Tag Archive for: MPL

Should All MPN Patients Undergo Molecular Testing?

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.  

How Driver Mutation Research Is Advancing MPN Treatments

How Driver Mutation Research Is Advancing MPN Treatments from Patient Empowerment Network on Vimeo.

How do driver mutations affect MPN care? MPN researcher Dr. Gabriela Hobbs shares an update on what’s being learned about the JAK mutation and how researchers are working towards targeted therapy for MPNs.

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:

There have been huge developments in the last 10 to 15 years in the field of MPN. So, I’d like to dig a little deeper. We hear about the common driver mutations in MPNs like JAK2, CALR, and MPL. How are these being studied , and what is being discovered?  

Dr. Hobbs:

Yeah. So, it’s amazing how in the last 15 years really so much has been discovered. You know. The JAK2 mutation was first published out in 2005 and calreticulin in 2013. So, those are relatively recent discoveries. And I think a lot of efforts has been put into learning about what these mutations are doing and how they lead to disease. And so, we have the JAK inhibitors, which block the signaling through a pathway called JAK-STAT. And all of these mutations will activate that pathway within cells.  

And so, many of the approved drugs, for example, ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo), work on blocking that pathway.  

But since then, we’ve also learned that there are other mutations and other pathways that are likely involved in the development of myeloproliferative neoplasms and also their progression. And so, what we’re seeing now is that many of the clinical trials that are being conducted don’t just target the JAK-STAT pathway or the pathway that’s influenced by these main mutations.  

But also block other pathways to try to really block all the variant expression of signaling in the myeloproliferative neoplasms. And so, we’re trying to attack it by many different angles.  

Katherine:

Yeah. Is there a possibility of specific targeted therapies at MPNs similar to those in AML such as FLT3 inhibitors? 

Dr. Hobbs:

Absolutely. So, similarly to AML, we know that we have mutations in similar types of genes called tyrosine kinases. So, these are enzymes that are turned on and always active. And so, I think there is definitely hope that we can develop some targeted agents. For example, ruxolitinib or the other JAK inhibitors are similar. They’re tyrosine kinase inhibitors where they block an enzyme, specifically the JAK2 enzyme.  

But I think that we can definitely do better and develop more specific inhibitors, for example, a molecule that just blocks the JAK2 mutation and not just every JAK2 molecule in every cell. Similarly to AML, there are mutations, for example, in enzymes called IDH.  

And we have IDH inhibitors for AML. And there are some studies that are using IDH inhibitors for MPN. So, I think we’re going to continue to see more targeted therapies specific to the mutations that occur in MPN. 

What Is Next Generation Sequencing for MPNs?

What Is Next Generation Sequencing for MPNs? from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasm (MPN) care may include the use of next generation sequencing.  Dr. Kristen Pettit from Rogel Cancer Center explains next generation sequencing and how it is used in MPN patient care.

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Transcript:

Dr. Kristen Pettit:

Next generation sequencing or NGS refers to tests done from the blood or the bone marrow that can look for many different genetic mutations at once. So we know that most patients with MPNs will have mutations in either JAK2, CALR, or MPL but many will also have additional genetic mutations.

These additional genetic mutations may be important prognostically as we know is, we know some of these additional genetic mutations can confer either higher or lower risk of the disease progressing over time. So, I think next generation sequencing or NGS panels should be a part of the work up for most patients with MPNs at the time of initial diagnosis, and probably again, at the time that there’s any concern for disease progression in the future.

What’s YOUR Role in Making Myelofibrosis Treatment Decisions?

What’s YOUR Role in Making Myelofibrosis Treatment Decisions? from Patient Empowerment Network on Vimeo.

How can you play a role in your myelofibrosis care? Dr. Joseph Scandura shares his personal philosophy on patient care and the important role of shared decision-making.

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.

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Transcript

Katherine Banwell:

Dr. Scandura, what is the role of the patient in making treatment decisions? 

Dr. Scandura:

My personal philosophy is I view myself and my interactions with patients as a partnership. And I have and I bring to this partnership medical knowledge, some scientific knowledge, experience treating patients, understanding the diseases and the biology of the diseases. 

What patients bring is their personal histories, what they want and need from therapy, what their expectations are, where their fears and concerns might be. And as we share our information, I think that provides the opportunity to come to an understanding where the patient can make an informed decision and I can support that decision, that we know what the groundwork has been between us. And so, I spend, often, a lot of time in the beginning with patients kind of trying to understand who they are as people and what they need and expect. And everybody, as you might imagine, is an individual.  

And I present to them the information, and I try to encourage questions so that I know that they understand the information that I’m giving so that they can make a decision in their best interest. And so, I think shared decision-making is the only model I practice.  

Now, patients have different needs, particularly some of my older patients. And, culturally, there are some differences where they don’t want to take that role of being the decision-maker. And so, then my role changes a little bit, and it becomes more to make sure they’re comfortable and understand the direction that we’re going in and, again, always trying to encourage people to take ownership. 

I think, in New York City, that’s not so common. People are pretty well-informed and interested and more than willing to express their opinions.  

And so, I would say it can be very rewarding to come to a decision where patients feel their needs are being met.  

Expert Perspective: Promising Myelofibrosis Treatment Research

Expert Perspective: Promising Myelofibrosis Treatment Research from Patient Empowerment Network on Vimeo.

Dr. Joseph Scandura shares optimism about myelofibrosis therapy in clinical trials, including excitement about anti-fibrotic agents and how they work.

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.

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Transcript

Katherine Banwell:

Dr. Scandura, you mentioned promising research in myelofibrosis treatment. What are you most excited about right now? 

Dr. Scandura:

I think there are a couple drugs that have been in clinical trials that have had activity in a significant subset. So, anywhere from 20 to 50 percent of patients where the bone marrow fibrosis is actually reversed. 

And this is really something that we haven’t seen with other agents. And the approved agents, when that does happen, it’s really in a vast, vast minority of patients. And so, these newer drugs and, often, they’re used in combination with other approved drugs, can reverse the fibrosis in the marrow. And that is what I find most intriguing and exciting. They seem to be well-tolerated medications with predictable and reversible side effects when they do exist. And I think that time will tell if the promise is long-lived or if it’s short-lived. I mean, obviously, new drugs we don’t have the experience with that we really need. 

The clinical trials that are available now with some of these agents are in the last stages before the companies go to the FDA seeking approval for use. 

And so, we don’t have their results from those studies yet. They’re just opening, so sometimes the excitement doesn’t bear out when we do the rigorous clinical trials. But I’m actually quite optimistic about some of these agents, and I think that there is going to really be a sea change in how we treat patients and some of the outcomes we can expect from our therapies.  

What Are the Considerations When Choosing Myelofibrosis Therapy?

What Are the Considerations When Choosing Myelofibrosis Therapy? from Patient Empowerment Network on Vimeo.

 When choosing a myelofibrosis treatment, how do you determine what might be best for you? Dr. Joseph Scandura shares expert advice, including a review of inhibitor therapy and stem cell transplant.

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.

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Transcript

Katherine Banwell:

What are the considerations when choosing treatment for myelofibrosis?  

Dr. Scandura:

I would say in broad strokes, the primary considerations are the patient, what they want, the disease, what our options are, and the overall condition in terms of what are our possibilities for therapy and what is the risk/benefit of some of these different therapies. So, in myelofibrosis, although there’s been a huge amount of research over the past 10 years, really blossoming and are very impressive in, I think, an exciting way, there really are only two therapies that are approved by the FDA in the treatment of myelofibrosis, and those both affect one class of agents. These are JAK2 inhibitors, and those can be ruxolitinib (Jakafi) and fedratinib (Inrebicare the two drugs that are approved. 

Now, we have a number of therapies that have been used off-label, meaning without FDA approval, so often and for so long that they’re considered alternative standards of therapy. These can be growth factors; these can be biological agents in certain situations. And then, clinical trials is really increasingly a common therapeutic option for patients.  

And then, on the most aggressive side, is hematopoietic stem cell transplant and allogeneic transplant getting blood-forming cells from another person and replacing the entire blood system through transplant. 

Katherine Banwell:

So, who is right for a stem cell transplant? 

Dr. Scandura:

I would say, first and foremost, an informed patient about the risks of transplant and a patient for whom a donor exists, and a good quality donor. Transplant is not an option for some people or if a donor can’t be identified, obviously. 

And it’s a patient for whom the risk balance, the risk/benefit balance is tipped so that the potential toxicity, frankly, of transplant is warranted. Transplant is our most aggressive therapy. Virtually every patient will have significant side effects from transplant. Some of them are short-lived, some of them can be chronic. People die from the consequences of transplant. And so, it’s not something that is considered in patients who are necessarily doing well or are frail. The risk of transplant versus the benefit may not be in favor of transplant at that time.  

My approach for transplant is to get advice from transplant physicians. I’m not a transplant physician, but I have colleagues who I refer to. 

And I refer in myelofibrosis fairly universally fairly early, with the rationale being that this is information. It is not a plan; it is to speak to a transplant, what kind of donor exists. If no donor exists, then transplant is not on the table. If we have a very good, high-quality donor, then this is something that wouldn’t make the decision in itself, but it’s kind of something we can keep in our hip pocket in case we need it. And I think it’s important for patients to understand and have a full and complete discussion with a transplant physician so they understand what that means. You know, it is a significant commitment of time and morbidity, and it comes with risks. 

It is also our only curative therapy. And so, it’s a double-edged sword, and I think informed patients and understanding what the options are are the gateway to any consideration of transplant.   

Primary vs. Secondary Myelofibrosis: What’s the Difference?

Primary vs. Secondary Myelofibrosis: What’s the Difference? from Patient Empowerment Network on Vimeo.

Are primary and secondary myelofibrosis different? Dr. Joseph Scandura, a specialist in myeloproliferative neoplasms (MPNs), explains the diagnoses and shares insight into each type.

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.

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Transcript

Katherine Banwell:

Dr. Scandura, would you start by introducing yourself?  

Dr. Scandura:

Sure. My name’s Joe ScanduraI’m an assistant professor at Weill Cornell Medicine in New York City. I’m a physician scientist. My laboratory studies blood formation, normal and malignant, and clinically I treat people with  myeloid neoplasms, particularly, and myeloproliferative neoplasms.  

Katherine Banwell:

Would you define myelofibrosis for us, and also provide an explanation of primary versus secondary myelofibrosis? 

Dr. Scandura:

Sure. Myelofibrosis is in the class of diseases called myeloproliferative neoplasms. And, really, its sort of marker feature is scarring in the bone marrow.  

Clinically, this comes along most commonly and fairly universally with anemia, and there can be abnormalities of both the white blood cell count and the platelet count, sometimes, often in the beginning, being too high. And then they can also become too low. 

It tends to be a progressive disease, or on the face on which it progresses is different in different people and there are a variety of different features that can go along with risk. But every individual, of course, is individual.  

A primary myelofibrosis is what we refer to when the diagnosis is made and there’s no antecedent, there’s no precursor malignancy. And so, you come in and the diagnosis is myelofibrosis, and we can’t find anything that came before it.  

Secondary myelofibrosis is what we refer to when somebody has another blood disorder, usually essential thrombocythemia or polycythemia vera, and in a small subset of these patients, the disease can change, what we call evolve or progress into a fibrotic phenotype or associated with the marrow scarring, and a lot of the features of myelofibrosis. Although there are some subtle differences between primary and secondary, they’re more similar than different in terms of their clinical features and how we treat them. 

How Does Inhibitor Therapy Work to Treat Myelofibrosis?

How Does Inhibitor Therapy Work to Treat Myelofibrosis? from Patient Empowerment Network on Vimeo.

What is inhibitor therapy? Dr. Joseph Scandura reviews approved JAK inhibitor therapies and explains how they work to treat myelofibrosis.

Dr. Joseph Scandura is Associate Professor of Medicine and Scientific Director of the Silver MPN Center at Weill Cornell Medicine. Learn more about Dr. Scandura, here.

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Transcript

Katherine Banwell:

How does inhibitor therapy work to treat myelofibrosis? 

Dr. Scandura:

So, the therapies that we have now that are approved therapies that are in this class are  ruxolitinib (Jakafi) and fedratinib (Inrebic) 

Both of these agents act to block signaling through a protein called JAK2. You can think of JAK2 as being part of the antennae system that a cell uses to communicate with the rest of the body. And so, our blood-forming cells have a lot of input from the body saying, “Okay, we need some of these kinds of cells, we need some of those kinds of cells,” and it’s a very adaptive system. And JAK2 is involved in a lot of the signaling in this as part of the antennae system.  

And what happens in the myeloproliferative neoplasms is that signaling is a bit excessive. 

And so, it’s like the volume is turned up too loud and the signaling is causing the cells to do things, make too many cells, make the wrong kinds of cells, and JAK2 is part of that signaling system. So, these inhibitors kind of help turn down the volume of the signaling in these blood-forming cells. They are drugs that have good activity in improving symptoms, they have great success in reducing the size of the spleen, they can be useful for a few years to many years. They are not curative therapies. We don’t think of them as therapies that change the course of disease, but they certainly have an important role in helping people feel better. There are other inhibitor therapies that are in clinical development. 

So, clinical trials of some of these drugs have really impressive activity, but none is approved yet by the FDA.  

I hope and expect we’ll have a couple more drugs available in the coming years. And there’s a lot of excitement in clinical trials in terms of some of the activities that are being seen, and really quite tolerable therapies, so not a lot of side effects for patients. And so, I think it’s kind of an exciting time for physicians and for patients and a lot more options now and, I think, a lot more options coming down the line.

Which Gene Mutations Impact Myelofibrosis Treatment Options?

Which Gene Mutations Impact Myelofibrosis Treatment Options? from Patient Empowerment Network on Vimeo.

Are there specific mutations that may affect myelofibrosis treatment choices? Dr. Joseph Scandura explains the factors that are considered when deciding a myelofibrosis therapy, including a discussion of high-risk and low-risk disease.

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.

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Transcript

Katherine Banwell:

Are there gene mutations that affect myelofibrosis treatment choices? 

Dr. Scandura:

Yeah. So, you know, the primary mutations in JAK2 or CALR or MPL in myelofibrosis aren’t that helpful in guiding therapy.  

And we look at the other genes for co-ocurrent mutations and those, as I was mentioning before, can come into one of two categories. So, there are a number of genes that we know tend to confer a higher risk, and so we call those high molecular risk mutations. And people who have higher molecular risk tend to have a more aggressive disease. 

Now, I want to add a word of caution because when we talk about patients and risk, we’re talking about groups of patients. For any individual, everything kind of boils down to it happens, or it doesn’t happen. And so, there’s nobody is 50 percent dead in five years, right. You either are or you’re not. And so, when we talk about risk, then we’re talking about risk of bad things happening like death or other complications of the disease, we’re trying to guide treatment decision-making and guided discussion based on a chance.  

But all of those things, for any individual, there are people who have high risk who do quite well for a long period of time, and people who don’t have high risk who don’t do as well as you think they should. And so, it’s a part of a conversation, it helps guide discussion, but it is not something carved into stone, and nobody has a perfect ability to predict anybody’s future. 

And all of these things are our best tools to estimate, but they are not a future; they are a possibility. And so, people who have higher molecular risk, we might think about more aggressive treatments than people who have lower molecular risk.  

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.

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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.