Tag Archive for: fibrosis

Why You Should Understand Your MPN Treatment Plan

Why You Should Understand Your MPN Treatment Plan from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasm (MPN) expert Dr. Mark Heaney discusses the importance of understanding the goals of your treatment plan, including key questions to ask your doctor before beginning therapy.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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Transcript

Katherine Banwell:

Are there questions that patients should ask about their proposed treatment plan?

Dr. Heaney:

Yeah. I think patients should ask a lot of questions. I think a lot of patients don’t ask as many questions as they should, but I think there are a number of things that are important for patients to know. Number one, the question is whether they need treatment at all and what happens if they defer treatment. So, really, what – and, that’s another way of asking what the goal of treatment is going to be. Now, I think patients should have an expectation of what their physician thinks the benefit of starting a particular treatment might be.

I think that they should ask questions about the drugs that they’re taking. Are they new drugs? Are they well established? What are the side effects? And, I think the side effects fall into a number of different categories. Some of the side effects are immediate side effects that patients have and notice soon after they start taking the drugs.

Some of the side effects can be much more subtle, and we know, for example, that some of the agents that are used to treat myeloproliferative neoplasms can suppress the immune system and can make patients more susceptible to infection. Especially today, with lots of infections out there, it’s important for patients to know whether this is something that they should be particularly attuned to. I think that patients should also find out whether there are any lifestyle inhibitions.

So, sometimes, how many times you take a drug, whether the drug has to be taken on an empty stomach or with food – those sorts of things, I think, can be really important in deciding whether this is a treatment that’s right for the individual patient.

Katherine Banwell:

Yeah. Dr. Heaney, how would you define treatment goals, and why is it important that patients understand the goals of their treatment plan?

Dr. Heaney:

Often – often, patients do start treatment without a clear understanding of what the goals are, and I think sometimes, the goals that physicians have may be different than the ideal goals of the patient. I think we’re really fortunate in myelofibrosis today that we now know that ruxolitinib is something that prolongs survival, and we have a drug that has that ability.

And, I think articulating that as a goal to patients is important in their understanding of why a physician might want to push through some toxicities and say, “I know that this may be causing some GI upset, but we’re doing this because we think this is something that may help you to live longer.” So, I think that’s part of – and, that may be the physician’s main goal. That may not necessarily be the patient’s main goal, and the patient’s main goal may be quality of life. And so, having – it goes back to the question about dialogue and understanding what the patient really wants out of his or her treatment and making sure that the patient and the physicians are talking to each other, not past each other.

Will Your MPN Progress? What You Need to Know.

Will Your MPN Progress? What You Need to Know. from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasms (MPN) expert Dr. Mark Heaney discusses how MPNs may progress from one to the next and addresses the possibility of slowing disease progression.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF? 


Transcript:

Katherine Banwell:    

Patients living with MPNs are often concerned about disease progression. Will everyone progress?

Dr. Heaney:

Now, we don’t know the answer to that question. There are patients with myelofibrosis and other MPNs who we know live more than 20 years with their disease.

In general, the natural history of the disease is one of gradual progression, and some people have more rapid progression than others. We know that there are patients who will die of complications of their disease, but not everyone will progress, and there are some patients where observation without treatment, even in the face of some progression, may be a very reasonable treatment plan.

There may be times, though, when it’s not really possible to maintain a quality of life without some treatment, and one of the ways of slowing that kind of progression may be with some of the available therapies of – approved therapies and investigational therapies. But, I guess the short answer to your question is not everyone will die of his or her disease, even if the disease does progress, and there are some patients in whom that progression is so slow that they’re able to live really full lives without it – without the disease’s interfering with their lives.

Katherine Banwell:

Is there a way to prevent progression?

Dr. Heaney:

Well, there isn’t a magic pill that stops progression. A lot of my patients ask if there’s some diet, if there’s something that they can do that will change the course of the disease.

And, the short answer for, I think, the overwhelming majority of patients is there isn’t anything that’s a magic bullet. We believe that drugs like ruxolitinib in myelofibrosis can slow the progression of disease.

There are drugs in other MPNs that we also think may slow disease progression even if they don’t completely halt progression. For some patients – admittedly, the minority – who might be candidates for allogeneic stem cell transplant, we know that that can be curative, and so, in that way, that can prevent progression in those patients.

And so, I think it’s important to, again, go back to your physician, understand what progression means, understand what – how the proposed treatment might interact with that progression, and again, getting back to the question of outcomes and goals of therapy, understand clearly what the treatment plan is aimed to do.

How to Partner With Your Doctor on Treatment Decisions

How to Partner With Your Doctor on Treatment Decisions from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasms (MPN) expert Dr. Mark Heaney explains the role of shared decision-making when choosing therapy and discusses how MPN patients can benefit from taking an active role in their care.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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Transcript:

Katherine Banwell:    

 The terms “shared decision-making” is being used lately when we talk about patient care. What does that term mean to you?

Dr. Heaney:

Well, I think it’s really important for patients to be involved in their care, and I think it’s part of shared care, and I think that patients who are really in partnership with their physicians are able to make better choices, and there’s much better communication.

So, to me, that’s the basis of the physician-patient relationship. It’s less of an asymmetrical relationship and much more of an equal relationship.

Katherine Banwell:

Why should patients take an active role in their care? How do they benefit?

Dr. Heaney:

Well, patients who take an active role in their care, I think, provide much more input to their physicians and let them know how they’re feeling, and I think that allows their physicians to know much better what kind of side effects they might be having, whether they’re getting any benefit from the drug, whether they’re having symptoms that are related to the disease, and that kind of communication is really central to patients being able to make the best decisions for themselves and getting the best advice from their physicians.

An Overview of ET, PV and MF Treatment Options

An Overview of ET, PV and MF Treatment Options from Patient Empowerment Network on Vimeo.

Treatment for essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) can vary greatly. Dr. John Mascarenhas breaks down the treatment types and the goals of treatment for each type of myeloproliferative neoplasm (MPN).

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.

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What Are the Benefits of MPN Inhibitor Treatment?


Transcript

Katherine Banwell:

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.

Dr. Mascarenhas:       

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. 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.

Katherine Banwell:                  

And, what about PV, polycythemia vera?

Dr. Mascarenhas:     

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.

Katherine Banwell:                  

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?

Dr. Mascarenhas:       

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.

Katherine Banwell:                  

What about stem cell transplants?

Dr. Mascarenhas:       

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, their 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.

What Are the Benefits of MPN Inhibitor Treatment?

What Are the Benefits of MPN Inhibitor Treatment? from Patient Empowerment Network on Vimeo.

MPN expert Dr. John Mascarenhas shares an overview of how inhibitor therapy works to treat myelofibrosis (MF) and the benefits of this type of treatment.

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.

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Transcript

Katherine Banwell:

Dr. Mascarenhas, what is inhibitor therapy and how does that work?

Dr. Mascarenhas:       

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 and fedratinib 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.  

 

How Do MPNs Progress From One Disease to the Next?

How Do MPNs Progress From One Disease to the Next? from Patient Empowerment Network on Vimeo.

Understanding how essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) are connected may be confusing to patients. Dr. John Mascarenhas, an expert in myeloproliferative neoplasms (MPNs), provides an overview of how the conditions are defined and how they may progress from one condition to the next.

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.

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Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

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Which Tests Do You Need Following an MPN Diagnosis

Which Tests Do You Need Following an MPN Diagnosis?


Transcript

Katherine Banwell: 

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?

Dr. Mascarenhas:

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.

Patient Considerations That Impact MPN Treatment Decisions

Patient Considerations That Impact MPN Treatment Decisions from Patient Empowerment Network on Vimeo.

How can personal choices play a role in your MPN care? Dr. John Mascarenhas reviews factors that should be considered, including lifestyle and overall health, when choosing therapy for essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF).

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.

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What Are the Goals of ET, PV, and MF Treatment?


Transcript

Katherine Banwell:

Outside of testing, what other factors should be considered when choosing treatment?

Dr. Mascarenhas:       

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.

Katherine Banwell:                  

Right. Right. And, there’s the patient’s overall health, comorbidities, other things like that?

Dr. Mascarenhas:       

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.

Katherine Banwell:                  

Are there specific biomarkers that may affect prognosis or treatment?

Dr. Mascarenhas:       

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.

What Questions Should Patients Ask About MPN Test Results?

What Questions Should Patients Ask About MPN Test Results? from Patient Empowerment Network on Vimeo.

What should you know about your MPN test results? Dr. Mascarenhas discusses how test results are used, including the importance of genetic mutations and risk stratification when analyzing results.

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.

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Which Tests Do You Need Following an MPN Diagnosis

Which Tests Do You Need Following an MPN Diagnosis?

What Are the Goals of ET, PV, and MF Treatment?

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An Overview of ET, PV and MF Treatment Options

An Overview of ET, PV and MF Treatment Options


Transcript

Katherine Banwell: 

Some patients may not know if they’ve received these important tests. So, what key questions should they ask their physician about testing?

Dr. Mascarenhas:       

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.

Katherine Ba:nwell:

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?

Dr. Mascarenhas:     

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.

 

Which Tests Do You Need Following an MPN Diagnosis?

Which Tests Do You Need Following an MPN Diagnosis? from Patient Empowerment Network on Vimeo.

After a diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), what testing should take place? Dr. John Mascarenhas shares an overview of essential and in-depth testing for patients with myeloproliferative neoplasms (MPNs).

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.

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Transcript

Katherine Banwell: 

What tests are necessary to help understand a patient’s specific disease at diagnosis?

Dr. Mascarenhas:

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.

Katherine Banwell: 

And, what is molecular or biomarker testing?

Dr. Mascarenhas:    

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.

Katherine Banwell:              

Right. Should all patients diagnosed with ET, PV, or MF undergo biomarker testing? Is that necessary?

Dr. Mascarenhas:       

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.

Which MPN Treatment Is Right for You? What You Need to Know Resource Guide

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Which MPN Treatment Is Right for You? What You Need to Know

Which MPN Treatment Is Right for You? What You Need to Know from Patient Empowerment Network on Vimeo.

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.

See More from INSIST! MPNs

Download Guide

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What Are the Goals of ET, PV, and MF Treatment?


Transcript

Katherine:

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?

Dr. Mascarenhas:

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.

Katherine:

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?”

Dr. Mascarenhas:

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.

Katherine:

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?

Dr. Mascarenhas:

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.

Katherine:

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?

Dr. Mascarenhas:

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.

Katherine:

And, what is molecular or biomarker testing?

Dr. Mascarenhas:

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.

Katherine:

Right. Should all patients diagnosed with ET, PV, or MF undergo biomarker testing? Is that necessary?

Dr. Mascarenhas:

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.

Katherine:

Right. Some patients may not know if they’ve received these important tests. So, what key questions should they ask their physician about testing?

Dr. Mascarenhas:

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.

Katherine:

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?

Dr. Mascarenhas:

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.

Katherine:

Right. You mentioned a couple of these already. But, outside of testing, what other factors should be considered when choosing treatment?

Dr. Mascarenhas:

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.

Katherine:

Right. Right. And, there’s the patient’s overall health, comorbidities, other things like that?

Dr. Mascarenhas:

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.

Katherine:

Right. Are there specific biomarkers that may affect prognosis or treatment?

Dr. Mascarenhas:

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.

Katherine:

Dr. Mascarenhas, what is inhibitor therapy and how does that work?

Dr. Mascarenhas:

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.

Katherine:

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.

Dr. Mascarenhas:

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.

Katherine:

And, what about PV, polycythemia vera?

Dr. Mascarenhas:

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.

Katherine:

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?

Dr. Mascarenhas:

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.

Katherine:

What about stem cell transplants?

Dr. Mascarenhas:

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.

Katherine:

Right.

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?”

Dr. Mascarenhas:

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.

Katherine:

Right.

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?”

Dr. Mascarenhas:

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.

Katherine:

Yeah. Before we close, Dr. Mascarenhas, let’s talk about research. Are there new developments that you’re excited about?

Dr. Mascarenhas:

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.

Katherine:

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.

Dr. Mascarenhas:

My pleasure.

Katherine:

And thank you to all of our partners.

To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today. Thank you so much.

 

How to Play an Active Role in Your MPN Treatment and Care Decisions

How to Play an Active Role in Your MPN Treatment and Care Decisions from Patient Empowerment Network on Vimeo.

How can you play a role in your MPN care and treatment decisions? Engaging with your healthcare team is essential and may lead to better overall outcomes. In this program, Dr. Naveen Pemmaraju provides tips for how best to advocate for yourself or a loved one, as well as tools for making treatment and care decisions.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju, here.

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COVID-19 Vaccination: What Do Myelofibrosis Patients Need to Know?


Transcript:

Katherine Banwell:    

Hello and welcome. I’m Katherine Banwell, your host for today’s program.

Today, we’re going to explore how to engage with your healthcare team when diagnosed with a myeloproliferative neoplasm, and we’ll discuss the patient’s role in care decisions.

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. Naveen Pemmaraju. Dr. Pemmaraju, would you please introduce yourself?

Dr. Pemmaraju:         

Well, thank you for having me, Katherine and team. I’m Dr. Naveen Pemmaraju. Associate Professor of Leukemia and the Director of the Rare Disease Program with Blastic Neoplastic Cell Neoplasm (BPDCN) here at MD Anderson, and I’m happy to be here with you guys.

Katherine Banwell:    

Thank you so much. We’re glad to have you with us today. As we move through this conversation, we’ll talk about the classic myeloproliferative neoplasms: essential thrombocythemia, polycythemia vera, and myelofibrosis.

But before we get into our discussion, let’s start with the question that’s on the minds of many of our audience members. We’re all hearing that the COVID-19 vaccine is safe, but how effective is it for MPN patients?

Dr. Pemmaraju:         

Well, I believe that this is one of the most important issues of our time.

I think the way I would approach the COVID-19 question is, one, is we know that if our patients contract the virus, that can be deadly in actually many of our patients. So, I think it’s actually important to remember that the virus is still out there and that getting the virus is potentially very life-threatening, not only for the general population but for our patients.

For the vaccines, I kind of have two stories to tell you. So, one is my own anecdotal experience in the clinic where it has been surprisingly and remarkably well-tolerated in most of our patients. This is both the mRNA vaccines and as well as the J&J vaccine. And so, overall, we’ve seen a very minimal amount of allergic or other reactions.

I think the most important part, as you said at the top, is for specific medical advice, we need to be talking to our own providers. But I think for our MPN patients, we’re giving some caution, looking at the blood counts, what chemotherapy folks are on. But, in general, I’ve been happy with that rollout.

Now, for the effectiveness of them, sure. That’s a question of ongoing research. There are some data that’s coming out, particularly in CLL and other leukemias that – correct – maybe some of our immunocompromised patients, as you would expect, may not be able to mount the appropriate response. But all that data is moving and fluid, so we’ll see.

And then I think the other point here is with this question of the virus itself and maybe some of these vaccines having a signal for increased blood clots or coagulopathy.

This is something I think we have to follow in our MPN community only because our patients are already at a high risk for both bleeding and clotting. So, the virus itself, COVID-19, post-syndrome coagulopathy, possible side effects – idiosyncratic and rare, for sure, from these vaccines that can lead to a vaccine-induced thrombotic state. I think these are some of the factors that we have to watch out for. So, in general, we don’t yet know the exact answer for each patient, PV, ET, MF, how effective the vaccine may be. But we are encouraging everyone to go for it unless there’s an obvious contraindication. Katherine?

Katherine Banwell:    

Okay. Good. Thank you. Let’s learn a little bit more about the disease itself. Dr. Pemmaraju, do a level set with our audience. Can you help us understand the differences between ET, PV, and MF?

Dr. Pemmaraju:         

Yeah, this is very important because we toss these words around as if there’s some big definition that was given, and oftentimes, that never happens. So, let’s pause to do that. So, this goes back to the 1950s when William Dameshek, who really postulated the modern MPDs at that time as they were known – myeloproliferative disorders – really thought that there were four diseases that were similar at some level and then presented differently. So, that’s polycythemia vera, essential thrombocytosis, myelofibrosis, and CML, chronic myeloid leukemia.

Then, as the modern era comes in, CML is divided off because of the Philadelphia chromosome, BCR-ABL, which is present in 100 percent of those patients.

So, now we know CML is its own thing. And now we have the big three, sort of non-Philadelphia chromosome MPNs, as they’re now known, because neoplasm – cancer – instead of disorder. Within the subtype, and this is important, the subtypes that you mentioned are the most common.

So, polycythemia vera – poly meaning many, cythemia, cells, vera is Latin for true. This is the designation for the patient who has a higher than expected blood red cell mass or hematocrit. And it actually, interestingly, Katherine, most patients with p. vera have an increase in all three of their blood lines, so the red cells, hemoglobin, hematocrit, platelets, and white count. Those patients with PV are especially at risk for both bleeding and clotting, transformation to myelofibrosis, and even transformation to acute leukemia in maybe 5 to 7 percent of patients.

So, the usual treatment there, Katherine, is to bring off the blood mass. That’s the phlebotomy.  And then in the patient who is above the age of 60 or has a prior blood clot, to give some form of chemotherapy, hydroxyurea (Hydrea) or interferon, for example.

Now, the second grouping is ET, essential thrombocytosis. Again, this word vera or essential, meaning not reactive, not benign, not from a regular cause like a surgery or a trauma or an inflammation. So, it means a cancerous cause, an autonomous cause, something that’s coming on its own.

Thrombocythemia or thrombocytosis, meaning too many platelets. So, usually, patients with ET have too many platelets as their predominant manifestation. But again, as with p. vera, patients can get into problems with that. Very, very high platelets, usually a million and a half or higher, can actually lead to bleeding. Not necessarily clotting, but extra bleeding. And then patients with any platelet levels, because the platelet level doesn’t exactly correlate, can have either bleeding or clotting. So, that’s usually the predominant factor. And again, the underlying problem with these MPNs is that they can transform to the other ones – PV, MF, even acute leukemia.

And then, finally, myelofibrosis, which we could spend the whole hour on just by itself, is the more advanced state out of these.  So, it can either arise out of the PV or ET or stand alone. And really here, this is an advanced bone marrow failure state with bone marrow scarring or fibrosis. And now, usually, most patients, their blood counts, rather than high are now low because the bone marrow is unable to produce enough cells. And then, therefore, the sequela of the disease – anemia, thrombocytopenia. So, low blood, low platelets.

Then you need transfusions. The liver and the spleen get larger because they remember how to make blood cells. People can have a wasting away appearance. And then here, more than the PV or ET, this is more of an acute disease for many where if you have intermediate to high stage, these patients can transform more readily to leukemia and have a decreased overall survival.

Katherine Banwell:    

When a person is diagnosed with an MPN, they have a whole healthcare team. Who is typically on that team?

Dr. Pemmaraju:         

Well, it’s interesting. Yeah, that’s evolved over time.

It used to just be patient and their local oncologist, right? And the oncologist office has become a very busy place with mostly solid tumors. So, breast, prostate, colon, and then maybe a few scattered patients in most practices with blood cancers. Obviously, blood abnormalities are common with platelets and anemia and all that, but to actually have an MPN patient in the general hem/onc practice is actually quite rare. Right? These diseases are 4 to 5 out of 100,000 people.

Now, fast-forward to the modern era. I think this is important. I think now, what I personally encourage – and obviously I’m biased because I’m here at the academic center. But I really think that patients with rare blood cancers such as MPNs should be co-managed. So, be seen by your local hematologist/oncologist, for sure. They know you the best. But also have a referral, if you’re able to and have the resources and ability to travel, to an academic center where you can see a blood cancer specialist such as me or my colleagues, as I only focus on blood cancer.

So, I’m not seeing patients with a solid tumor. So, local oncologist. If you can have a blood cancer expert as part of your care, it doesn’t have to replace the care. And then to have a member of the nursing allied professions – nursing and APP, advanced practice providers – is really becoming essential to help with acquiring the prescriptions from the specialty pharmacy, prior authorizations, teaching of the injectables, such as interferon, figuring out enrolling on clinical trials.

So – and then, if a patient, young and fit, with myelofibrosis, you’ll want to be consulted with a stem cell transplant doctor. And then, finally, as if that wasn’t enough, I think a good pharmacist team is important nowadays to go over the drug-to-drug interactions, side effects. It’s not just about the JAK inhibitors but all the other medicines – antibiotics and everything else – that may be a bit unique to the MPN patient compared to the general cancer patient.

Katherine Banwell:    

Right. Lately, we’ve been hearing this term “shared decision-making,” which basically means the patients and clinicians collaborate to make healthcare decisions. And it can help patients to take a more active role in their care. So, I’d like to get your thoughts on how best to make this process work.

Dr. Pemmaraju:         

This is a passion area to me. I think this is so important that  you bring this out. I think a generation or two ago, Katherine, it may have been common for there to be more of a one-way monologue, if you will, doctor to patient, and that may have been the majority of the conversation before.

I don’t see it that way anymore, and most of my colleagues don’t either. I think it should be a dialogue, as you said. It should be a back-and-forth communication, one that learns and evolves over time as any real relationship would, right? Outside in the real world. So, I think that’s important. Number two, I think trust needs to be earned, not just given.

So, that means patient and physician, and really the physician team – so, all the other members of the team – building that trust over time through frequent communication, visits, all of this. And then, finally, I think the key here is that a lot of patients always ask, “Hey, what can I do on my own?” I’ll tell you what you can do. You can be involved and read and empower yourself if you’re able to, if you’re able to and you can. Many may not be able to due to their illness or for other reasons.

But if you are able to, I think it’s great to read online. There, I just said it. Let me repeat it to make sure everyone heard that. I want you to read. I think it’s fine. Consult Dr. Google. What’s the worst that happens? The worst that happens is you find misinformation. Well, don’t keep it to yourself. right? So, Google, look up things, go to social media, see what experts in your area are talking about, go to Facebook, go to the patient groups. But remember, everyone’s case is different. Someone else’s is different from yours, and yours is different from the next. So, gather information like a sponge.

Formulate it, synthesize it in the way that only you know how to do, bring some notes, and then talk about it with me at the next visit, “Hey, I saw this on the Internet.” “Okay, great, let’s talk about that.” Or, “Hey, this new formulation of interferon is coming.” “Great, let’s talk about it.” So, gather information, sort out signal from the noise with your healthcare team. Sort that out and then move on, move on, move on. So, I think these are some of the aspects of what’s called shared decision-making. No longer a monologue, one-way street. Let’s have a dialogue, let’s have a partnership, let’s figure out a way to empower each other in this journey.

Katherine Banwell:    

We’re going to talk in a few moments about online research and how well that works or how well it doesn’t. But let’s talk about treatment goals first for ET, PV, and MF. What are the goals of treatment from a clinical perspective?

Dr. Pemmaraju:         

Well, I think the goals are divided up into three factors. So, I think for the MPN patient, goal number one has to be what the patient themselves want to achieve.

Oftentimes, that’s different than what’s on the numbers with the labs and what the physician wants. So, I think a lot of our patients correctly are suffering from – or mentioning to us that they’re suffering from quality of life issues. So, fatigue is the most common manifestation of all the MPNs, followed by bone pain, night sweats, inability to concentrate, etcetera, etcetera.

So, I think quality of life is the goal of most people, and I think that’s an admirable goal. And some of the medicines can help that. Some can actually hurt that in the short term. So, let’s put that as bucket number one. What does the patient want to achieve? Usually, it’s the alleviation of fatigue, itching, bone pain, etcetera.

Number two, I think, is the sort of on-paper game, if you will, right? So, what do the labs show, what does the bone marrow biopsy show, what does the spleen show? I think all of that is good, too, in that bucket. And clearly, if someone has transfusion dependent anemia, two times a week needing blood transfusions, and whatever treatment you can do can alleviate that down to once a week, once a month never – okay, that’s a win for the patient.

And then I think, finally, our goals. You’re right. You asked me specifically “What are my goals for our patients?” Well, I want to see that your overall survival has improved if I can. So, your length of life, your quality of life has improved, minimization of side effects from whatever therapy we’re doing. If we’re going on a clinical trial or combining therapies in a novel way, that you’re not experiencing some brand new or idiosyncratic toxicity or side effect.

And then, finally, I think the key is to monitor for, let’s say, other things. Are you developing a second cancer, a second blood cancer? Are you having another problem that’s outside of your MPN, such as iron deficiency anemia or thyroid disease? Something that’s extremely common, has nothing to do with the MPN, but is also happening. And then do you have a healthcare team?

I failed to mention in your earlier question the primary care doctor, right? Let’s mention that person as well. If our patients have the general practitioner who they had already been seeing before the MPN diagnosis, or at least established one after, then some of these important aspects, like cancer screening, cholesterol checks, some of these other important things can be done in parallel to the MPN therapy and then, of course, combined at different points.

So, these are kind of my benchmarks for goals of therapy. They will vary from patient to patient and, of course, from case to case. The patient with advanced intermediate to high-risk myelofibrosis going to transplant, well, that’s markedly different from the patient who’s young with ET with no blood clots and relatively controlled blood counts. So, different goals there, Katherine.

Katherine Banwell:    

Right. Right. So, you just mentioned a couple of factors that you take into consideration, but there are others as well, I think. What about the patient’s age and overall health, for instance?

Dr. Pemmaraju:         

Could not be more important. You’re right. I think age – and let’s use that as a surrogate for what we call ECOG performance data. So, the overall kind of fitness of a patient, as you said, may be the most important factor. And then followed by these other conditions, so-called co-morbidities. I’d like to talk about that for a second because that’s a lot of the program here. Depending on a patient’s age, performance status, fitness, and other organs that are involved, that actually leads to a couple of important points.

One, it may limit or reduce the number of treatment options that a person has based on their ability to even tolerate it in the first place. Both oral chemos that are available, some of these clinical trials that need to use an IV drug.

Number two, it may predict how your overall survival is going to be. So, perhaps your MPN, as we used in the other example, you have an earlier stage MPN that really doesn’t require treatment. It requires active observation.

But then on the other hand, you have advanced heart disease or kidney disease. That may actually do you more harm in the end. So, that’s actually very important that you bring that up.

And then, finally, right, is this concept that you have the co-morbidities and then you have the MPN, and then they kind of change and morph over time where one is the dominant issue, the other isn’t. And so, you do need that decision care team as you were mentioning earlier. So, let’s definitely say that out loud that that matters. And I think it also reminds us that nothing is in a vacuum. The MPN doesn’t exist in an isolated space, right? So, your MPN co-exists with your heart disease, your kidney disease, your lung disease, your past, your present habits, anything.

Katherine Banwell:    

Exactly.

Dr. Pemmaraju:         

So, I’m really glad you brought that up. And I think also, to your point with the shared decision-making model, I think sometimes, as physicians, we may not ask, and as patients, we forget to mention, “Oh, X, Y, Z in my history,” or “Oh, I’m taking this herbal supplement.” Sometimes these things are important to mention.

So, when in doubt, bring up everything to your care team so that you can make decisions together.

Katherine Banwell:    

Right. It might help to make notes before you go in to talk to your doctor.

Dr. Pemmaraju:         

Sure. Sure, absolutely. That doesn’t hurt, and it could help you at least organize your own thoughts even if you don’t use them in the visit.

Katherine Banwell:    

Exactly. Yeah. Dr. Pemmaraju, let’s talk about biomarker testing. Can you help us understand what biomarkers are and how they may affect treatments?

Dr. Pemmaraju:         

Yes. Biomarkers – I think that word gets mentioned a lot with really no definition, because it’s one of those words that can be whatever someone wants it to be. So, you’re right. For us, it’s a very important word in MPN. Bio meaning of life, scientific, and then marker meaning some kind of a measuring stick that has a value.

Well, there are two ways to look at biomarkers. One is the obvious, which is we have the defined big three molecular mutations. So, that’s JAK2V617F, followed by CALR mutation, followed by MPL. Those are the big three. Those make up about 90 percent of all patients with MPNs. You’re technically not born with them, although new data suggests that you may acquire these mutations right after birth. So, those markers are important, because they can be used to diagnose the disease, right? Particularly in the challenging patient. They have high platelets, you can’t tell if it’s reactive or ET. Okay, so they’re helpful with diagnosis.

Maybe some studies have shown that some of these markers can be predictive, Katherine, of blood clots. Let that research be ongoing. And then, obviously, some of these may be helpful in terms of designing the future treatments, particularly targeted therapies. So, I think biomarkers are part of our field, if you look at it that way, at diagnosis and risk stratification prognosis. But there are other factors that are starting to come out. One is there are molecular mutations outside of these big three.

So, outside of JAK2, CALR, and MPL, that are very important actually. Not everyone is checking for them. They are ASXL1 mutations, EZH2, IDH1 and 2, so on and so forth.

So, these are extended molecular markers that can be checked at some doctors’ offices that now, in the latest scoring systems, if you have one of those or more than one or two, they can elevate your risk score. So, if you have low-risk or intermediate-risk myelofibrosis, they may make you intermediate or high risk.

So, that may be a bit more complicated than what most people are aware of. But just so you know, there are markers that can be readily checked that can tell if your disease may be a bit higher risk than we though, say, 10 years ago.

I think other biomarkers that we look at are some of the labs that are just the regular labs that are on almost every panel, but they can tell a lot about the disease. There’s the LDH, lactate dehydrogenase. There are several markers, such as CRP and sed rate.

So, anyway, there are a lot of labs that we can check depending on where you are in your disease state that can kind of tell us a lot about how inflamed you are, how active your disease is at the moment, and then that will lead to further confirmatory tests. So, I think, yeah, in general, this is an active, developing area of research in our MPN field.

Katherine Banwell:    

It seems like results could really influence therapy choices then. So, do you think patients should ask for these tests specifically?

Dr. Pemmaraju:         

I’m a big fan of patients being empowered to ask anything that comes to mind. And again, that’s why I love this discussion because maybe there might be some people out there who are shocked, frankly, at what we’re talking about here. I think it’s great to do what you said. Yes. I think do your research, online or otherwise. Come up with a list of questions. Bring – if you’re able to, of course – if you have the ability to, bring one person with you. Or nowadays, on the telehealth, we put one person on through the phone during the pandemic time.

And then – yeah. I mean, yeah, sure, just you hear about something, ask about it. The worst thing that your doctor says is, “Hey, that’s only a research test. That’s not available.” It doesn’t hurt to ask. And it may help to lead to other discussions. I think it’s also a good idea to get a second or a third opinion if you need to. There, I said it. It’s your body, it’s your life, it’s your choice. I think, yes, advocate for yourself, because at the end of the day, who else is going to do that?

Katherine Banwell:    

Absolutely. Dr. Pemmaraju, are there other questions that patients should consider asking about their proposed treatment plan?

Dr. Pemmaraju:         

You know, I think the biggest thing that I think is getting left out in the rare blood cancers that I spend all my time in is the ability and access to clinical trials. And that’s one thing I wanted to discuss with you this morning, which is you’re seen in your local doctor’s office. They’re doing the heroic work, and I really think it is, of seeing breast cancer patients, prostate, lung, colon, PV.

It’s just the difference between the frequent, common tumors that get chapters dedicated to them in the board review testing and whole months dedicated in the oncology fellowship compared to the patient with the rare blood cancer that, really, you may only encounter once or twice in your career. As compared to, say, me, where I’m a specialist in only that area.

I think that we – look, here’s the deal. Even today, only 5 to 7 percent of all oncology patients are ever referred to – are ever enrolled on a clinical trial. Clinical trials oftentimes are seen as last resort, last ditch. And I understand that. In fact, I even thought that before I went into medical school.

Then once you get to this point where I am, you realize, wait a second, clinical trial, oftentimes, are frontline programs. Yes, sometimes they’re randomized, sometimes they’re not. Very few times does anyone get placebo, right? Which is what a lot of people are worried about. Or if they do, it’s two drugs versus one plus placebo. Anyway, so there are a lot of different things that are clinical trials.

But we realize now that oncology has so little known information still in 2021 and beyond. So the ability to enroll in a clinical trial, be referred to it, travel to it, know about it, get on it, you’re contributing so much information to not only yourself and patients in your cohort but possibly for the future. So, that’s my only plug, is I wish that we would all ask each other more about “What clinical trials are available, how do I look them up, do you recommend this for me, or can I figure out with you how to travel and do all that stuff?”

So, I think clinical trials in rare blood cancers such as MPNs are underutilized, under-referred to, under-thought of. And then even when we are able to get people there, Katherine, it’s difficult to keep people traveling, particularly vulnerable people.

Katherine Banwell:      

Yeah. We have a question from a newly diagnosed PD patient. Sharon says, “I’m just about to begin Jakafi. What can I expect?”

Dr. Pemmaraju:         

Yeah, great question, right? So, with ruxolitinib or Jakafi, I think the biggest couple of points here is, for what’s known, this is the first-in-class JAK inhibitor that we have the most experience with.

So, now we have over a decade-plus of experience. I guess general things are general, right? This is not specific medical advice. That’s not the intention of this program. But, in general, I would stick with what’s on the package label insert, and there are a couple things we know.

One is this is a highly effective drug. This drug, which we have tested now in multiple, multiple, multiple different trials in myelofibrosis, polycythemia vera, now approved in a form of graft-versus-host disease, different doses. So, I would say check the dose for your particular disease and indication. Double-check it with your pharmacist. Make sure there are no drug-to-drug interactions.

Number two, I think what’s important is that some patients on this drug can experience immunosuppression. So, that means that you may be at risk for some infections, and there’s some nice literature about that.

So, check with your doctor about that, particularly reactivation of old infections, looking out for viral infections, such as herpes zoster or shingles. And then I think the other key here is to watch out for the modulation of your disease. So, a lot of folks have big spleens, Katherine. Those shrink down. Then patients get their appetite back, they’re able to eat, and so some people can have weight gain that then goes the other way. So, these are some of the things you want to watch out for.

But, in general, read the package insert. If you have the ability to, it’s worth reading the – if you can, read the paper, right? Go read the New England Journal paper or – if you can look at that. And then make sure you talk to your local pharmacist and ask the same question there. You might be surprised at some tidbits and pearls you can pick up.

Katherine Banwell:    

Right. Once on therapy, how is the disease monitored, and how do you know if the treatment is working?

Dr. Pemmaraju:         

Yeah. So, it differs from each disease, but let’s take polycythemia vera for a good example. So, let’s suppose you have polycythemia vera. I think there are three markers here that you can check. One is the blood counts, right?

So, you want to make sure that the blood counts are controlled. New England Journal, five or six years ago now, our Italian colleagues published a very seminal paper which shows that the goal of therapy should be that the hematocrit should be below 45. So, that’s actually a very nice number to have. So, not just waiting for symptoms of the disease but keep the number low. And if you do that, that correlates with decreased cardiac events, thromboembolic events.

Number two, I think that, besides the blood count, the spleen. The spleen and liver size also is a nice surrogate for how the disease is doing. So, if that’s enlarging or getting out of control, that may be time to stop what you’re doing, reassess. The disease may be progressing to myelofibrosis, for example.

And then I think, lastly, the absence of stuff actually helps, too. So, the absence of major bleeding, the absence of blood clots, the absence of transformation to MF. I think if the quality of life is good, you’re decreasing blood clots and bleeding, you’re not going to a more advanced disease state, these are all wins for us with p. vera.

Katherine Banwell:    

You touched on this briefly, but I’m wondering when a patient should consider changing treatments.

Dr. Pemmaraju:         

Yeah, changing treatments is more art than science, I would say. So, it does – that’s one of those that is kind of specific from patient to patient. In general, what we just talked about gives you that guidance. So, in polycythemia vera, since we brought that up earlier, uncontrolled blood counts despite maximum medication intervention, the phlebotomy requirement being untoward and impossible to keep up with, the spleen size growing out of control, the quality of life being impossible – these are some aspects to look into changing therapy and/or clinical trial.

But remember, it’s not a one-size-fits-all, right? So, some patients, the counts – some of these things may or may not actually play out. So, it has to be more of a gestalt, more of a total picture there.

Katherine Banwell:    

Yeah. Why is it so important for patients to speak up when it comes to symptoms or treatment side effects?

Dr. Pemmaraju:         

Well, I’m going to be that magician who you watch the TV show, they give away all the secrets. So, this is the big secret. Your doctor cannot read your mind. I hate to say that, Katherine. I just said it here, and it’s going to surprise some people. No, I mean, seriously. Right. So, I think the problem with the MPNs – not the problem, the caveat, the difficulty – is if you are a patient, you have this war that’s suffering inside of you. I know that as an expert person. You know that as a patient. But whoever you’re sitting in front of is not going to know that.

And there are two reasons for that. One is you don’t look like that. Most of our patients – whatever this is, I’m going to put this in big air quotes, so in case someone’s not watching this and they’re only hearing, I’m putting air quotes. People say to my patients, “Wow, you don’t look like a cancer patient.” Whatever that means, right? So, most of our patients don’t have their hair falling out, etcetera, etcetera. So, there’s that aspect of it, the visual education part of it.

Then there’s also the part, which is a lot of these symptoms burdens are not obvious on the physical exam. You cannot tell by talking to someone or looking at them if they have night sweats, bone pain, even itching, any of these things. Fatigue. You can’t tell if someone has fatigue most of the time unless you ask them. So, this is one of those where shared partnership in decision-making is not just a generic phrase. This is important.

I would say that for a patient with an MPN, the MPN symptom burden – the questionnaire, the 10 questions that we now have settled on – that can tell so much more or as much as the physical exam or the blood counts.

So, it’s imperative. It’s not just a luxury. It’s imperative. And if the patient themselves is unable to speak up, then if the advocate or caregiver or loved one can, if that person is available.

The other point I would say to this is that oftentimes the symptoms can precede – they can come before laboratory changes, physical exam changes, all these things. So, a constant, constant communication, “Hey, I was playing 18 holes of golf last year.”

“Now I can’t even get out of bed.” Hello? That tells you more than almost anything you can read on a piece of paper. So, you, as always, are spot-on with what you said. And this is the case where people say, “What can I do to help my care?” This is it. Speak up, speak out. It’s your body, it’s your life, make sure you feel empowered to do that.

Katherine Banwell:    

Right. It’s important to have that dialogue. Dr. Pemmaraju, you’re very active on social media, and patients often share information with one another. So, what advice do you have for patients to ensure online sources are actually credible?

Dr. Pemmaraju:         

Wow, great question. First thing I would say is I encourage everyone to get out there, so that’s key opinion leaders, local physicians, nurses, pharmacists, patients, caregivers, everyone. But Part two is what you said is true. Most everything out there is noise. It could be garbage. It could be background. It could be misinformation. So, you do have to have some way to filter it.

I call it signal from the noise. That’s a common phrase that a lot of people on social media use. I guess three things that I would give as tips. One is don’t be afraid to read and get on there, but I would just say whatever you read, take it with a grain of salt, as you said, and just write everything down where you have it organized.

Number two, tend to gravitate towards known experts and known sources. So, for example, you mentioned that I’m on there. That’s great. Ruben Mesa, our great friend and colleague, etcetera, etcetera. So, if you know who the 10 or 15 thought leaders are on Twitter or social media, see what they’re saying directly. That’s nice, because it’s straight from them to the public.

And then three is stick with the organizations and entities that are trusted sources. New England Journal of Medicine, ASCO, ASH, programs such as yourself, etcetera, etcetera, who are trying to put out there the latest and honest information.

Okay. So, now the fourth part, though, I think is the most important, which is what we said earlier, which is whatever you look up, discuss it with your doctor and your physician team. Period. Because no matter what research you did, no matter what patients groups you join, there might be something that either doesn’t apply to you, or worse, as you said, it could be actual misinformation, and it’s a red herring.

So, maybe find information, figure out a way to filter it, cross-check it, and then bring it up to your doctor team. I think that’s a winning way for success with information nowadays.

Katherine Banwell:    

Yeah. That’s really helpful information. Well, we have another audience question. This one is from Richard. He wants to know, what advice do you have for caregivers, and how can he be supportive during appointments?

Dr. Pemmaraju:         

Yeah. Richard’s question really is so important. Really, before the pandemic and now with the pandemic this extended time, this is the most important question that’s coming up. This is a challenge. I think a lot of our patients who are older, frail, live alone, they don’t even have the option to do that. That may be 25 percent of our patients right there,

And that’s very heartbreaking and difficult, and clearly, their care – it may not be compromised, but it’s certainly limited in some ways without getting that other perspective, right? So, I think that’s important.

Now, out of the 75 percent of the people who may have someone that can be a part of their life, a lot of these folks, Katherine, are limited because of the pandemic. Most hospitals, smartly, I think, still have restrictions on not allowing every single person in the building just for health and safety protocols. So, telehealth has had to be a substitute, I would say, for that, and in a lot of cases, has been helpful. In some cases, frustrating, obviously, with technical difficulties, etcetera, etcetera.

I would say that the key is – and I really want this to be very specific. It would be easy to just say, “Yep, bring a loved one to your visit.” No, it’s not that easy, right? So, now, during the pandemic, I think two things are very important and what I’ve noticed. One is, if the patient is able to, if their health allows them to, prime the loved one or caregiver, “Hey, I’m going to be in the doctor’s office from this time.”

And I always say make it like the cable person visit, right? From 8:00 to 5:00. So, “Hey, today, on Tuesday, if you can have your cell phone on you, that would be nice, because I’m going to patch you in, and you can listen in the background.” This is actually a key pearl I can give to people. You’d be surprised how helpful that is. Because most people, if they’re not living in the same household or whatever – “Oh, I didn’t even know you were going to be,” – okay.

Number two, when the loved one or caregiver is involved, which I encourage for everyone, try to discuss with them the night before, if your health allows you to, to go over some of the key questions. Say, “Hey, guess what? I only understand about 7 to 10 percent of what goes on in these visits, but I need you to ask this.” So, you can kind of prime your loved one to do that.

And then, lastly, you had mentioned earlier to have this list of questions. Well, that’s a great thing to give to the caregiver, right? So, if you’re able to use email and your family member is in California and you’re in Texas, maybe a quick email the night before.

“Hey, here’s what I’m thinking. In case I forget, will you ask this to the doctor?” A lot of these visits may only be five or 10 minutes, but you’d be surprised, if you have a list of two or three questions – boom, boom, boom – and then it’ll alleviate those worries there.

Lastly, I would also say don’t feel – I want to tell this to the viewers out there. Don’t feel pressured when you’re in the visit with us that you have to get every single thing out. And what I mean by that is now with email and the electronic medical record portal systems, there is some ability to contact people during – I’m sorry, after and between visits. So, maybe that might help you to not feel so much pressure in the visit.

Katherine Banwell:    

Yeah. Very good advice. Thank you. Before we end the program, have there been any recent developments in MPN treatment and research that make you hopeful?

Dr. Pemmaraju:         

I have a lot of optimism and hope. It really blossomed over the last two years. I’m happy to report to our viewers – and this is incredible, I never would have predicted this. There are over 10, maybe 13, Phase 3 clinical trials that are in the clinic now or opening soon.

Phase 3 meaning sort of the latest – one of the latest stages of clinical trial development for new drugs. And a lot of these drugs are combinations. So, a lot of them, you’re on your ruxolitinib, for example, you’re on your JAK inhibitor, and then you add in the second agent. This is very exciting. I, myself, am leading or a part of several of these. I mean, we could have never envisioned this five years ago. So, not only these drugs have shown encouraging activity in the Phase 1 and 2 – so, the earlier stages – so, now we have to confirm and test them in larger trials. So, stay tuned for that, whether you can participate directly or at least follow along with the information.

And then the other piece of excitement is that there’s a lot of beyond JAK inhibitor drugs. So, that means novel pathways, new drugs that have nothing to do with JAK that can either stand alone by themselves or be combined. That’s another exciting area. We have multiple classes of drugs emerging from the lab into the clinic now that I hope will have a lot of benefit for our patients.

So, tons of optimism and excitement, frankly, that just wasn’t there five years ago.

Katherine Banwell:    

That’s wonderful. Dr. Pemmaraju, thank you so much for joining us today.

Dr. Pemmaraju:         

Thank you, Katherine. I just love the chance to spend time with you guys. I hope to do this soon one day.

Katherine Banwell:    

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.

Have You Had These Essential Myelofibrosis Tests?

Have You Had These Essential Myelofibrosis Tests? from Patient Empowerment Network on Vimeo.

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.

Related Programs

Which Gene Mutations Impact Myelofibrosis Treatment Options?

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Transcript

Katherine Banwell: 

What testing should take place following a myelofibrosis diagnosis? 

Dr. Scandura:  

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. 

Katherine Banwell:

Is there any other testing that you usually want to do? 

Dr. Scandura:

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.   

Katherine Banwell:

How often should patients have a bone marrow biopsy? 

Dr. Scandura:

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.  

Shared Decision-Making: The Patient’s Role in Treatment Choices

Shared-Decision Making: The Patient’s Role in Treatment Choices from Patient Empowerment Network on Vimeo.

What is the role of the patient when it comes to treatment choices? Dr. Brady Stein details how he partners with patients in decision-making for their MPN care. 

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.


Related Resources

MPN Symptom or Treatment Side Effect? Know the Difference

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How Often Should You See Your MPN Doctor?


Transcript:

Katherine:                  

What do you feel is the patient’s role in the decision for therapy?

Dr. Stein:                   

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 want to hear. I want to 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 are 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 going to give you a much better framework to help make decisions together.

Katherine:                  

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?

Dr. Stein:                   

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 want to 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.

Self-Advocacy: Advice for Being a Pro-Active MPN Patient

Self-Advocacy: Advice for Being a Pro-Active MPN Patient from Patient Empowerment Network on Vimeo.

How can myeloproliferative neoplasm (MPN) patients be more pro-active in their care? Dr. Brady Stein shares advice to help patients educate themselves about the disease, while finding the right balance of knowledge to prevent them from feeling overwhelmed. 

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.


Related Resources

Tools to Help You Learn More About MPN Clinical Trials

How Often Should You See Your MPN Doctor?

Which MPN Treatment is Right for You? Factors to Consider


Transcript:

Katherine:

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?

Dr. Stein:                   

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 got to 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.