change it.
Right. Patients are often concerned about progression in MPNs. Would you explain the progression of MPN and the indicators that one might be progressing?
So, I think the important but hard thing to know about MPNs is that they’re chronic progressive illnesses, but what we don’t know in an individual is how long it’ll take to progress. Is the ET or PV gonna progress in 10 years, 25 years, or 35 years? Those are difficult things to predict. And, MF is progressive as well. I think it’s a little easier to identify those patients who may progress more rapidly compared to more slowly.
So, MPNs progress, and that’s the first important thing, is that they’re chronic illnesses and patients have to be aware that they can change. ET and PV can move to myelofibrosis, and when that happens, generally, symptoms change, the spleen enlarges, and blood counts change. We start to see anemia when we didn’t before.
And, when MF progresses, the symptom burden is one thing, maybe more fatigue, unexplained fevers, drenching sweats, or weight loss. On exam, measuring the spleen and seeing it get larger, seeing a fall in the platelet count, a need for red cell transfusions or a rise in the blast count. Those are all features that we’re looking for that can indicate a progression.
Let’s talk about patient self-advocacy now, Dr. Stein. Patients can sometimes feel like they’re bothering their healthcare team with their comments and questions.
Why is it important for patients to speak up when it comes to symptoms and side effects?
I smile a little bit because patients – I get a lot of patient emails by MyChart. That’s our medical record, and it’s a secure patient email, and a lot of patients will start their message by saying, “I’m sorry to bother you.”
And, I always say, “Why do you think that? It’s my job. Please don’t apologize for reaching out to me.” So, that’s kind of the first thing. Don’t feel like you’re bothering your doctor. There are certain things that we won’t know unless you tell us, and so, I think that’s pretty clear. When we’re in a patient room and there might be a husband and wife together, and whether it’s the husband is the patient or the wife is the patient, we might ask a question, and we might get, “No, everything is fine,” but all doctors kind of sneak over to the partner, and the partner may be saying – they’re making gestures to us. There may be nonverbal forms of communication to tell us there’s something much worse than what the patient is telling you.
So, again, “advocate” meaning you have to tell us what’s going on with you. If you’re worried about something, please don’t be stoic about it. These diseases are treated a lot based on your symptoms, and so, if you don’t tell uls about your symptoms, we won’t know.
And, in terms of advocacy, I think one of the things is that these are pretty rare diseases. In an academic center, no, this is our focus, but if you’re in a community practice where the doctor’s seeing 10-15 different things during the course of a day, it’s basically impossible to keep up with myelofibrosis, especially if you have one patient in your whole practice. I can’t do that for diseases that I see that I have only one patient. The medical literature can be overwhelming.
So, patients can quickly outpace their doctor in terms of their knowledge of these diseases, but I think it’s really important to read, to learn, and to think about the illness because you may find out things through your research that your doctor wouldn’t know are available. You may find a clinical trial, a new strategy, or a new test that they simply haven’t had the time to keep up with or learn about. So, that’s what advocacy is about. Reading is really important, but you have to find a balance. I want my patients reading, but you’ve gotta find the right amount because there’s a certain amount of reading where the patients start to get overwhelmed.
All patients kind of get to this point. They take it in – like taking it in like a fire hydrant in the beginning of the disease, and it’s overwhelming, and then they start to find their balance. I think there’s a point where the reading becomes anxiety-provoking rather than ameliorating anxiety, and all patients just generally find their balance.
What I also say is if you read something that alarms you, write to me, write to us, and let us verify that because there’s a lot out there, and I think the patient communities are a phenomenal form of support, but there’s a lot of patients giving advice to each other, and sometimes that needs to be double-check – or, always, it needs to be double-checked by another doctor because sometimes, the advice is simply not – may be very individualized or not generalizable, or sometimes it’s simply inaccurate.
What would you like to leave the audience with? Are you hopeful?
Oh, of course. Of course, I’m hopeful. What I leave the audience with is that things are changing; things are changing for the better, and the therapeutic choices in three years could be entirely different. I think there’s progress. Progress in medicine – some patients feel it, it’s slow, but having been in this field for a decade, there’s more and more therapeutic options emerging. Kind of what I’m looking to see most, honestly – I’m following everything really closely, but what I’m starting to think about more is paradigm shifts.
What I’d like to see in the field is to move away from a reactive type of approach and think more about early initiations of therapy, more of a proactive type of strategy, not really – because when we talk about therapeutic choices with a patient and the patient says to us – we don’t say it like this, but the way they say it back to us is, “So, wait, we’re gonna wait for something bad to happen, and then we’ll start treatment?”
I think that – I share discomfort, as – I’m uncomfortable with that approach. The reason we haven’t been proactive is because we’re kind of waiting for highly safe, highly effective therapies that could potentially change the course of the illness. That’s why we have been reserving our therapies, and that’s why our secrets sometimes include less aggressive watchful waiting with later initiation of therapy just because physicians haven’t been satisfied with their choices, but I’m hopeful that that’ll change.
Dr. Stein, thank you for joining us today.
Thank you very much for having me.
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.
Dr. Srdan Verstovsek provides an overview of myeloproliferative neoplasm (MPN) progression and reviews indicators that essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis may progress.
Dr. Srdan Verstovsek:
When we talk about ET and PV, they should be life-long conditions without much of a change. It’s uncontrolled blood cell count and thromboembolic events, which are then subject to a therapy, and the goal of therapy is to decrease the thromboembolic risk.
There is still, in some smaller proportion of the patients, a risk of a disease change on its own. We talk about the genetic testing that can reveal a change in genetic complexity of the disease, which may be responsible for a change down the road. Or abnormalities in chromosomes that can be seen at the time of diagnosis in some of the patients with ET and PV, not very often, which may predispose patients to a change down the road, a change to more aggressive condition.
So, a smaller proportion of the patients, perhaps 10 – 20 percent of the patients between ET and PV, can over time, long time, acquire fibers in the bone marrow.
That can lead to anemia actually, progressive increases in spleen, bone marrow cells in blood, that would be then a change to myelofibrosis. And a very small percent of the patients actually can change to acute myeloid leukemia, with the baby cells in the blood and the bone marrow, these are called blasts.
They should not be in the blood in the wrong person. They should be below 5 percent in bone marrow in normal person, but if they go above 20 percent, we call that acute leukemia.
So, transformation of ET or PV to myelofibrosis or acute myeloid leukemia, are fear, and obviously can lead to a shorter life expectancy. And so, one can certainly worry about that, but again, it is in a smaller proportion of the patients, and we don’t usually worry that much about it. However, the worry does exist, that’s why you are asking me about it, and the problem is we don’t have medication that would be known and proven in prevention of that biological change of the disease in some patients.
In myelofibrosis it’s similar situation, 20 – 25 percent of the patients change to acute myeloid leukemia, and we don’t have real medication that would be preventing that change.
MPN specialist, Dr. Srdan Verstovsek discusses the latest research and progress for the treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF).
Dr. Srdan Verstovsek
When we talk about the new therapies in development, there are many in myelofibrosis in particular, and a few are in essential thrombocythemia and polycythemia vera. Let’s start with ET and PV. Here we are expecting either studies, or possibly even approval, of a long-acting interferon called Ropeginterferon that was approved a year ago in Europe for PV patients.
We gonna have, hopefully here in the United States, that drug for our patients in a year or perhaps studies in PV, or perhaps most definitely, I would say, studies in ET with this drug. That would be enhancement of what we done off-label using interferons that are approved for some other conditions. We know that interferons are biological agents active in these conditions to control the bone marrow, and perhaps even decrease the number of malignant cells in the bone marrow of patients with ET and PV, which may be beneficial down the road.
In myelofibrosis, the picture is completely different. In this setting, the life expectancy, unfortunately, is affected as we discussed, and we need therapy that would be perhaps improving that life longevity. As we know, the ruxolitinib JAK inhibitor that has been around for nine years can extend the life a few years, but not cure people.
So, helping JAK inhibitors by combinations with other active agents that would be biologically modifying that bone marrow, decrease the tumor burden, improving the quality of life or anemia, are at forefront of what is happening right now. So, combinations with Navitoclax which is Bcl-xL cell inhibitor, CPI-0610, which is BET inhibitor, Luspatercept which is anemia drug.
These are phase three studies that are planned to start soon for possible approval for combinations over JAK inhibitor alone for different problems that people face.
Or, later on in the course of the disease, JAK inhibitor may fail. What do you do then? So, we have studies announced that will be done in what we call a second line, after-JAK inhibitor. And the MDM2 inhibitor was announced. Imetelstat inhibitor in the second line. Momelotinib JAK inhibitor in the second line. Fedratinib is being studied, another JAK inhibitor. Pacritinib for patients with low platelets
These are all phase three studies. That’s means for approval of this drug, so that will be three and four, seven different phase three for myelofibrosis patients with different clinical scenarios, different clinical problems are being done, or about to be done, in very near future. So, my prospect is here. My view on that is that we will have, hopefully, at least some of these seven studies leading to approval of some new drugs for our patients with myelofibrosis.
MPN expert, Dr. Srdan Verstovsek reviews factors that may indicate a treatment change for patients with essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF).
Dr. Srdan Verstovsek
The real definitions of a failure of a given therapy, it’s not easy to come by. Experts in the field, doctors that see a lot of myeloproliferative neoplasm patients, occasionally get together and try to put in place some guidelines. What would be a failure to a therapy mean for patients with ET or PV?
Would that be, for example, polycythemia vera patients too many phlebotomies when you are on hydroxyurea.
Hydroxyurea is a chemotherapy by mouth, should be eliminating need for phlebotomy, should decrease the white cells and platelets, and the spleen enlarged, and improve the quality of life.
If that’s not possible, and you have to define what that means, then you would say, you should change. So, guidelines do exist, which are always used in clinical studies to define the failure and justify a change. But they should also be applied in clinical practice to apply possible.
If you are on hydroxyurea for ET and PV, and you are not controlling blood cell count very well, you can’t take more because there are side effects from hydroxyurea, you should change. Right?
If you see a progression of the spleen, or worsening of quality of life despite the control of the blood cell count, something is wrong, maybe you should change.
In myelofibrosis is similar situation. You may be experiencing a good therapy on JAK inhibitor or anemia medication, but then after a while, spleen starts to grow, quality of worsens, or anemia develops, then you should change.
It’s not as easy to see exactly to define, but you get the point I’m sure because people are different, the benefit extent or benefit is different, pattern of a failure is different, and we have a lot of difficulties in really objectifying what this means to fail.
My approach is when I see a failure developing – nothing happens overnight. You try to modify what you do by adding another medication, adding medications for whatever is causing that failure, or modifying what you’re doing by changing the schedule or the dose. So, not to give up and say, “Oh, it’s not working,” but trying to work with the patient, and with the medications that you have in different way, for benefit to last the longest possible.
Dr. Srdan Verstovsek, discusses how multiple factors, including diagnosis and symptom burden, determine which MPN treatment path may help improve a patient’s outcome.
Dr. Srdan Verstovsek
So, we talk about diagnosis, and then prognosis, and then go over [stem cell] transplant. Now, the transplant is done in only less than 10 percent of the patients because most of the patients are elderly. That’s why you have the disease.
They might not have a donor. They may be sick. There are multiple reasons, so transplant happens in less than 10 percent of the patients. Once we are over that, you say, “What’s wrong with the patient?” Not wrong in terms of dying, but do you have a significant anemia? Do you have an enlarged spleen? Do you have a bad quality of life when we talk about myelofibrosis? All of this that I have talked so far, applies to myelofibrosis. These are the three main reasons for initiating of therapy, usually. Significant anemia, significant bad quality of life, and significant symptom related to the big spleen. You would then introduce therapies.
For the splenic symptoms, we usually prescribe JAK inhibitors. That would be standard practice. For anemia, we have medications from injections under the skin, to some pills. No real approved therapy for anemia, but whatever we can do help patients counteract those problems because slowly over time they’ll get worse and worse, and people die with myelofibrosis between five and seven years.
So, we wanna combine medications. We’re gonna introduce medications as soon as something wrong with the patients to improve whatever is wrong so that the quality of life can continue at a decent level.
Let me go back a little bit to essential thrombocythemia and polycythemia vera, ET and PV. These two conditions are considered rather benign. They should not much effect the longevity, perhaps PV can. And if they do, the main reason for dying from ET and PV is the blood clot or thrombotic event.
This is what we say, usually. A blood clot or some bleeding usually clots in the heart, or the brain, or the lungs, can kill the person. So, we don’t usually talk about the life expectancy in terms of genetic mutations, or abnormalities in chromosomes, or something that will kill the patient outside of the blood clotting risk.
So, what we are talking about then, is after diagnosis, we are talking about the prognosis, when we talk about ET and PV, prognosis is related to what’s your thrombotic risk? So, we talk to patients with ET and PV about thrombotic risk assessment.
And typically, age over 60, or having a history of blood clot, we’ll say yes that patient is a high risk patient with ET, or high risk patient with PV, for the blood clot. And we will be treating patients for that risk in different ways.
So, it’s a little bit different angle here on what we try to achieve in ET and PV patients. More benign, more chronic, assessment of the risk of clotting and control the blood count, and occasionally when we need, control the spleen symptoms. But different ballgame and ballpark then the myelofibrosis part.
There are, obviously, standard practice protocols in terms of what do you do? Right? So, if we are talking about ET and PV, you would say, if you are – as your remember now, we divide patients in those with the low risk of blood clot, and high risk for blood clot. For low risk, we just give people baby aspirin, and if they have PV, we phlebotomize the patients, blood-letting.
So, not much experimentation there. But there are studies that one can join if there are too many phlebotomies, for example, too many blood-letting episodes. And there are studies with medications that would be decreasing that need completely.
There are also studies in patients that are high risk for blood clotting, which typically would be treated with hydroxyurea, chemotherapy by mouth.
There are new versions of the interferons, biological agents given under the skin every two weeks, that would perhaps be taken instead of a standard practice hydroxyurea.
Not too many studies in ET and PV, really. Some. But in myelofibrosis, there are many because with ruxolitinib, for example, which has been around for about nine years, it’s a JAK inhibitor, you get in many patients good control of the splenic symptoms, but it does not last forever, and in some patients, it may benefit to some degree, but not completely.
So, there are many studies where you can add another medication to ruxolitnib a JAK inhibitor, to boost what it does more of the splenic symptoms controlled, or to add another benefit. The JAK inhibitors do not, by and large, improve the anemia, so how about adding anemia drug to ruxolitnib.
So, combination studies are many underway, so you can actually enroll – even with the newly diagnosed myelofibrosis patients, in the need of therapy, in a clinical study. Not to say, after JAK inhibitors in a second line. That’s what we call it. After JAK inhibitors you need to do something else, that second line, there are many studies because there is no other approved therapy. So, for myelofibrosis, no question in my mind, there are so many studies underway, you can be participant in study to get your result boosted by whatever else is added to what you’re doing, and discover for the large population of patients, novel therapies.
Testing for mutations can influence treatment options available to patients with MPNs and provide a more in-depth understanding into their essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF) diagnosis. MPN specialist, Dr. Srdan Verstovsek reviews three key mutations that may impact treatment timing and approaches.
Dr. Srdan Verstovsek:
So, what we know is that ET, PV, and MF, these are these three, and we will use the abbreviations for simplicity, are so-called classic myeloproliferative neoplasms. Myeloproliferative means that it is disease of the bone marrow where cells grow without control.
Now, with ET we have high platelets, but ET is the disease of all the cells. In PV you have high red blood cells, and in many patients you have high white cells and platelets. In myelofibrosis, it’s paradoxically many patients present with too few cells because of reactive bone marrow fibers or fibrosis that limits the growth of the cells.
So, these are the three diseases that have underlying problem, same problem in these three conditions, which is high activity of proteins inside the bone marrow cells, proteins inside the bone marrow cells.
A cascade of protein that makes cells grow without control. We call this a JAK-STAT pathway. I had patients; they say JAK-STAT highway. It’s active all the time. This is a protein JAK too, and then the JAK2, and then other, so we call it JAK-STAT pathway.
It’s super active. Active in normal person when we need to make blood, but in the diseased person, active because of acquired mutations that affect that highway, JAK-STAT pathway or highway.
It makes it work all the time, that’s why we have so many cells. And there are three mutations, which are part of diagnostic process. You test for these. You can test in the blood or in the bone marrow sample, and these are JAK2 mutation, calreticulin mutation, and the MPL mutation.
They are almost always exclusive of each other, and about 90 – 95 percent of patients will have one or the other. They are still very few patients that have none of these three, which is interesting. And we are, in others, looking for other reasons in these few patients.
But one of the three is present, and it’s part of the diagnostic process as well. I didn’t emphasize this before, but it is present as a part of the bone marrow evaluation. That’s where it goes. And it is therefore, helpful to test for it. But one can test for other mutations. Many patients have many other mutations that have nothing to do with the JAK-STAT pathway, and that in large part is responsible why people have different disease ET, PV, or myelofibrosis. We explain this that way because of other genetic abnormalities, other abnormalities that we cannot really describe yet.
Genetic is not the whole picture. There are other parts, I’m sure, in bone marrow environment, in other factors they control the genetic expression, and so on, that contribute why a patient with JAK-STAT hyperactivity has ET, and why another has myelofibrosis.
We don’t really fully understand that. And of course, there is a plethora of patients in between that are not all the same. So, genetics do carry a lot of weight in what happens with the patients, and we do test for that, in addition to testing for JAK2, calreticulin MPL. We test for multiple others. That’s routinely done in academic center. It’s very valuable, and it should be standard practice.
The main utility of widespread testing for additional mutations is to assess the prognosis of the patients. If we are looking at the bone marrow blood chemistry and physical exam, a splenomegaly, and presence of this driver mutation, the JAK, calreticulin or MPL.
We call them driver mutations. They drive that highway. If that is the complexity of the diagnosis, then the next step is, as you remember, the patient will say, “How long I’m gonna live?” Well, obviously, that information comes from the historical experience, and I always emphasize that. But there is valuable information from historical perspective to some intelligence to tell the patients what to expect in general terms. Since the introduction of the genetic testing in academic centers, we have enhanced our ability to prognosticate. Initially, ten or more years ago, we would be looking at the age of the patients, how the patient fares, the symptoms, the anemia, or white blood cell count, or blasts.
These would be kind of common prognostic factors for assessment of the outcome of the patients. But now, we add information on the presence of one or the other of the driver mutations, and the presence of the number and types of these other additional, which call them somatic mutations that have nothing to do with JAK-STAT pathway.
And you can see now how the prognostication also has the flavor of complexity, and it is really not that easy, and we keep moving forward. That prognostication effort is keep moving to assess the outcome of the patients better and better for one particular reason.
If we have we a sense that a patient, based on this prognostic scoring systems, have a poor outcome, which we define as the life expectancy less than five years, then that patient should be referred to the [stem cell] transplant.
And transplant should be done because the benefit of a cure, and the risk of dying through transplant procedure – unfortunately, that’s the reality, is just justifiable if the prognostic scoring system tells you that the life expectancy is less than five years.
That’s the main role for the genetic complexity testing. Looking also at the chromosomes that might be broken. That’s done on a bone marrow sample. And dividing patients in prognosis scoring groups to guide the decision making on the transplant.
MPN expert, Dr. Srdan Verstovsek provides insight into what factors determine whether MPN patients should undergo additional bone marrow biopsies and genetic testing over time.
Dr. Srdan Verstovsek:
We already know, everybody knows, I would think, that the living tissue does change over time. And when a patients have doubt, I tell them, “Look, my hair has not been grey all my life.” Everybody laughs. That happens with the bone marrow biopsy results, right? They change over time because the bone marrow does change over time. It’s not the same, and if you have the disease, disease cells, let’s call them malignant cells, they may acquire new mutations as they divide. If they already have some mutations that they’re present at the time of diagnosis, they are actually more prone to get more of those mutations over time.
And so, it may then be wise, and that’s what your question is about, to occasionally test patients and see whether there’s any change. Not perhaps in the number of fibers, or number of different cells, but genetically are there any new mutations which would make that disease perhaps more aggressive.
Unfortunately, the situation with repeated testing is complicated by price of the test. The testing can be done on blood, but it’s very expensive. We’re talking about thousands of dollars, and it’s not justifiable at the moment to do that every six months, or once a year for example, to see about any change because, it may not change what we do. It requires a clinical change, not just a genetic change for one to do something different, and something different would be referral to a bone marrow transplant, sooner rather than later.
So, first of all, repetitive testing would be useful in patients that are borderline for the decision of the transplant, not in everybody, because that’s the only intervention that would be affected by that testing. And then, even in these situations, you would need to have a clinically relevant abnormalities beyond just a new mutations.
That means a bigger spleen, or losing weight, or having profound anemia now. So, what basically this comes down to is, we follow the patients closely, and when there is a clinically relevant change, that would ask for a bone marrow biopsy and genetic testing, then we can justify that, and then we change what we do. So, it is cumbersome to sit tight and wait for a change, I understand that, but that’s the reality at the moment.
MPN expert, Dr. Srdan Verstovsek, explains why a bone marrow biopsy is essential following a myeloproliferative neoplasm (MPN) diagnosis and its role in confirming whether a patient has essential thrombocythemia (ET), polycythemia vera (PV) or myelofibrosis (MF).
Dr. Srdan Verstovsek:
By and large, we would like people to have a bone marrow biopsy done. In fact, I would say that myelofibrosis cannot be diagnosed without a bone marrow biopsy. Polycythemia vera, in occasional cases, can be diagnosed without the bone marrow biopsy, even by the national guidelines. And essential thrombocythemia, I would say, that should have, although that is not norm in clinical setting, a bone marrow biopsy as a part of the disease diagnostic process.
This is to say that the diagnosis of any of these three conditions, ET, PV, or myelofibrosis, does not depend solely on the bone marrow biopsy.
I’ll give you an example of the myelofibrosis. You have to have a biopsy that shows abnormalities in different cells in the bone marrow. Megakaryocytes are the key. So, cells are different in number, size,shape, and colors, and you have fibers. Sometimes you don’t even have a fibers. But then, you have to combine this.
Maybe, abnormalities in blood cell count. In the blood chemistry there is an LDH, lactate dehydrogenase chemistry test that usually is tested for. And then, you have a physical exam, enlargement of the spleen. And the type of the white cells in the blood. So, you have a combination of the bone marrow, blood chemistry test, and the physical exam that all have to come together for diagnosis to be made for myelofibrosis.
I always ask my fellow, and doctors in training, who actually makes the diagnosis? It’s the clinician. If you just look at the bone marrow, you may say there is myeloproliferative neoplasm and there are some fibers, but you have to have these other factors to make a diagnosis of myelofibrosis. And fibers, for example, do not really say that the patient has myelofibrosis. Fibers can be present in PV, polycythemia vera, in 20 percent of the patient at the time of diagnosis of PV.
So, fibers on its own doesn’t mean myelofibrosis. Of course, there are other diseases that can cause fibers, other bone marrow diseases that have nothing to do with myelofibrosis or polycythemia vera.
So, it is rather complex problem, and it is not easy to make a diagnosis. We actually looked at that, and 15 percent of the patients that come through the door here at MD Anderson, have a change in diagnosis after our own assessment. So, some experience does count, I would say does counts a lot, because of complexity.
Dr. Srdan Verstovsek provides guidance for patients with myeloproliferative neoplasms (MPNs) related to coronavirus (COVID-19), stressing the necessity of continued communication with their healthcare team.
Dr. Srdan Verstovsek is Chief of the Section for Myeloproliferative Neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Verstovsek, here.
Dr. Srdan Verstovsek:
When we come to the COVID pandemic here, and the effect on our patients with myeloproliferative neoplasms, of course, that is something that is very serious. Our patients, particularly those with advanced myelofibrosis, are at a high risk of having complications from infection if they get infection. Perhaps less so for patients with ET and PV, which are more healthier, if you like, although they have myeloproliferative neoplasms.
So, our focus here is, first of all, like it is for anybody else, including myself, on prevention.
Obviously, that would be common sense and logical to try to prevent getting infected. And then, also to try to be in best possible health. Taking medications as prescribed. Being in touch with your doctor. If you cannot come to a physical exam, which is understandable because of possible increased risk through the transportation perhaps, then being in touch through telemedicine. We call, and we see our patients online. That is fine. We can do the bloodwork from the distance.
So, taking medications, being fit, and being as healthy as you can with the disease. But taking medications and controlling your risks, not allowing disease to take ahold of you, and then you get infection and you’re gonna be in trouble.
So, really communications with the doctors, taking medications, and I would say, occasional, with all precautions, visits.
Because, for example, with myelofibrosis patients, I really need to feel that spleen and the liver and see how is the patient’s weight, and not only ask over the telephone, what’s your symptoms are, or what your blood count is. I can see this on the computer. We really need, occasionally, myelofibrosis patients to come over to our clinic to be examined.
And here, in the clinic, we have extraordinary precautions. No visitors. No people to accompany patients in. So, to minimize any interactions with anybody who possible can bring any undesirable infections through the door, not just COVID, but any other. And the staff is prepared to provide excellent care with protection that is in place.
So, I think that will be my message: Prevention; staying on top of your disease; being in best possible shape with the disease; staying in touch with your doctor; and, occasionally, still visit the doctor if at all possible, particularly for myelofibrosis patients.