Tag Archive for: JAK2V617F

How Driver Mutation Research Is Advancing MPN Treatments

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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. 

MPN Treatment: What Is the Role of Biomarkers?

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MPN Treatment: What Is the Role of Biomarkers? from Patient Empowerment Network on Vimeo.

What role do biomarkers take in myeloproliferative neoplasm (MPN) treatment? Dr. Naveen Pemmaraju defines biomarkers and explains how molecular mutations play into MPN disease risk levels and treatment options.

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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Transcript

Katherine Banwell:

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.