Tag Archive for: JAK2 mutation

Should All MPN Patients Undergo Molecular Testing?

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Should All MPN Patients Undergo Molecular Testing? from Patient Empowerment Network on Vimeo.

Dr. Gabriela Hobbs discusses the necessity of molecular testing for myeloproliferative neoplasm (MPN) patients, including the pros and cons of this in-depth testing for patients with polycythemia vera (PV) and essential thrombocythemia (ET).

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

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Transcript:

Katherine:

How useful is having a genetic panel done? Should all patients get molecular or genetic testing? 

Dr. Hobbs:

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

And genetic testing involves more than just testing the JAK2 mutation. So, we know that the JAK2 mutation is the most common mutation in patients with MPN. But that being said, there are other mutations that also occur such as the calreticulin mutation and the MPL mutation.   

And so, I think having genetic testing that at least tests for those three mutations is very important so that we can actually help a patient know that they have an MPN. In addition to those three main mutations, many clinicians now have access to what’s called extended next-generation sequencing, where there’s a panel that tests for many different genes at the same time and can test for a variety of other mutations.  

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

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

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

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

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

What Is a JAK2 Mutation?

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

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

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

The V617F mutation in the JAK2 gene is found in:

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

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

What Is the JAK2 Gene?

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

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

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

What Causes JAK2 Mutations?

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

V617F Mutation

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

Multiple Mutations

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

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

Do JAK2 Mutations Cause MPNs?

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

JAK2 Mutations and MPN Diagnosis and Prognosis

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

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

Quantitative Polymerase Chain Reaction

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

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

Fluorescent In Situ Hybridization

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

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

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

JAK2 Mutations and MPN Treatments

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

Jakafi

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

Inrebic

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

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

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

Finding Support With an MPN

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

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

What Are the Signs of MPN Progression?

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What Are the Signs of MPN Progression? from Patient Empowerment Network on Vimeo.

Dr. Abdulraheem Yacoub, an MPN specialist, explains how essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) may progress from one disease to the next, including potential signs and symptoms of MPN progression. 

Dr. Abdulraheem Yacoub is a hematologist oncologist at the University of Kansas Cancer Center. Dr. Yacoub is an active researcher and is an Associate Professor of Hematologic Malignancies and Cellular Therapeutics. Learn more about Dr. Yacoub, here.
 

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Transcript:

Katherine:

We have a couple of questions from the audience. This one is from Sarah. She writes, “I’ve been living with essential thrombocythemia for three years, and have been relatively stable. Of course, I’m worried about progression to PV or MF. What is my chance of progression, and what are the signs of progression?” 

Dr. Yacoub:

That’s a very good question. And unfortunately, we’re very good at describing those numbers. Unfortunately, our tools at interfering are not as good. So, in general, patients with ET, statistically speaking, have a life expectancy that is not different from their age match peers. And Sarah’s story will be not too indifferent from her sisters and her mother, in terms of what’s going to happen to her long care and her health, provided she gets good medical care. The exception to that is that there is a transformation risk. For ET we caught around a 4 percent every 10 years in which ET will actually change into a different cancer, a higher risk cancer.   

Could be MF, could be MDS, could be acute leukemia. And that will be a much more serious diagnosis. So, it’s about 4 percent in 10 years. We do have a – or we extrapolate some of the data from other cancers. So, certain mutations are more favorable, certain mutations are more risky. And we try to forecast that but worried it’s really hard to predict that since it’s such a long journey with disease. The first symptoms or the findings, when patients start suspecting that their disease has changed, is that the pattern of symptoms that they have are different.   

They often become worse. So, they have more constitutional symptoms, more tiredness, more fevers, more night sweats, losing weight, not being able to eat a full meal, abdominal distension, the spleen gets bigger.  

So, these are some of the feelings that patients can experience that lead to this. Other objective things is when the blood tests change in a less favorable way. So, for patients with ET who always run at 800,000 platelet count, if they’re suddenly 200, and that’s in the normal range, but that’s actually not good news, because the cancer changed. And this change is not favorable. So, as the doctors run routine labs, if they see the sudden change in labs, that’s also abnormal.  

If the doctor can feel that the spleen gets bigger every time, that’s also concerning. If the patients suddenly have anemia or very high white cell count or immature white cells in the blood, that’s also a concern.  

So, that’s why it’s great or important to establish a baseline symptom burden.  A baseline spleen, a baseline bone marrow biopsy with mutation analysis, so that patients have a clear reference point to where they started, and if things change, they can always go back to that point and compare.  

Updates from ASH: How Biomarker Testing Has Changed MPN Care

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Updates from ASH: How Biomarker Testing Has Changed MPN Care from Patient Empowerment Network on Vimeo.

MPN specialist, Dr. Andrew Kuykendall, discusses how the identification of specific biomarkers in myeloproliferative neoplasms (MPNs), such as the JAK2 mutation, have moved research forward. Dr. Kuykendall shares promising findings that were released at the 2021 American Society of Hematology (ASH) annual meeting and how this may impact MPN care in the future.

Dr. Andrew Kuykendall is an Assistant Member at Moffitt Cancer Center in the Department of Malignant Hematology. Dr. Kuykendall’s clinical and research efforts focus on myeloproliferative neoplasms (MPNs), MDS/MPN overlap syndromes and systemic mastocytosis (SM). Learn more about Dr. Kuykendall, here.

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Transcript

Katherine:

How has molecular or biomarker testing changed the field of MPN care and treatment?

Dr. Kuykendall:

Well, I think, first and foremost just understanding – going back to 2005 and knowing that we have JAK2 mutations. I think that gave really a lot of clarity to the diagnosis and really understanding the biology of how the disease acted through the JAK-STAT pathway. And certainly, that led to the understanding of MPL mutations and then calreticulin mutations.

We’re still figuring out exactly how calreticulin mutations work. There was a great abstract, a preclinical abstract, this year talking about the impact of interferon on calreticulin mutations and how that may differ from what we see in the impact of interferon on diseases that are driven by JAK2 mutations.

Clinically, we see a little bit of difference in how those diseases respond and we may understand a little bit better about why that happens. Additionally, that’s kind of gone down to looking at these big next generation sequencing panels where we identify high-risk mutations and that can certainly change our understanding of the prognosis of these diseases.

We’re starting to get, at least in the AML world, we’re getting targeted agents that can potentially target some of these mutations such as IDH1 and IDH2 mutations that have specific inhibitors.

Those are mutations that occur in myeloproliferative neoplasm patients and convey a worse prognosis, so there are ongoing trials looking to see if we can use those IDH inhibitors in myeloproliferative neoplasms either in the chronic phase or maybe in the more accelerated advanced phase.

You know the big thing, this meeting, was actually looking at polycythemia vera patients and what’s the relevance of the JAK2 mutant allele burden. I think this is something we’ve talked about a lot as far as how significant this is. We know in chronic phase myeloproliferative neoplasms that that JAK2 mutation tends to be associated with more thrombotic complications.

There are more blood clots in the veins and the arteries. There were a couple great abstracts that looked at the really the implications of the JAK2 mutation and the fact that it is associated with more thrombosis, but maybe more venous thrombosis. That might be a big risk factor for venous thrombosis and it may be that cardiovascular risk factors, such as diabetes, hyperlipidemia that’s really what’s driving the arteriole thrombosis. It also looked at the variant allele fraction, the number of cells that have that JAK2 mutation.

One abstract showed that if you have over a 50 percent allele fraction, if more than 50 percent of the alleles have the mutation – a higher burden of that mutation that’s associated with an increased thrombotic risk even in low-risk polycythemia vera patients. Whether or not that’s enough evidence to really change the paradigm of how we treat low-risk patients is to be determined, but I think very interesting and provocative work. 

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

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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.

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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

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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.

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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.

Is My MPN Treatment Working?

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Is My MPN Treatment Working? from Patient Empowerment Network on Vimeo.

During myeloproliferative neoplasm (MPN) treatment, specific blood tests and diagnostic measurements help to gauge a patient’s treatment response. Dr. Brady Stein details the criteria he assesses in monitoring the efficacy of a therapy, including patient-reported outcomes.  

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.

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Transcript:

Katherine:                  

Once a patient has started treatment, how do you know it’s working?

Dr. Stein:                   

That’s a good question because this is a very unique area. Yes, of course, in some respects, it’s straightforward with ET or PV. If we’re starting a medication to control a blood count in hopes of having lowered the thrombosis risk, you can look objectively at blood counts.

Okay, your hematocrit is at this goal? Yes, therapy’s working. You have not had a blood clot?

Yes, therapy’s working. So, there are some objective things. In myelofibrosis, there are some objective things like measuring the spleen and seeing it reduce. You can feel that with your hands, or you can do an ultrasound. So, there are some objective parameters of success. But, in this area, patient-reported outcomes are really important, and so, a measure of success is really just asking the patient, “Do you feel like your drug is working? Do you feel better?

It’s kind of a simple question, but it’s really important, and it’s what we ask in patients who are on certain therapies. “Do you feel like the net effect of your therapy is still positive? Do you feel like it’s helping?” Seems like a straightforward type of question, but I think the answer is extremely informative. When a patient says, “Yes, definitely, my medication is still helping me,” then I know that I don’t need to change it.

MPN Treatment Choices: Where Do Clinical Trials Fit In?

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MPN Treatment Choices: Where Do Clinical Trials Fit In? from Patient Empowerment Network on Vimeo.

When considering MPN treatment approaches, clinical trials are a viable option for care. Dr. Brady Stein discusses clinical trials and factors to keep in mind when considering participation.

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.

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Transcript:

Dr. Stein:                   

Clinical trials are always a treatment – always an option for patients with myeloproliferative neoplasms because while we have some standards, we can definitely improve upon those standards for certain. So, clinical trials are always a therapeutic option. I think the one thing is that it may not – it’s not always the most convenient option, but it could be a really important option if available to you.

So, clinical trials basically offer something new or novel that would not otherwise be available to other patients. So, ruxolitinib (Jakafi) was approved around 2011, but the first clinical trials were in 2007, so that’s the example I give to a patient about the benefit of a clinical trial.The patient can get access to a drug that’s effective perhaps three to four years before it’s commercially available.

That’s really the biggest advantage, is you can get early access to something that could really help you. The downsides are that clinical trials are not usually as convenient as regular care, there are often more visits, and there are a lot of unknowns – unknowns about whether it will work. Some side effects are known and expected; there are others that are unknown. So, it’s a lot to think about, but I think it’s always important to consider, especially if your first-line therapy has not been effective, if it’s losing its touch, it’s a good thing to think about for a second line.

Katherine:                  

Are there emerging approaches for treating MPNs that patients should know about?

Dr. Stein:                   

Yeah, absolutely. I think the first question – I think patients are often worried that they have a really rare disease, and why would anyone do research in this area, and that’s – the research community is extremely engaged, the productivity is pretty impressive, and there’s a lot of clinical trials in the space, and I think what I try to explain is pharmaceutical companies aren’t just targeting the most common diseases.

They have interests in rare diseases, and findings in rare diseases can be extrapolated to other diseases that you might think are unrelated, but they can share features, so when you find something working in one space, it can have broad applicability. So, there’s an abundance of research in myeloproliferative neoplasms which are emerging?

In PV, I think there’s quite a possibility that there’ll be a drug approval in 2021, a novel type of interferon called ropeginterferon

That is a drug that’s approved abroad; it’s approved in Europe, and I believe it’s approved in Taiwan, and the FDA is looking at it now. So, it’s a possibility that there’ll be a future option for patients with polycythemia vera. So, yes, it’s research now, but it could be available, and so, that’s the drug that I’m starting to talk more and more about for patients with PV.

In myelofibrosis, you have two JAK inhibitors that are approved, ruxolitinib and fedratinib, you have two others in clinical testing, momelotinib and pacritinib, and then you have a whole other class of what we call non-JAK2 type of therapies targeting the vast array of pathway abnormalities in myelofibrosis.

So, there are a number of different clinical trial options, especially in myelofibrosis. I think that’s the disease area where there are the most clinical trials.

Understanding High-Risk vs Low-Risk Disease in ET, PV & MF

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Understanding High-Risk vs Low-Risk Disease in PV, ET & MF from Patient Empowerment Network on Vimeo.

When looking at polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), how is risk determined? Dr. Brady Stein explains factors he examines when assessing risk to provide ideal care for each patient. 

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.

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Transcript:

Dr. Stein:                  

For ET and PV, when we talk about high versus low risk, we’re talking about vascular complications, risk of having a blood clot. We’re not really talking about risk of transformation. We don’t have, I think, wonderful, widely used toolkits to predict those things. We know they can happen, but our treatment is still really based on clotting for ET and PV.

And, MF – each couple of years, the tools that are available to assess prognosis become more and more. So, in MF, we’re using the most comprehensive approach – of course, taking into account things like age and demographics, but also, looking at symptoms, looking at the depth and severity of blood count changes, looking at bone marrow features like the degree of scarring, looking at the rise in blast counts, and then, looking at chromosomes and novel genetic markers. So, we’re definitely the most comprehensive in myelofibrosis at assessing prognosis.

What Are Treatment Options for Essential Thrombocythemia (ET) & Polycythemia Vera (PV)?

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What Are Treatment Options for Essential Thrombocythemia (ET) & Polycythemia Vera (PV)? from Patient Empowerment Network on Vimeo.

When considering treatment options for essential thrombocythemia (ET) and polycythemia vera (PV), where do experts begin? Dr. Brady Stein details treatment considerations and how he determines the best approaches for ET and PV patients. 

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

Which MPN Treatment is Right for You? Factors to Consider

Promising ET, PV & Myelofibrosis Therapies in Development 

MPN Treatment: Why Testing for Mutations Matters

Transcript:

Katherine:                  

Let’s start with essential thrombocythemia, or ET.

Dr. Stein:                   

So, I think the first thing is taking an inventory of symptoms, seeing how symptomatic the patient might be. Again, there are some patients who are asymptomatic or have few symptoms, and they were told of a high platelet count during a routine visit, so some patients can be observed if they have few symptoms, and especially if they fall into a lower vascular risk category.

So, symptom assessment first. Second, looking at vascular risk, and there are four categories of risk in in ET in terms of predicting the likelihood of a future blood clotting event. There’s a very low, low, intermediate and high risk group, and that’s based on a patient’s age, whether they’ve had a blood clot before, and the type of mutation they have. JAK2 mutations increase the risk of clotting.

So, if a patient falls into a higher-risk group – say they’re older than 60 with a JAK2 mutation or they’ve had a prior blood clot – those are patients who are generally treated more aggressively with cytoreduction.

And then, the other thing is aspirin. We often see aspirin given to all patients with ET, but not all patients with ET necessarily need it. The role of aspirin is actually a little less clear in ET. For a very low-risk patient, there’s a potential for more harm than benefit, especially if the patient lacks a JAK2 mutation. So, the evidence base to support aspirin for all ET patients is just not there; it’s evolving.

Katherine:                  

What about polycythemia vera, or PV?

Dr. Stein:                   

So, there are a few standards. It’s different – the aspirin question in PV is generally answered by randomized data from 16 years ago in 2004. It’s been shown that aspirin reduces the risk of clotting in PV patients, so, generally, we give low-dose aspirin to all patients. And, hematocrit control is really important.

At least, a goal of 45 percent is mandated in PV. And then, there are patients who might fall into a higher-risk category – older than 60 or have had a prior blood clot – they need something more. And then, I’d also emphasize that there are lower-risk patients who may not be traditional candidates for cytoreduction, but they could have symptoms that really interfere with quality of life, and symptoms alone can be the trigger to add something more to the phlebotomy and aspirin program.

Katherine:                  

What about things like interferon?

Dr. Stein:                   

So, interferons have been used in MPNs for decades and decades. So, a longstanding history with interferons. The issue has been tolerability.

These days, there’s a class called pegylated interferon that’s longer acting, and I think there’s been a lot more use, at least in the last 10 years, still much more in an academic setting than a community practice.

But, interferons have a pretty established role in MPNs, especially polycythemia vera, for sure in ET, less so in myelofibrosis.

What Factors Guide Treatment Choices for ET, PV & MF?

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What Factors Guide Treatment Choices for ET, PV & MF? from Patient Empowerment Network on Vimeo.

When making a myeloproliferative neoplasm (MPN) treatment decision, several factors come into play. Dr. Brady Stein explains what criteria he considers to determine the optimal approach for a patient’s unique situation and specific MPN.

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

Monitoring MPNs: When is it Time to Switch Therapies?

An Expert Shares Key Steps to Take Following an MPN Diagnosis

MPN Treatment: Why Testing for Mutations Matters

Transcript:

Katherine:              

Dr. Stein, I understand that therapy is different for each of the MPNs. What do you take into consideration to help guide the treatment choice?

Dr. Stein:                   

So, that’s a good question. It’s going to require maybe a little bit of a longer answer. It’s fairly nuanced. The treatment of ET and PV – right now, the goals are – the treatment is largely based on a patient’s vascular risk. That’s largely what influences the choice of therapy. And so if a patient has a perceived high risk for vascular complication in ET or PV, that’s when we’re going to be a little bit more aggressive – so, more aggressive than watchful waiting, more aggressive than using aspirin alone, more aggressive than using phlebotomy and aspirin alone in polycythemia vera.

So, if the patient has a higher vascular risk, in general, we’re going to need to do something more than what we consider to be the standard, and that’s where we enter into the question of cytoreductive therapy – therapies designed to lower blood counts apart from phlebotomy.

Maybe that’s going to change. I hope it will change. Right now, the therapy for ET and PV is generally reactive. We either predict high risk and react, or if a patient is lower risk, if something changes – God forbid there’s a blood clotting event – then we may react to it.

So, ET and PV treatment are generally more reactive. In myelofibrosis, certainly, there are patients who can have lower risk and minimal systems, and there are some patients who can be observed with watchful waiting for sure, but more patients are symptomatic, more patients are going to need therapy in myelofibrosis, and there’s sort of two big categories of therapy.

One is the risk-adapted, deciding if the patient is eligible and should consider stem cell transplant versus thinking only about medical therapy in a patient that may be transplant-ineligible.

And, the medical therapy is based on the worst symptoms for the patient. Is the symptom that’s the worst the spleen enlargement? Is it excessive fatigue? Is it weight loss, or inflammation, or fevers? If it’s that category of symptoms, we have a set of therapies. If it’s really the anemia that is the most problematic issue, then we follow a paradigm to treat anemia.

Katherine:                  

What about considerations like the patient’s health, age, genetic markers, things like that?

Dr. Stein:                   

So, of course. The comorbid illnesses can influence therapy choices, so if a patient is older and has other medical conditions, they’re not going to be treated as aggressively.

So, in myelofibrosis, if a patient is older, with other medical illnesses, then it may be inappropriate to consider something like stem cell transplant, for sure. So, age and health comorbidities are highly influential. In terms of genetic features, if you’re asking about things like the type of mutation that a patient has, right now, we’re – in terms of vascular risk, for ET, the type of mutation matters for blood clotting risk, so if patients have different mutations, it could be treated differently. In other subtypes, like PV or myelofibrosis, in general, there’s – the mutation can be prognostic, but it may not be – it may not lead to a precise and distinct therapy just yet.

How Do Test Results Inform MPN Prognosis & Treatment?

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How Do Test Results Inform MPN Prognosis & Treatment? from Patient Empowerment Network on Vimeo.

Dr. Brady Stein explains the diagnostic tests and genetic mutations that are assessed to determine prognosis and what MPN treatment may work best.

Dr. Brady Stein is a hematologist focusing on myeloproliferative neoplasms (MPNs) at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 

Related Resources

Which MPN Treatment is Right for You? Factors to Consider

Resource Guide: Choosing an MPN Treatment: What Option is Best for You?

MPN Treatment: Why Testing for Mutations Matters

Transcript:

Katherine:                  

Once a patient is diagnosed with MPN, what sort of testing should take place?

Dr. Stein:                   

So, the test that’s going to lead to suspicion is going to be a blood count, and that’s probably going to be done in the primary care doctor’s office, so that’s going to be the first suspicious test, and in general, there’s going to be some abnormality. Myeloproliferative diseases are characterized in general by an overproduction of blood cells, so it’s going to be a higher white count, it’s going to be a high hemoglobin or hematocrit, or a high platelet count, or a combination of the three that’s generally going to lead to suspicion.

Some patients may have pretty unremarkable blood counts and may present with a blood clot in an unusual location that could ultimately lead to the hematology referral. Some patients might have pretty unremarkable blood counts, but they might have palpation of their spleen, enlargement of their spleen in a physical examination. So, they’re generally the ways that patients are getting to the hematologist.

Katherine:                  

And, what about bone marrow biopsy?

Dr. Stein:                   

So, a bone marrow biopsy is a diagnostic test, and it’s generally recommended for all patients who have a myeloproliferative neoplasm either confirmed or suspected.

It’s advised in WHO criteria – World Health Organization criteria. PV can be made without a bone marrow biopsy – a diagnosis of PV – because it’s the most unique of the MPN subtypes. It’s the one that presents with a high hemoglobin.

So, that diagnosis can be straightforward at times for a hematologist when the setting is right, when there’s a high hemoglobin – or, high enough hemoglobin, I should say, a JAK2 mutation, which all patients with PV have that, or a subnormal erythropoietin level.

Oftentimes, we can make that diagnosis without a bone marrow, and the bone marrow becomes more prognostic. ET, a bone marrow is necessary for diagnosis, and myelofibrosis, you can’t make a diagnosis without it.

Katherine:                  

What do the results of these tests tell us about prognosis and treatment choices?

Dr. Stein:                   

That’s a good question. The bone marrow can be diagnostic in the setting of ET and myelofibrosis. In the setting of polycythemia vera, it can be more prognostic. In general, when a bone marrow is done, 1). To confirm diagnosis, 2). To assess prognosis, what we’re looking for as prognostic features are generally the degree of fibrosis or scarring.

So, each of the MPNs can have that. Of course, MF is characterized by the most pronounced scarring. It can happen to a more subtle degree in ET and PV. That’s going to be prognostic in the setting of ET or PV. The pathologist will alert us about immature cells called blasts.

We basically never see them at diagnosis in patients with ET or PV. We can see them rise in patients with myelofibrosis at diagnosis or through the course of follow-up. So, that’s prognostic.

All bone marrows generally have a chromosome analysis that’s called cytogenetics, and so, if there’s an abnormality, that can help place the patient’s prognosis into different risk categories.

And then, nowadays, more so in myelofibrosis than any of the others, there are extended panels done. These are called NGS, or next-generation sequencing, kind of looking at mutations in a greater degree of detail.

So, not just what we call main mutations – JAK2, calreticulin, or MPL. These are looking at additional mutations that basically hold prognostic significance.

These are pretty well defined, and I think more important in MF compared to the other subtypes.

Katherine:                  

Would you explain the driver mutations in MPNs? What are they, and how they – or, what they mean for patients?

Dr. Stein:                   

So, there’s three of what we call driver mutations, and the most common is JAK2V617F, the next most common is calreticulin, and the least common or most rare is a mutation of MPL, the thrombopoietin receptor. So, the driver gene mutations are the three that we assess to help with diagnosis, and the prevalence varies. In ET, about 60 percent have JAK2, 25 percent have calreticulin, 5 to 10 percent have MPL.

In PV, 99 percent have some type of JAK2 mutation, and in MF, the situation is a lot like ET – 60 percent JAK2, 25 percent calreticulin, about 5 to 10 percent MPL. So, the driver mutations – we think of those as the genetic abnormalities that really drive the disease. They’re the main ones we can test for in a diagnostic setting.

I refer to them as the – to a patient, what I’m describing is you have a car, and the driver mutation is the one that’s sort of driving the car, and it’s doing it somewhat recklessly. It’s in the front seat, driving. And, along the way, the driver can pick up hitchhikers, which we should never do. I refer to those other mutations that are found by NGS as hitchhiker mutations that sit in the back seat, cause trouble, and really shouldn’t be there. They’re not the driver, they’re not fully responsible for the disease, but they can make it a bit worse.