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What Genetic Markers Mean for Your MPN Care

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Published on December 10, 2020

Can Genetic Markers Impact the Course of MPN Care?

Our understanding of myeloproliferative neoplasms (MPNs) has radically shifted in the past fifteen years, following the discovery of genetic markers in many cases of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF). There is a good chance you know what your markers are, but what do they mean for your care? Do they impact the type of treatment you are able to receive, your chance for progression, or other aspects of your care journey?

In a recent Answers Now: Facing MPNs program, patient and writer Ruth Fein talked to Dr. Ann Mullally, physician-scientist at Brigham and Women’s Hospital/Dana-Farber Cancer Institute, about translating genomics and prognostic models into everyday practices. Watch the segment to learn more!

This program is sponsored by Incyte and is produced in partnership with the MPNRF. This organization has no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | What Genetic Markers Mean for Your MPN Care

Ruth Fein: Let's start with the basics, Dr. Mullally. What are genetic mutations that we're here to talk about today? And in MPNs, are they always acquired rather than something we're born with?

What Are Genetic Mutations?

Dr. Mullally: That's a great question. So the mutations in MPN are acquired. So they are not something you're born with and they are something that are solely in your blood and your bone marrow. So when we talk about the blood and bone marrow, they're interchangeable because they're part of what we call the hematopoietic system or the blood system. And so the mutations that cause MPN and there are three main mutations, the JAK2 mutation, the CALR mutation, and the MPL mutation. These are acquired in the blood and they are not in your whole body.

So, for example, if we talk about, for example, the JAK2 mutation, so JAK2 is a gene, and we know that the JAK2 gene is very important in blood production, and then the mutation, the V617F is the location within the gene where that mutation occurs. So you can think of it as like the postcode, right? That’s that the precise location within the gene where the mutation occurs. And by virtue of having that mutation, that gene is turned on, it's more active than normal. So the more correct term, I guess, is mutation. There's a change in the sequence of the DNA that causes that JAK2 gene to be turned on.

Ruth Fein: What I think our audience really wants to hear about today is how these genetic mutations are steering us toward new and better MPN treatments.

Dr. Mullally: So, I think the first part about the genes and the mutations is that they give us understanding of how these diseases arise. In 2005, when the JAK2 mutation was discovered, it was found in all three diseases. And that was really critical, because now we understood that the reason these diseases occur, we understood why they were related, because we had a common genetic origin. And so it's like, you can't really work out how to treat something and fix something if you really don't understand what causes it.

And so then, in 2006, we had the MPL mutation discovered in 2013, the CALR mutation. And it turns out they all converge on what we call the JAK-STAT pathway. And so they're really fundamental to understanding how these diseases are caused. And therefore, that's the first step before you can work out how to treat things, right. So maybe I'll stop there, and I could move further if you want to get into more details.

Do Genetic Markers Have an Effect on Disease Progression?

Ruth Fein: What about progression generally? How much are we learning about progression and genetic markers?

Dr. Mullally: So broadly speaking, JAK2, MPL, and CALR are what we call mutually exclusive, which means if you have one, you generally don't have the other. Now, there are rare examples that have been described, and I have a few patients in my clinic where they coexist. But generally, if you have one, you don't have the other. And we think of these as the causative, or what we call disease initiating mutations, right? They are acquired in a single stem cell in your bone marrow, and they result in overactivity of this JAK-STAT pathway, and that generally results in increased blood cell production, right? White cells, red cells, platelets, sometimes one, sometimes all depending. Sometimes progression can happen through the acquisition of additional mutations on top of those mutations, and sometimes it can happen without that.

For example, you mentioned ET to PV to MF. We think that's probably related to the amount of cells that have the JAK2 mutation. So having a higher burden of mutated JAK2 cells pushes you further into polycythemia vera and even into myelofibrosis. So there are many factors that can contribute to progression. We think the genomics or the genetics is a major one, and some of it relates to these JAK2, CALR and MPL genes, and some of it relates to other genes.

What Does it Mean to Be Triple-Negative for Genetic Markers?

Ruth Fein: What about what people... we are calling triple-negative? So what do we mean by triple-negative and how do triple-negative ET patients, for instance, factor into the treatments, such as JAK2 inhibitors or ropeginterferon that you haven't really touched on yet?

Dr. Mullally: Right. So triple-negative basically means that you don't have JAK2, you don't have CALR, and you don't have MPL. And approximately 90% or more of people will have one of those three mutations. And then the remainder, which is less than 10% are so-called triple-negative. And that's always a challenge because it's like when we worked out the JAK2 was the causative gene, it's so clear, right? It's like you have the mutation, and therefore, it's definitive, right? In the triple-negative group, you have to make sure that, for example, if somebody has a high platelet count, that it's not a reactive cause, and exclude all those reasons, some type of inflammatory process that could be causing a reactive cause.

And then to make the diagnosis in that situation, it really hinges on the bone marrow biopsy, that the bone marrow shows evidence of myeloproliferative disease in the bone marrow because we don't have a genetic marker to make the definitive diagnosis. And so it really hinges on the bone marrow biopsy looking consistent and there's certain features that the pathologists can say, “Okay, this looks like myeloproliferative disease in the bone marrow,” versus, this could just be reactive inflammation in the bone marrow. So the triple-negative group is always a little bit harder because you want to be... it's less easy to be fully confident of myeloproliferative disease as the cause as compared when you have one of the gene mutations. And then in terms of...

Can JAK2 Inhibitors Be Used on Triple-Negative MPN Patients?

Ruth Fein: Let me push you just a little bit toward treatment on that same question. So much of what we’ve learned is how to inhibit JAK2, right? If you are triple-negative, are we treated the same way? Are they treated the same way since we're talking about JAK2 inhibitors? And so how are they treated differently?

Dr. Mullally: Yeah, so for example, the JAK2 inhibitors, if we think about where they use most, they're approved by the FDA, the Food and Drug Administration for the treatment of myelofibrosis, right? And then they're approved for the treatment of polycythemia vera, where you're resistant or intolerant to hydroxyurea (Hydrea). So the most commonplace JAK2 inhibitors are used is in myelofibrosis. And so they can be used in a triple-negative patient if you're confident that the diagnosis is myeloproliferative disease, and that usually comes down to the clinical situation. Are the blood counts, is the pathology, the bone marrow biopsy, consistent? Maybe the patient has a big spleen. You need to be confident the patient has myelofibrosis, and then yes, they can be used in that situation.

The thought is that the triple-negative patients probably have activated the JAK-STAT pathway in a more uncommon way, right? That the JAK-STAT pathway is activated, but that it's not through those three main mutations. It may be actually through, for example, there is some evidence that the JAK2 is gene is mutated in triple-negatives, it's just not at that very common location, the V617F location, but at other sites in the gene. And when we do the sequencing, we just focus on the V617F region because that's so overwhelmingly common that, that's the region we focus on.

So yes, they can be used if you're confident of the diagnosis, and it's likely that probably the JAK-STAT pathway is activated. And remember the original JAK2 inhibitor trials on myelofibrosis were done before calreticulin was discovered. And it was an enigma of why were they working in people who didn't have the JAK2 mutation?

And now we know it's because the calreticulin mutation also activates the JAK-STAT pathway. And so that pathway is really central to the origins or the pathogenesis of these diseases, is the medical term.

What Genetic Tests Should All MPN Patients Undergo, and How Often?

Ruth Fein: Elaine and Marie both sent in similar questions though they have different mutations. The question is which markers need to be repeated to determine progression or regression of the condition, and at what frequency do you recommend repeating bone marrow biopsies and molecular studies?

Dr. Mullally: I would say broadly speaking, at diagnosis, it's good to do everything at that point. And then generally, we repeat things if something changes. And that can be a clinical change, the patient feels worse in some way, or now their spleen is really big, or now just something has changed substantially in their clinical scenario. It can be that something changes in their labs. So before their counts were very high, now they're gone very low. It could be that the type of white blood cells that we see are different, that there's more immature white blood cells, those type of things. But generally, we don't sequentially monitor gene marker tests preemptively. We do it at diagnosis and then if something changes or evolves.

Now on clinical trials, sometimes they do that because they're trying to get a sense of, is the drug hitting the target? That type of thing. But in general, in standard clinical practice, at diagnosis, we tend to do quite a detailed thing at diagnosis to make sure we have the right diagnosis, all of the criteria. And then if something changes or evolves over time, we repeat them.

Ruth Fein: How important is it to run the allele burden blood test? What information does it provide? Is it an accurate predictor of the course of ET?

Dr. Mullally: Yeah, so this is a great question, and it comes up quite a lot. So just so everyone's on the same page, let's define what allele burden is. So this basically mostly pertains to the JAK2 mutation, but it could pertain to any mutation. And what it does is, so, to make the diagnosis of any of these diseases, you just need to demonstrate the presence of the mutation, right? So you actually don't need allele burden. And in most cases, we don't do the allele burden. For example, the Brigham, we do a PCR test that says the mutation is present or absent, right? And that's sufficient to make the diagnosis.

And in these newer tests, these next ... what are called next-generation sequencing tests, they do give you some quantitative measure, right? So, what they'll say is, for example, we sequenced the region of where the JAK2 mutation is 500 times, and in 250 times, we found mutations — terrific chance we did, right? So, that could mean that half the cells have one copy of the gene mutated or a quarter of the cells have two copies of gene mutated, right? So, that's the information we get.

There can be a lot of variability depending on whether you sequence the blood or the bone marrow, depending on what the blood counts are at the time you do the sequencing, depending on the methodology that's used. So, for example, you can do this gene sequencing, DNA, NGS next-generation sequencing test, it can be done during what's called PCR, there's really no standardized gold standard in the way it's done, and it can vary quite a lot.

And so, in general, I don't pay too much attention to the allele burden. We know that it can change over time, that it can be higher for example, in polycythemia vera than in ET, that it can be higher in MF than ET. But it's not really something that I pay a lot of attention to. And the most times I think it's used is again, in clinical trials, where it's measured sequentially, typically by the same method to try to understand what is the drug that's understudy doing to the cells that have the mutation?

But in clinical practice, other than to say the burden is greater than 50% or less than 50%, I don't think it's that meaningful and we don't certainly monitor it sequentially in standard clinical care, and you don't need to have it measured to make the diagnosis.

Do Genetic Markers Have an Effect on Treatment Plans?

Ruth Fein: So, that's actually a great segue into the next question. This is someone who has MF and he says his name is Dave. And he says, "I know my DIPSS score," which stands for, anybody doesn't know, it stands for Dynamic International Prognostic Scoring System, which is what of course you were talking about. His question is this, while appreciating the importance of individual patient experience, clinical symptoms, et cetera, how much weight should genetic markers be given in formulating a treatment plan or taking a long view of his diagnosis?

Dr. Mullally: Yeah, so I think it very much comes down to the overall situation. So for example, the genetic markers generally are a way to indicate if there's a reason to be more concerned, right? Because we can look for mutations that are called high molecular risk mutations, right? We can look for those and pick them up, the idea is before they start to cause problems or have manifestations clinically. So back before we had these markers, we would be waiting on something to happen to the patient to get a sense that something was not going well. We would start to see them becoming unwell, the blood counts will go up, their spleen will get big, something would happen, right? The idea of the genetic markers, is to say, can we pick this up earlier before things start to change clinically because we have these gene tests that can help us work out if that might happen?

And I think that's really most important, where we're considering more aggressive therapies like for example, a stem cell transplant. So for example, if somebody is young, and I remember the only currently curative therapy we have from myelofibrosis is a stem cell transplant, the only way we can replace those mutated stem cells is to give you new ones, then sometimes we try to get a sense of, is this something that's going to be problematic or not earlier in the course of the disease? And that's where I think it can be particularly important. Some people want to know, right? Some people want to know just because it's important for them to plan their life and those types of things.

And then sometimes there are some mutations, for example, the IDH mutation, for which there are drugs that inhibit that. There are IDH inhibitors that are used. So sometimes in a situation where maybe the JAK2 inhibitor has stopped working, things are progressing, you're considering a clinical trial, you might want to do with them to see if there's any what we call, actionable mutations. Mutations for which we have drugs that inhibit that mutation. So that might be another particularly relevant situation where these additional mutations can be helpful.


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