Living Well with MPNs – What You Should Know About Genetic Mutations

What You Should Know About Genetic Mutations

Living Well With MPNs: What You Should Know About Genetic Mutations from Patient Empowerment Network on Vimeo.

Should you get a genetic test? JAK2, MPL, CALR, ASXL1: Mutations associated with myeloproliferative neoplasms (MPNs) can bring up lots of questions. What do they mean, and how do they impact your disease? The goal of this webinar, featuring Dr. Alison Moliterno from Johns Hopkins School of Medicine and Dr. Stephen Oh from Washington University School of Medicine, is to help patients understand genetic mutations.


Transcript:

Andrew Schorr: Hello and welcome to this Patient Empowerment Network program, produced by Patient Power. I’m Andrew Schorr joining you from Carlsbad, California. Over the next hour we’re going to talk about something that’s very personal to me and probably to you, and that is the whole idea of genetics related to living with an MPN. What does it mean? Does it change over time? What is your version of an MPN? What does it mean for prognosis? What does it mean for treatment? What does it mean for clinical trials opportunities? So we’re going to be discussing all of that.

I want to thank our sponsor, Incyte Corporation for supporting this educational activity. We’re going to cover the country and we invite your questions as we go along. Send them to MPN@patientpower.info. Many of you have. And remember if you have to bow out at some point, the replay will be available and we’ll have video clips. So we’ll reach literally a few thousand people living with MPN worldwide, and we’re happy to do that.

Let’s get started. First I want to introduce you to one of our medical experts who’s joining us. He’s been on programs before. He joins us from Washington University and the Siteman Cancer Center in St. Louis; that’s Dr. Stephen Oh, who is an MPN expert there. Dr. Oh, thank you so much for joining us.

Dr. Stephen Oh: Hi, Andrew. Thanks for having me.

Andrew Schorr: Thank you, Stephen. Okay, let’s go from St. Louis to Baltimore, Maryland and the Johns Hopkins University Medical Center and another expert in MPNs who’s been with us before, and that is Dr. Alison Moliterno. Dr. Moliterno, thank you so much for being with us today.

Dr. Alison Moliterno: Thank you, Andrew. Thank you for having me.

Andrew Schorr: Sure, pleasure. We’ve got a lot to cover. And then also I want to welcome back one of the members of our community, someone who was diagnosed many years ago, a couple of decades ago with ET, and then a year ago it became myelofibrosis. She’s a preschool teacher in Peoria, Illinois. She’s been with us on our programs before; Marsha Krone. Marsha, thank you for being with us once again.

Marsha: Thank you. Hi, Andrew.

Andrew Schorr: Marsha, let’s visit for a minute. I was diagnosed in 2011 and then eventually had a genetic test which came up with a bunch of results. One of them for me, if I get it right, JAK2V617F.

I had no idea what that was, and then a couple of other genes that to me seemed kind of like alphabet soup. And I had one of the peers of these experts here, Katrina Jamison. We went over it and she said I think it’s the JAK that’s kind of driving things. We’re going to talk about what are the driver genes, and what may not be, or what do we know at this point. Marsha, you had a genetic test, too. What did it say?

Marsha: My genetic test came out as Calreticulin type 2.

Andrew Schorr: Okay, so we’re going to figure out what that means. Dr. Oh, let’s start this way. People think genetics. I know genetics maybe had something to do with being bald, and I see you have a similar hairline; or dark hair, or brown eyes, or whatever. Hereditary genes; are we talking about that or are we talking about something different?

Dr. Stephen Oh: That’s a basic question that comes up with almost every new patient that I see.

The short answer is that when we’re talking about genetics with relation to the MPNs, we’re not talking about those kind of things that you’re born with that may affect your hairline and whatnot. These are genetic mutations that are acquired over time that you’re not born with; they’re not passed down to your children or your relatives, etc. So that is a very important distinction that I try to make clear with every new patient that I see.

Andrew Schorr: Okay, and one follow up question to you. People say okay, Doc, what gave me this genetic injury, if you will, to lead to these illnesses? Do we know?

Dr. Stephen Oh: That’s another question I cover with almost every new patient; that I think for that one I guess the answer is a little less satisfying. My answer is that for the most part it’s random chance.

What I mean by that is that we know particularly from research that’s come out n the last five or so years that all of us acquire mutations randomly over time as we age. But fortunately for most individuals, those mutations land in spots where they really have little to no consequence. But for those that, for instance, acquire the JAK2V617F mutation or acquire a Calreticulin mutation, that really becomes most likely the main driver for what ultimately becomes an MPN.

Patients of course ask did I do something wrong, was I exposed to something? And while we can’t necessarily exclude that those are factors, I think for the most part it’s that just kind of randomly these mutations landed in the wrong place.

Andrew Schorr: Dr. Moliterno, we’ve mentioned a couple of these onco genes I think you call them – cancer genes, the JAK2 gene and Calreticulin type 2, I didn’t even know about that.

Can you first of all rattle off some of them just so we know the landscape of what are genes that seem to be associated with MPNs today, knowing that this will probably expand?

Dr. Alison Moliterno: I always like to tell patients a little bit about the history when these were first diagnosed because we talk about them now as if they’re common knowledge, but they are really quite recent in our understanding. We’ve known about the myeloproliferative diseases for more than 100 years, but it wasn’t until 2005 until the driver of many of the diseases was understood to be JAK2V617F. So that discovery occurred in 2005. Before the JAK2 discovery, we didn’t understand really if it was acquired mutations and what genes were involved. JAK2 is the most common of these.

If you look at 100 patients with the classical MPN, meaning PD, ET, and myelofibrosis, 75 percent overall of those individuals will have the JAK2V617F mutation. Not long after the JAK2V617F mutation there was a discovery in mutations in M-P-L or MPL. That accounts for about 5 percent of those 100 individuals with either ET or myelofibrosis and then in 2013, that was the discovery of the calreticulin mutations that comprise about 20 percent of individuals who have ET or myelofibrosis. So 2013, that’s fairly recent and those are the three drivers.

I like to say that if you could put the same mutation, the JAK2V617F or Cal or MPL mutations that we see in our patients, if you could put those, say, in a mouse; they would drive a similar disease in the mouse so that you get polycythemia vera in a mouse if you make the mouse have the V617F mutation. That’s how we’ve kind of come to understand that they drive the disease. They may not drive all aspects of it but they drive the basic process.

Andrew Schorr: I know there’s another gene that people have seen too; ASXL1. What is that one?

Dr. Alison Moliterno: In addition to these drivers we’ve also discovered a lot of genes that seem to modify the MPN or associate with certain subtypes of MPN. So for instance I said usually JAK2 MPL or CALR can all drive platelet count high and give a disease like ET. Then what happens when patients develop myelofibrosis? We find that perhaps other lesions are acquired.

Those are genes that don’t drive myeloproliferation so much but they seem to drive the way that the chromatin or the nucleus is managed; they seem to maybe set up the other aspects of MPN that associate with myelofibrosis. And ASXL1 is probably the most common additional genetic lesion or acquired mutation that occurs in individuals with myelofibrosis.

Andrew Schorr: Okay. Dr. Oh, people may be tested and we’re going to talk about who should be tested and when. How do you know what’s the driver gene? And it sounds like this continuation of identifying genes just keeps going, too.

Dr. Stephen Oh:Certainly Dr. Moliterno gave a nice circle overview of when the three primary driver mutations were discovered.

We’re sort of lucky now that in today’s day and age we kind of look at this now as standard testing. So JAK2, MPL and calreticulin so much so that many physicians including myself, we kind of go about this in an algorithmic fashion. So for instance if I have a patient with newly diagnosed myelofibrosis, I’ll start by screening for the JAK2 mutation; if that’s negative, go to Calreticulin and if that’s negative go to MPL.

And so with those three genes, the majority of patients with any of the three main MPN subtypes, whether that’s QV, ET, or myelofibrosis; they’ll be positive for one of those three. There’s a subset that’s at least on the order of 10 to 15 percent of patients with ET and myelofibrosis who will be negative for all three of those mutations, what we’re now calling the triple negative category. But the vast majority of MPN patients will have one of these three mutations which we consider the main driver of mutations.

So, in some sense again we’re sort of fortunate that it’s become almost straightforward in terms of at least the top level genetic testing for these diseases.

Andrew Schorr: So that was my question to you, Dr. Moliterno. Some people have maybe had fights with their insurance company or their doctor as related to testing. How do you view this now and how could it be positioned on how it’s really not elected, if you will, but essential to get a clear picture of an individual patient’s situation?

Dr. Alison Moliterno: This comes up in my practice and I’m sure Dr. Oh’s practice all the time, in that in the olden days before our understanding of what causes these diseases, and again the cause was these acquired mutations and in the olden days we would use histology, looking under the microscope, looking at blood counts and sort of put a name to this polycythemia vera and myelofibrosis.

But within that was such a vast variability of what the disease actually was, that that name really did not tell us too much. Now, we’ve really come to understand that what you have is defined by these molecular lesions. They’re not just of academic interest; they actually really tell us quite a bit about what you’ve got, what your prognosis is, and where it’s going. So physicians, we really can’t function and counsel patients appropriately without this knowledge. So there’s no longer elective or of interest; it’s really critical in defining what you’ve got.

Andrew Schorr: Okay, everybody. You heard it, so this is what you’re advocating for with your MPN specialists, which hopefully you have like the two with us. This is standard operating procedure; there shouldn’t be nay question with an insurance company or anybody to help you and your doctor know what you’re dealing with

But then the next question is, Dr. Oh, where are we now even in research, where things are headed so there will be treatments that line up with the different genetic situation?

Dr. Stephen Oh: I’ll start my answer to that question by going back to when the field began to develop inhibitors of JAK2 for the treatment of patients with MPNs and extrapolating from other diseases, I think there was an assumption that the patients that would respond best or if at all to JAK2 inhibitors would be those that carry the JAK2V617F mutation. What we now know quite clearly is that even those patients that do not carry the JAK2 mutation, they also tend to respond to JAK2 inhibition. So again in the case of myelofibrosis, patients who are calreticulin mutants, they also respond to JAK2 inhibitors as well.

So that’s an example where I think in a good way the use of those kinds of treatments is not limited or defined or restricted mutational profile. But otherwise in terms of the research front, identifying or defining treatments specific to different mutations, we haven’t made a lot of headway there. For instance, you can imagine now we have identified the calreticulin mutation in many patients with MPNs; can we devise a treatment specific for that? So while again on the one hand like I mentioned, it’s a good thing that those patients do respond to JAK 2 inhibitors; can we come up with something very specific to calreticulin with the patients there?

There are certainly a number of research groups that are working on that kind of question, but we currently do not have anything specific in that regard.

Andrew Schorr: Dr. Moliterno, I want to get a question from you about that because I’m sure you’re asked. Somebody says well – Marsha could come to you and say well, I’m CALR so what do you have for me? And/or you also mentioned triple negative, and I think often I’ve heard that term in breast cancer; women who were triple negative there, and say what do you have for me in that situation? So talk to us a little bit about those situations, and does it vary now with treatment approaches yet?

Dr. Alison Moliterno: I think another aspect of this is we may not today have the specifically targeted treatment but as Dr. Oh mentioned, what we’ve learned is that these three main lesions, CALR, MPL, and JAK2 all seem to over signal or work their effects through this JAK pathway.

So even though you may not have the JAK2 mutation but you have the CALR, it seems like the end result of over signaling is in the same pathway and therefore JAK inhibitors would be beneficial in individuals who have that over signaling pathway. So that’s one thing we’ve taken away; that while even though we don’t have – and that’s a good thing because that tells us that inhibiting this pathway overall will benefit the majority of individuals with these lesions, whether they’re JAK2 or CALR or MPL.

The other thing about the profiling is how much of the mutation you have. So another I think we’ve learned is that we can measure the amount of these mutations, and that’s a variable across patients and gives us quite a bit of information about – again – the type of lesion, disease you have and gives us  better information about the prognosis and why you might have a little more fibrosis than someone else.

So again, the type of lesion you have and the amount; we’re now learning to use that information. I think another thing we’ve learned is these terms triple negative, which is a term that we understand okay, that means you don’t have any of the three drivers that we know of.

But as we’re learning more about extended mutation paneling or doing different tests to look at the entire genes, we’re finding that most of those individuals really do have lesions in the JAK2 gene, or the CALR gene or MPL that maybe aren’t in the specific areas that the test was sent for. So that’s another benefit of this revolution in being able to define these lesions personally so that your disease really can be diagnosed.

Andrew Schorr: Okay Marsha, you’ve been sitting there quietly and I wonder, is this making sense to you? You’re my co-host with this; is it making sense?

Marsha: It does make sense. When I first was diagnosed, they just said you simply have ET because you have it. Then they discovered more mutations. I like to know everything about how my body is working, so I wonder how valuable it is to have additional genetic testing to see if you have other mutations that may affect prognosis?

Andrew Schorr: Right. So Stephen, and also like serial testing at some other time? She went from ET to MF over many years, so when do you test again or how does this change?

Dr. Stephen Oh: Speaking sort of broadly at first, the more extensive genetic testing which is available through numerous laboratories now, which can test for any – quite often these panels went through 20 or 40 genes; some of them hundreds or more.

The use of those in the clinic has evolved pretty rapidly over the past three, four, five years. In my own practice five years ago I was certainly not routinely recommending that kind of testing. But today, particularly with patients with myelofibrosis, I am doing it much more frequently and the question of course is as you raised; what utility does it have in terms of prognosis.

And there especially I think in myelofibrosis, is where more and more literature has come out giving us a better handle on what effect these different mutations might have on prognosis. That’s why more and more I’m beginning to recommend this kind of testing for my patients with MF.

In the case of QV and ET, it’s a little bit further behind in terms of data to indicate what these different mutations might mean, but we have also seen more literature come out, not as often but do consider that kind of testing for those patients as well. In every case it’s kind of an individualized discussion with the patient. I always start out with how much do you want to know. Marsha said I want to know everything, so that’s the kind of patient where you say alright, well, maybe let’s do this.

Others say well, I don’t really necessarily know I’m going to interpret this; it’s alphabet soup. Do I necessarily want to know what the statistics say to expect in 20 years, etc.? Again, it’s an individualized decision with every patient.

Andrew Schorr: Dr. Moliterno, there was another patient who was going to join us who couldn’t make it because she’s being scheduled for a transplant. She’s getting her life in order for that; someone with I think myelofibrosis in the Seattle area.

But she did have three mutations identified, so let’s see if this makes sense: ALX1, if I get it right, TP53 and SFB1, if those are other ones? So the fact that she has this sort of alphabet soup, does that mean that that meant you’re headed for transplant because that shows up? You know, one knows is more – more weighty, if you will.

Dr. Alison Moliterno: This is knowledge that we’re kind of pulling in as we speak, and that the meaning of more than one mutation, different types of mutations do seem to have prognostic significance.

So as we’ve learned that generally the more mutations you have, more individuals at a certain point of time generally is concerning. It means that there’s a lot going on in that stem cell and that maybe there’s some instability to allow these mutations to occur. And then it does matter which type. Some mutations seem to have more independent prognostic than others. ASXL1 tends to be one that is seemingly more associated with developing myelofibrosis. SF3B1, one of those she has, may be a less negative prognostic indicator.

But again, these are important and having three at once is a concern, and it sounds like a reasonable plan to move forward with transplant because we understand that we don’t really have a medicine that can address all of those lesions and that this is more high risk disease.

Andrew Schorr: I want to remind our audience a couple of things. One is you’re hearing how sophisticated the testing is, and then you can imagine the interpretation.

We have two noted experts. The typical hematologist is not going to see this very often. So whether you go to Washington University, I go to UC San Diego, Marsha goes to the Lurie Cancer Center, Dr. Moliterno is at Johns Hopkins. You know some of the others where you go; you want to consult with an MPN specialist. As the data comes back, what does it mean for me now or on your journey in the future.

The other point I wanted to make is of course we want to take your questions. So send them to MPN@patientpower.info and our wonderful MPN community manager, Jamie, is standing by and she’ll be forwarding these to me. Obviously, a lot of you ask very personal questions; what should I do, Dr. Moliterno, Dr. Oh; I’ve got XYZ. And that’s not fair to do that here, so that’s our disclaimer. You want to go back to your MPN specialist – it could be one of them – to discuss it.

We did get some questions in earlier. Dr. Oh, Tammy wrote in and she said can you provide more information on being PV JAK2 negative? She says I know we’re limited in number compared to other patients. It would be nice to know the basics. How much more different are we and is our treatment any different? So, JAK negative PV.

Dr. Stephen Oh: That’s a great question and it’s a challenging question. I would say that in part because we know that in the case of PV, at least 95 percent or greater of patients with bonafide PV carry the JAK2V617F mutation and it’s at least 95 percent; it may be higher than that. And even those that are negative to the JAK2V617F mutation, there’s another small group, probably less than 1 percent, who carry an alternative JAK2 mutation, an exon 12.

 So between those two, patients with PV, again the vast majority do have a mutation in JAK2. That does leave a small sliver that you could call JAK2 negative PV, and there – it’s sort of being a skeptic – the first thing I say when I’m asked to evaluate a potential case like that is am I convinced that is the correct diagnosis? Do they truly have PV versus a potentially secondary cause of erythrocytosis?

And so there, sort of again you have to rely on the old school diagnostic criteria; do they otherwise have the features of the disease? Does the bone marrow, is it consistent with the diagnosis? Are they like a classic patient in that they have a low epo level, etc. But to get to more specifically to the question, if you’re convinced that that’s the correct diagnosis, essentially I treat the patient the same way I would treat a JAK2 positive PV patient.

In other words, I would use the same kind of treatment calls in terms of a hematocrit less than 45, treat them with cytoreductive therapy and the appropriate circumstance if they’re considered high risk, if they have had a prior history of thrombosis; aspirin considered standard therapy for these patients. Again, if I do believe that is the correct diagnosis, I essentially treat them similarly to patients with JAK2 positive PV.

Andrew Schorr: Okay, and Alison, do you concur in that?

Dr. Alison Moliterno: I do. I think we have a name for the disease, polycythemia vera, where you make too many cells due to an inherent stimulus of the bone marrow. I think now in this age, we are really coming to redefine PV as the disease that has mutations in the JAK2 gene. I’m always concerned when someone has been diagnosed with JAK2 negative PV because as Dr. Oh says, maybe they have something else.

A couple circumstances that I’ve observed is that sometimes the diagnostic testing, when it was done and it was done with JAK2V617F testing that was not sensitive enough. So again we have this issue of how much of this do you have? And some PV patients can have very low levels of the JAK2 mutation that if you use an assay in a laboratory that wasn’t very sensitive and you only detected levels of 10 or 20 percent, they would be read out as negative. That’s happened in my practice a few times where patients went high and low all over the place trying to get a diagnosis; JAK2 negative. Finally when a more sophisticated or sensitive test was done, they’re positive.

The other issue is that there are other mutations aside from V617F in the JAK2 as Dr. Oh said; there’s exon 12 and then there are some others in various parts.

So when we do some of this more expanded molecular profiling, the laboratories are able to look not just at the V617F site, which is where most tests – they only tell you yes or no at that site; but they’ll look at the entire part of the coding region of the JAK2 gene. You’ll find patients who have an unusual mutation down the way that’s like – And I think it’s important because there are some people who really don’t have a myeloproliferative neoplasm; they have something else and they’ve been told for 25 years that they have PV.

And it is nice to either make that diagnosis or not. And so I think Stephen has been in that situation also, where maybe they were labeled because that was the best information we had at the time, but they really should be reevaluated.

Andrew Schorr: And I think that’s the point for our audiences. You with the best testing, with the best specialists you can get to, you want to know what you’re dealing with; what is your situation.

Here’s a question we got so Marsh, just for you. You mentioned at the beginning, Marsha, that you have CALR type 2. Can you describe that? So let’s make sense of that. There was a support group leader, Kim, who wrote in. Kim wanted to know how do CALR types 1 and 2 manifest and progress? Dr. Oh, what’s the difference between CALR1 and CALR2? What does it mean?

Dr. Stephen Oh: There are a variety of different types of mutations in the calreticulin gene, but the so-called type 1 mutations are the most common and the type 2 are the second most common; slightly different. Functionally they may have slightly different effects, although I think as a class, these calreticulin patients have more similarities than they do differences.

But there has been some literature to suggest that overall, calreticulin mutations are felt to be associated with a more favorable prognosis, at least compared to patients whoa re JAK2 mutant or perhaps triple negative. But specifically those that have the type 1 calreticulin mutation, the data is strongest that they have the most favorable prognosis. So based on that, you could say – the simplest thing is to say if you’re calreticulin mutant, you have a more favorable prognosis.

But perhaps the more nuanced is that that is particularly so for those that have the type 1 calreticulin mutation. In Marsha’s case it’s interesting, and to me a little bit of a paradox in that type 2 calreticulin mutations are, relatively speaking, more common in ET than they are in myelofibrosis.

So in that sense it’s perhaps not surprising that she has the type 2 calreticulin mutation. But overall, of course, ET has a more favorable prognosis than MF so it’s a little, in that way, a bit of a paradox. And the other way to look at this, and this has certainly happened for myself and I’m sure it happens with Dr. Moliterno is these patients with ET or myelofibrosis who were diagnosed many years prior, before calreticulin testing became available, you then tested for the mutation and confirm they were calreticulin once that test became available.

It’s one of those sort of: well, I just confirmed what I already knew which is that they had a more indirect course over these many years.

Andrew Schorr: It’s just amazing. Fortunately we can talk about this, and hopefully the word better prognosis sounds ] great.

So I, with primary myelofibrosis diagnosed with the JAK2V617F gene, Dr. Moliterno. But when you talk about prognosis, now you’re introducing medicines that we haven’t had that long; like for me. I’ve been on ruxolitinib now four and a half years and it’s been working. So how do we – when you talk about prognosis related to genes, though, that relates to what treatments you have, right?

Dr. Alison Moliterno: Right. We have a lot of work because these genes do have meaning; what version you have, and they’re going to have meanings in terms of prognosis but hopefully also we’ll start to gain information about really how you respond to therapy. So far, it seems that it doesn’t matter too much whether you have JAK2 or CALR mutation in response for  ruxolitinib.

But I think as we extend or molecular profiling, maybe we will learn that some lesions are less responsive or less favorably responsive to have some of these agents, and might be more responsive to agents that we have in the future. So I think we have to use this information both diagnostically, prognostically, and also just kind of monitoring our treatment expectations to some of these new agents.

Andrew Schorr: Right, it’s a moving target and I know you have a few things in trials. So just to tie the knot on testing, Dr. Oh; somebody wrote in and said: look, my doctor doesn’t require genetic tests. Where do I start and how do I ask for it? Because we’re hearing the two of you saying it’s pretty standard for you to get a clear picture of what the situation is. So is, how shall I say it, self advocacy related to testing today for an MPN patient important?

Dr. Stephen Oh: I think it definitely is. These diseases, while they’re not super rare, they’re not as common as hypertension or whatnot. When you go to a hematologist or oncologist who does not see very many of these types of patients, they might not be TransDigm on the testing that’s available. And so from that standpoint, I think certainly self advocacy is important. This has been emphasized already but getting to an MPN specialist is important.

If we’re talking about in the workup stage, it’s just sort of imagine different scenarios. There certainly could be a situation where the physician, whether they’re an MPN specialist or a more general hematologist or oncologist; they may not feel there’s a testing and that could certainly be the case.

[00:54:02]

But if there is a strong suspicion of a possible MPN, then I think there’s no question this kind of testing should be done. Even in the situation I’ve encountered with some patients where the insurance may require preauthorization, if you go through that it’s almost never rejected.

Andrew Schorr: Dr. Moliterno, here’s a question we got in from Jane. Jane writes: my understanding is that JAK2 is an acquired genetic mutation, and you both spoke about that; not inherited so we’re clear on that. Is it known what variables cause this mutation? I got the impression from what Steve said, no. But then she asks; can this gene expression be reversed?

Dr. Alison Moliterno: Right. First, why did this happen. I always joke with my patients; I tend to think MPN patients tend to be the most highly educated, intelligent, beautiful and have healthy lifestyles; why would they get this? MPN or not, disease is a lifestyle or other processes that we can sort of point to. I think in terms of if we just focus on JAK2V617F, that’s an acquired mutation in the bone marrow stem cell, but we’ve come to learn that this is a fairly common mistake, acquiring this mutation.

So if you look at my bone marrow stem cells, you can find evidence that this occurs frequently as a mistake; almost like a typing error that we all make on our keyboards, and that this happens at a fairly high rate. Most of the time as Dr. Oh mentioned, it is deleted or it’s in a cell that doesn’t have a long lived lifespan so it really doesn’t propagate in the bone marrow.

 Some fascinating studies looking at the cause of this; what are the factors? So, this Danish study looked at 43,000 individuals that participated in a healthy Danish lifestyle activity. They said they had stored DNA samples from blood. These were well people; they did not have myleoproliferative disease. But they found that they could detect the JAK2 mutation, V617F in a reasonable percentage of these well individuals, and that this was more prevalent the older they got. So that over 80, I think it was .2 percent of individuals actually tested positive for this. They were able to look back and show that yes, most of these people didn’t have an MPN, although some of them did have higher blood counts.

When they followed them, some of them did go on to develop MPN. But the point of that is wow, this is a common, natural occurrence and it most strongly associated with aging. Most MPN patients are in their mid 50s when they’re diagnosed; some very young and some are much older. So again, while gee, 50 isn’t that old, 50’s not that old. So again, there must be other factors that allow that to occur. And these large population studies, I think smoking has been an association; again maybe helps accelerate that mutation growing.

There’s host factors, and that maybe we have reasons that we will make that mistake more often; s genes that we have perhaps that we’ve inherited that influence how well we have integrity in our DNA. So that just gets a little to why did this occur.

Andrew Schorr: What about turning it back, though?

Dr. Alison Moliterno: Right, turning it back and I think this is another thing that is important. Again, when we think about surveillance, we do know there are some therapies that can specifically turn down or squash that clone and I think many of us have heard or even experienced patients who are on interferon, or pegasys, pegylated interferon. And we can see that if JAK2 disease can go into a hematologic remission and even molecular remission that the JAK2 clonal burden reduces and may even go to zero.

This has also been shown with CALR mutation positive individuals in small studies that perhaps we can suppress that. So we hope someday to – it’s still a little frustrating; not all patients have that benefit. It’s not clear which patients will go into these molecular remissions of turning it down.

But I think we will get there and we hope that JAK2 inhibitors would have that effect. I think the data still there are not pointing in that direction, but I think we will ultimately be able to actually target that clone and control how it expands and turn it back.

Andrew Schorr: So Stephen, take us into your labs and into the research that’s going on around the world. How fast is this changing now? Alison talked about 2005 with JAK2 discovery and you had CALR and some of these others. What’s the rate of change now?

Dr. Stephen Oh: I think there’s different perspectives you can look at this. For those of us that are doing laboratory research, we feel in the field that things have progressed quite rapidly.

To go from 2005 discovery of the JAK2 mutation to small molecule inhibitors going into patients I think within two years or less to this one drug being FDA approved a few days later; that pace of discovery and development has been quite rapid. The identification of the calreticulin mutation in addition to MPL, those are really landmark discoveries in this field.

For patients, I think the perspective might be that wow, I wish it could move faster and we kind of know as a class in general what JAK inhibitors do; can we move onto the next level, or next phase, or next class of treatments? And I think there is where my long term outlook is very optimistic, but in the short term we don’t really have that  kind of next candidate clearly identified as to what to do next after the JAK inhibitors.

Andrew Schorr: Dr. Moliterno, we always talk about clinical trials. This relates to the progress you all are trying to make. We’re your partners in that. As you do the testing and you say oh, now we see this gene, and we see this one and this one and we’re trying to figure out who’s the bad guy, or is this new one a factor that we’ve identified? So what would you say to us as we lived hopefully long term with these conditions about considering being in a clinical trial to help you make these discoveries?

Dr. Alison Moliterno: We have had great support from our patients, not only in participating but also helping design these trials or partnering with us. As Stephen said, these are rare diseases so we don’t have 50,000 individuals to test whether aspirin works or not like you can in a cardiology trial, and get that answer in a year and make a difference for individuals.

I would say that the trials now are going to be a lot more molecularly based. So instead of just disease, MF yes or now; these trials are now going to have the molecular profiling and response to therapy as part of their design. I think that will give us a lot more information overall than we’ve had in the past. So there’s many benefits to this molecular revolution.

One is understanding the cause of the disease, the other is monitoring it over time, and then response to trials which individuals respond to; which therapies. I think we’ve all seen the television ads about Keytruda and patients, as you mentioned early on with different solid tumors and particularly lung cancer, and how really the profile of that tumor needs to specific targeted therapy, and that’s what we want for MPN.

 Then now we’re even learning that it really doesn’t matter where a cancer may have started; if it’s in the kidney or in the lung, that again the molecular – the drivers of that indicate that you may respond regardless of what organ it started in; it’s really the lesion that you’ve got. And I think we will be bringing that to MPN patient trials.

Andrew Schorr: I’m involved in an initiative called Precision Medicine for Me, and it started in lung cancer but it is about this testing to see is there either existing therapies or investigation ones that line up. Or F dot now and as you know one of the major cancer medical societies called ASCO, American Society of Clinical Oncology.

The whole mission of the new president, a guy named Bruce Johnson from Dana Farber in Boston, a lung cancer specialist, is that these precision medicine approaches of each patient and their doctor knowing what are they dealing with at the molecular level to push that out throughout oncology; certainly in the U.S. if not worldwide. So I think we’re all in this together. Marsha, you’ve been listening patiently.

Now you’ve had this transition from ET many years, which Stephen was talking about we know often a very good prognosis. But then it changed, and a little scarier. I’ve already started that point, myelofibrosis. But when you hear this, how do you feel, just listening?

Marsha: I think when I was first diagnosed I was scared to death. But I think through education, I’ve learned to calm down and I just try to tell myself that this isn’t a sprint in my case, hopefully it’s going to be a marathon.

And until then, I’m just going to learn what I can do to help myself. I’m very curious about additional mutations; however my doctor said that really would not affect the treatment I would be currently undergoing. And the big thing, insurance, has come about. He’s very concerned about whether or not insurance would cover the cost and the value of it.

Andrew Schorr: Right. Stephen, is this – it sounds like maybe we’re making progress with insurance companies; that they want us to get a clearer picture with our doctor? What’s your take on that now?

Dr. Stephen Oh: The driver mutations, the JAK2, MPL< calreticulin testing, I think it should be and almost always is covered by insurance.

But when you get into the more extensive genetic testing, that’s where the insurance companies will often balk at covering it. Then it becomes somewhat problematic as to is this really worthwhile. Obviously that the costs for it and for any particular patient can vary in terms of what insurance will cover, what the copay is, and what they can reasonably afford. In general, while I do believe that there’s much utility to this kind of testing these days, if the cost is prohibitive I do not push it and I certainly do not think it’s mandatory.

Andrew Schorr: Dr. Moliterno, and I’ll mention to our audience we have a few more minutes; if you have a question and we haven’t covered it, please send in your question to MPN@patientpower.info, MPN@patientpower.info.

Dr. Moliterno, so we have the JAK inhibitor now, ruxolitinib. There are others that are being tested in various trials. As you look not just at the genes but at the treatments, are you fairly encouraged there that you will have a broader array to line up with people’s different situations, and also what the side effects of treatment, if somebody gets anemic or whatever their profile is?

Dr. Alison Moliterno: Yes, I am very optimistic. I think many of us, again if you look back at where we were five years ago in terms of the options that we have and where we assume we’re going to be in five years, hence I think there’s lots of room for application of these therapies, for combination therapies to use therapies together, even the ones that we have. So I’m very optimistic.

And I think I would say it is very anxiety-provoking to hear you need molecular profiling, and yet your doctor is saying we don’t really need that, or we’re concerned about the cost, which is certainly a concern. One thing I always say is that’s fine; the molecular profiling isn’t going to go away as an option, and the cost will come down in the next few years. We are now able to do things that we couldn’t even imagine we could do clinically in terms of looking at all aspects of genes, and this cost will come down.

So I would say to, for instance Marsha, yes we may not need it today but we can always get it in two years when things are different in terms of the availability of it and the interpretation of it. So again, I think it is reasonable to say your treatment is this, you’re responding well; happily we don’t need this at the moment.

I would agree with that, but I’m also certain that in three or four years, we won’t be having this discussion so much about the cost of this testing.

Andrew Schorr: Dr. Oh, here’s a question we got in. you’ve got to decipher this one for us. We have some really smart people out there, like PhDs. Is a germ line ASXL1 mutation a high risk or detrimental factor in the same way as a somatic mutation? So what’s germ line, what’s somatic, and is this germline ASLX1 mutation bad news, basically?

Dr. Stephen Oh: That’s a great question, and I think it also connects to a broader question. But to first answer you, talking about our acquired mutations which is the same thing as somatics; somatic means acquired.

If you’re talking about a germline mutation, in this case ASX01, it’s not the same thing as an acquired or somatic ASX01 mutation, which is what we’re generally referring to when we talk about that gene and its affect on prognosis. That also connects to the more broader point which is that the devil’s in the details.

Whether it’s ASX01 or another gene, the exact mutation may matter a lot in terms of what the significance you attribute to that. In many of the labs that do this type of testing, they will have a column for each mutation where they’ll make a call as to what they think it’s significance is, and they’ll say yes, pathogenic or it will say no pathogenic, or it will say uncertain. Part of that interpretation depends on whether it’s the germline or somatic AKA acquired mutation.

Oftentimes they can’t say for sure because the only way to determine that conclusively is to test tissue that’s not from the MPN. So, sometimes it’s uncertain as to even whether it is germline or somatic/acquired. So again, just to be clear on this particular question; if it’s thought to be a germline ASX01 mutation, it’s unlikely to be relevant or have a prognostic impact on that particular patient.

Andrew Schorr: So Dr. Moliterno, the other question you must get from people is do I have to worry about a family member? Because when they start talking about genes, you’re talking about what your hair color is, or hairline as I was joking with Stephen, or whatever characteristics herein are hereditary.

But then we’d say gee, is there a hereditary factor to an MPN?

Dr. Alison Moliterno: That is a very important question, and long before the JAK2 discovery, we realized that about 10 percent of individuals with an MPN will have a first or second degree relative with either an MPN or another cancer. So there does seem to be heritable factors at play here. Some of the interesting – and again, it’s not because you inherited – in your individual case you inherited the JAK2 mutation from the germline directly from Mom, but you inherited a risk of acquiring it.

We’re trying to understand that and again, what does it relate to; does it relate to germline variation in genes that allow this to occur, that allow you to get mutations in blood stem cells or in other tissues?

So yes, we are still working on that. It does seem to be a component of that. And that’s not unlike CLL, chronic lymphocytic leukemia also has sort of a familial –

Andrew Schorr: And I have that, too. I’ve got them both. I understand. So I think about that all the time. Marsha, you have children, don’t you?

Marsha: Yes, I have two children. But I think even more importantly, I have a cousin who has CML and another cousin who had stem cell transplant for AML. So I think that’s interesting.

Andrew Schorr: This is all in the hematology world, so Dr. Moliterno, do we have, Marcia or me, with two blood cancers? And I have three kids; what about this and is there a testing they should have, or how do we go forward?

Marsha: We don’t have – I would to recommend that they need a JAK2 test or specific MPN testing. If they have normal blood counts and they’re well, they don’t need to be evaluated for disease at the moment. The question is are there family genes that need to be elucidated, and if you have a lot of cancer in the family, so for instance families that have a lot of breast cancer, we often will send them for genetic counseling to understand what their particular risk is. And in breast cancer and some other cancers, we do understand some genes to test that can give us that information; familial genes. So far in the MPN, we don’t really have the knowledge of which genes are at play. 

Andrew Schorr: Dr. Oh, any comment on that because I’m sure you get the same questions. People say oh, my God, should I worry about family members?

Dr. Stephen Oh: Absolutely. It comes up pretty routinely and just to echo Dr. Moliterno, I generally do not recommend any special screening for family members, of those who have an MPN. I would also point out that even if there is, certainly it’s established that there is a slight increased risk for family members of patients with an MPN. Even if the risk was, let’s say, four fold higher for a first degree relative, the overall risk of developing MPN is so low that that overall risk for a family member is so unlikely that they’re going to develop an MPN.

Andrew Schorr:  Really? That gives some comfort; maybe you too, Marsha.

Marsha: Certainly.

Andrew Schorr: We’ve covered a lot of ground over the last hour, and I think on a very important topic now as mirroring the progress related to some treatments either approved or developing is, understanding our slice of an MPN, and the working with you on monitoring that and how does that relate to care. We have two noted experts with us who are helping propel this forward. So we’re your partners in helping that. Dr. Stephen Oh from Washington University and the Siteman Cancer Center, thanks for being with us once again and giving us of your time; I really appreciate it.

Dr. Stephen Oh: My pleasure.

Andrew Schorr: Okay, and Dr. Alison Moliterno, being back with us again from Johns Hopkins in Baltimore; thank you. Thanks for both of you; your very clear explanations, and Marsha Krone, we learned a lot, didn’t we Marsha?

Marsha: We sure did.

Andrew Schorr: Okay. Marsha’s my partner here; she’s done it twice and we’ll have you back sometime, Marsha.

Also, we should tell you Marsha is a very active preschool teacher so she has these little rug rats running around all the time, and thank God you have the energy to do that and I’m really glad you do, Marsha.

Marsha: Me, too.

Andrew Schorr: All the best to you. Well, this has been a wonderful program. We want to thank the Patient Empowerment Network for leading the way in this series, and Incyte Corporation for its support of this educational activity, and Patient Power our wonderful team Alan and Jamie who make it happen behind the scenes. We’ll be having more throughout the y ear. We welcome your questions; always send them to MPN@PatientPower.info.

And all of us moving forward living with an MPN, we’re going to live well and we have wonderful physician partners to help us do that as they understand the genetics and all those people working with them to develop therapies to help us live a long and strong life. Thanks for being with us in Carlsbad, California near San Diego.

I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.