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Genetic Markers and Treatment Implications for Myelofibrosis

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Published on July 14, 2021

Can Genetic Markers Influence MF Diagnosis and Treatment?

Can new information about genetic markers influence the diagnosis, treatment, and management of myelofibrosis (MF)? Find out in this video replay of a recent live show. Host and MPN patient advocate Ruth Fein talks with renowned myelofibrosis expert Naveen Pemmaraju, MD, of the MD Anderson Cancer Center. They discuss the genetic markers for MPNs, how a diagnosis can inform treatment decisions, and if new learnings about genetic markers could help to prevent MPN progression or lead to a cure.

This series is supported by an educational grant from Incyte. This organization has no editorial control. It is produced by Patient Power and Patient Power is solely responsible for program content.


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Transcript | Genetic Markers and Treatment Implications for Myelofibrosis

Ruth Fein: Hi everyone. Thanks for joining us for the new series on myelofibrosis. It's one of the myeloprolific neoplasms, or MPNs, and I'm Ruth Fein. I'm a health and science writer. I'm a patient advocate for Patient Power and very pleased to be here with you. We're here today to speak to one of the rock stars of myelofibrosis research and treatment and also advocacy. And that's Dr. Naveen Pemmaraju. He's at the MD Anderson Cancer Center at the University of Texas. So first of all, welcome, Dr. Pemmaraju.

Dr. Pemmaraju: Hi, Ruth. Thank you to you and the Patient Power team for having me live this afternoon.

Ruth Fein: My pleasure. And I'm going to call you Dr. Pem since everyone else does it if you're happy with that. So, I don't…

Dr. Pemmaraju: Yes, please. Thank you.

Ruth Fein: So I don't stumble on it, but…

Dr. Pemmaraju: Thank you.

Ruth Fein: Thanks for spending some time with us today. We're all looking forward to hearing the latest from you on genetic markers, and particularly on how they can influence diagnosis and management of myelofibrosis. So we're talking about genetic markers for myelofibrosis, which also may be associated with other MPNs, which are essential thrombocythemia, polycythemia vera, and of course the MPN myelofibrosis.

So, Dr. Pem, would you start with just a brief rundown of what the different genetic markers are that have been identified in MF patients? So, from a 3,000-foot view first, what are they? And maybe how common is each one?

Dr. Pemmaraju: Well, thank you, Ruth. What a great starting point for our discussion. So, for everyone out there, what we're talking about is the myeloproliferative neoplasms. There are really three. We call them the big three or the drivers of mutations that lead to all three of these MPNs. And it's important. We always use the word genetic, but just to tell everyone, almost everyone, they're not born with it or hereditary, but it's acquired or picked up maybe even as early as just after birth. So, these are somatic mutations, non-hereditary, and there's three of them, JAK2, CALR, MPL. Those are the big three.

Now there's a host of other alphabet soup markers that are starting to come out, which you and I will talk all about I'm sure, but those are the big three. They make up 99% of all MPNs. And then there's an important subgroup, Ruth, who are negative for all three. And we call those patients triple-negative, borrowing that nomenclature from breast cancer, suggesting that you don't have any of those three. So those are the big three, JAK2, CALR, or MPL.

Ruth Fein: So, we learn what the markers are. We find out what mutations we have. The question is, how does that help us? Why is it important? So, can you give us a few examples of maybe how a genetic marker informs treatment decisions?

Dr. Pemmaraju: Yeah. Nice. So initially, these markers were helpful just to help us diagnose. As we are here in 2021, we are reminded that the MPNs as a field is still a "rare" disease field. And again, let's compare that to some of the more common cancers – breast, lung, colon, prostate cancer – which are in the magnitude of hundreds of thousands of patients a year diagnosed. This is just four to five per million, per year.

So in this rare disease field of MPN, we needed some help to just diagnose. In fact, Ruth, the MPNs used to be called MPDs, disorders, because nobody really fully appreciated the C word, that these were cancer, clonal. And the elucidation of the JAK2 mutation just in 2005, not that long ago, helped us to understand that. So first you use these markers to help diagnose.

Importantly, for example, the CALR mutation only came out elucidated in 2013. So, it helped us to really understand patients with ET, for example. If you needed to stort out a patient who has platelets that are high for a benign reason, so a non-cancerous versus a cancerous. So, diagnosis is one. Two, as you were asking, prognosis, believe it or not, yes, exactly right. These markers in many cases can help to prognosticate, which means tell us where a patient out of, say, a hundred or a thousand may lie. Now we have all these fancy scoring systems that use 10, 15 different markers.

But it is correct what you said in myelofibrosis, that if you have CALR alone, for example, in myelofibrosis, we think those patients have a better chance at the long-term outcomes. If you have JAK2 or MPL, maybe an intermediate outcome. And then unfortunately, if you have that triple negative where you don't have one of those three, you might likely have something else driving, and that's a bit tougher outcome for our patients.

So diagnosis, prognosis. Now for treatment, not quite yet there. The good news is that the JAK inhibitors, this is an important point that a lot of doctors still are not appreciating, the JAK inhibitors as a class are not JAK mutant inhibitors. So ruxolitinib (Jakafi), fedratinib (Inrebic), these newer agents coming, they are JAK-STAT pathway inhibitors. So that means whether you have the JAK, CALR, or MPL mutation, these medicines still work because they're inhibiting or blocking a growth pathway. And so even though it's convenient to say, “Oh, JAK2 mutation, we have JAK2 inhibitor,” it's actually not as simple as that. And so, thinking about diagnosis, prognosis, and treatment, these markers have revolutionized the way we treat our patients. Ruth?

Ruth Fein: I think about specific things that have changed. Coming from somebody who's had an MPN for probably 30 years, the whole wait-and-see approach was common for a long time, particularly for ET and PV. How does knowing what mutation we have affect something as specific as wait-and-see? Are you taking that approach less often because you know more about what might come down the pipe?

Dr. Pemmaraju: Yes. Yes, to everything you said. The main breakthrough has been in the prognostic scoring systems. So, the first one was in 2009 by Cervantes in Spain. And what they showed is that if you have several simple factors that can be easily calculated, you can tell who would be wait-and-see, which we call active observation. That's low-risk. Then there's people who are a little bit more advanced, that's intermediate one or two risk, and then high-risk.

That was called the IPSS score. It took into account age greater than 65, a white blood cell count greater than 10,000. If you have anemia that's due to the myelofibrosis of hemoglobin less than 10, constitutional symptoms or so-called B symptoms, so fatigue, night sweats, weight loss of greater than 10%. And then finally, circulating blasts of 1% or higher. Now, importantly, I did not mention JAK2, CALR, MPL mutation status, or splenomegaly, big spleen, because in that original scoring system, those factors were either not included or tracked with the others.

But to your point, exactly right. In the modern day, now fast forward 10, 12 years later, the modern-day scoring systems, DIPSS, DIPSS plus, GIPSS, MIPSS, there's all these different ones that indicate including molecular and cytogenetic data. It does take into account exactly what you're saying. So, which of the big three mutations do you have? Which of the other ones, ASXL1, et cetera? And then it puts it all into one big formula.

I think at the bedside for our patients it doesn't have to be that complex. In other words, if you're a low-risk patient, most of us agree on who those are, indeed, Ruth, those patients may not ever need pharmacologic treatment or stem cell transplant. That's wonderful. If you're intermediate risk one or two, that's sort of a gray area, active area of investigation. Some patients will transform and progress, some won't. And then if you're high risk, the highest of the high risk, most of those patients need a more aggressive approach or clinical trials.

So you're exactly on the money that the molecular mutation, and each patient should know it. You should feel empowered to ask your physician, ask your clinic team, look it up, talk about it, but that can have implications for you now and in the future. Ruth?

Ruth Fein: So, I'm anxious to get to the good stuff, which I'm sure some of our listeners are as well. And what I mean by that is, what's new? So, what have we recently learned about these genetic markers that may not only inform diagnosis and treatment as we started to talk about, but could actually help to prevent progression or prevent MPNs altogether or lead to a cure?

Dr. Pemmaraju: This is the hottest area for research among me and my colleagues, and you hit on it. I think there's three areas here. One is, outside of the big three, JAK2, MPL, CALR, we have now identified a series of molecular mutations. This is big news, that informs everything you just asked. Those other mutations, ASXL1, TP53, EZH2, SRSF2. I know it's an alphabet soup, but you'll see all these on these reports now. Those can tell us if you have a higher risk to progress to, say more advanced myelofibrosis, or even hate to say it out loud, but AML, acute myeloid leukemia. A good percentage of our patients may end up going to outright leukemia. So, we can prognosticate that. That's important.

Number two, therapies. Sure. There are active labs all around the world, working on either doing therapeutic targeting of just those mutations or combination therapies, as I'm working in and others, or even going beyond JAK-STAT to these other new classes of drugs. So, you're right. That's guiding that.

I think a second principle here is what you said was very important. Can I tell beforehand, 10 years before, five years before, who's going to progress and when? Not exactly there, but we're getting there. Right. So, if you have a, for example, a TP53 mutation, just to use one for example, that one usually portends bad news for our patients. That usually means at the time of transformation to AML. Or if you have two or more of these mutations or three or more, those each get an individual point in these scoring systems. So, we are starting to be able to tell that.

And then finally, will this be useful for targeted therapies such as immunotherapy or CAR T-cell therapy? A lot of people ask us that. Possibly. The CALR appears to be what's called having immunogenicity, which means it may be amenable to these kinds of therapies, monoclonal antibody, immune therapy, and CAR T. Now that's five, 10 years away, but people are working on that right now.

Ruth Fein: Yeah, we get lots of questions about immunotherapy almost as commonly as personalized medicine, which of course is what we're talking about. I have a question to start from the audience, one of the first questions to come in, and then I'm going to go back to that. But here's the first question from the audience and it says, any news on the prognosis for someone with prefibrotic primary myelofibrosis who has both the CALR and JAK2 mutations?

Dr. Pemmaraju: Excellent question. So, with my colleague, Dr. Srdan Verstovsek, we published on one of the first reports of patients with this so-called dual mutation complex. So, let's back up here. Most patients with MPN will have one of the big three, JAK2, or CALR, or MPL. And then if you have CML, chronic myeloid leukemia, that has a fourth different program, that's called BCR-ABL or Philadelphia chromosome.

Now, what we started to notice because the sequencing were really uncommon and then they became super common and available all the time is that the dogma was that you'd only have one of these and that's it. Okay. One and done, not mix and match. But as we started to sequence everybody all the time for everything, we found that that's not the case. So, we published on this. Patients can have CML, BCR-ABL, and JAK2. They can have JAK2 and CALR, JAK2 and MPL, MPL and CALR, et cetera, et cetera.

Now, overall, these are only a handful of our patients. So, a very rare group out of a rare group of patients. So, you can't make a whole lot of conclusions, but you can say that driver mutations don't always exist alone. Usually if you have more than one, probably one of them dominates over the other. Okay. So that's part one.

Part two of the question, prefibrotic MF, this is important. We're not mentioning this enough. In between ET and MF, Ruth, there is a provisional, a hypothesized working category, not yet finalized by all of us. So in between ET and MF, this is called prefibrotic MF. And so, it's to try to design or illustrate an in-between group of patients who have features of both. They're not quite outright MF. They're not quite as benign, if you will, as our ET patients. So, they have the start of fibrosis. They have the start of molecular mutations.

The only two things we can say so far about that group, one, they do appear, in most studies, not everyone agrees, that they may have worse outcomes than just pure ET alone. That makes sense. Because if you're closer to an advanced disease, okay, I buy that. And then two is that they should have features under the microscope that differentiate between the two, and that's actually tougher. So, if you ask 10 pathologists, this is actually a very complex category.

So European groups, our groups, other groups are looking into this. And the question will be, if it is established as its own entity, then will it have its own guidelines? Will it have something hybrid in between ET and MF? And so, for our questioner out there, yes, we believe this entity exists. Yes, it can have molecular mutations, multiple mutations. Possibly has a tougher outcome than the ET itself and not as bad as the MF. Mostly in the clinic, we're not doing anything special yet. So, you treat as you would one of these entities, but I think longer-term follow-up and investigation in the lab and in the clinic of these patients will be necessary. So that's the prefibrotic MF. It's a new category that we're not talking about very often.

Ruth Fein: Yeah. I have a personal interest in that, and I'm sure that by me talking about my situation, people are always interested that they're not alone, obviously. So, for a long time, I would have been in that category. But of course, nobody put me in that category and probably didn't have a label for it. But the reason that's important to me is that a lot of us who have ET are asymptomatic. We go on, maybe we progress. For instance, I progressed to PV after about 15 years, but they didn't do a bone marrow biopsy for years, almost 20 years. And so, I was considered an ET patient. And that was that. Whereas in today's world, perhaps I might've been diagnosed earlier under this new category, prefibrotic. And my question to you is, what might you have done differently? You started to address that, but what would you have done differently for somebody like myself? I was asymptomatic, but there was the beginning of fibrosis.

Dr. Pemmaraju: Yeah, nothing much. That's the problem with this in-between category, it appears that patients have heterogeneous outcomes. So, we still don't do a bone marrow in the clinic unless somebody has a, quote, "dramatic" or real-life change in the blood counts. Some of that is because the bone marrow is an uncomfortable and painful procedure. And then some of it is also that if you get 100 bone marrows done, 90 of them, just to give a number here, may not show a whole lot of new change.

So, I think, as you said, you want to do bone marrows not regularly, because that's what we do on clinical trials. But you want to do them at the time of an actual change. I think this prefibrotic MF, it's worth discussing, not a whole lot different. Maybe you might watch patients a bit closer. You may watch the CBC closer. You may watch for transformation more. But again, the problem with these entities, these provisional entities, is there's not a specific medicine. There's not an, oh, let's give a JAK inhibitor earlier or something like that. So, but that's the exact question that we need to ask.

I will say there are studies out there. One is called the MOST observational study. Exactly asking the question you are, which is, can we follow patients with early-stage MPNs, ET and PV, and exactly what you're asking, Ruth. So, can we follow their natural history and progression? So that's an observational study. Non-interventional observational study. A lot of our patients, maybe some watching this signed up for. And I think in the next few years, we'll have a readout. Exactly who's progressing, who isn't, and then try and identify these in-between categories.

Ruth Fein: That's exciting. That leads me to my next question, which is, specifically, what are you excited about? Let's move over to myelofibrosis more than ET and PV, and what are you really most excited about?

Dr. Pemmaraju: Well, it's a perfect time to do this live program with you, Ruth, because we just finished a successful ASCO and EHA. So American Society of Clinical Oncology and the European Hematology Association meetings back-to-back, both done virtually to be safe during the pandemic time. And there's quite a bit to bring to you and the viewers. I would categorize it as three different buckets. So, bucket one in myelofibrosis is some exciting developments on the JAK inhibitor front. So, let's review that. So that's the tried-and-true. We know that there's two, not just one, but two FDA approved JAK inhibitors in the U.S., that's ruxolitinib and fedratinib.

But now, did you know that there are three or four other JAK inhibitors in active and late state development? So, we heard exciting new data for pacritinib, which is in phase three trials right now, the PACIFICA trial. And then momelotinib, which had some benefit in terms of anemia and transfusion dependence going to independence, that our friend and colleague Dr. Ruben Mesa showed. And then there's still other JAK inhibitors such as jaktinib coming out of China.

So that's category one. And I find it to be very hopeful for our patients. I'm always thinking from the patient experience, which is bring them all on. Let's have four or five choices. Let's sequence them together. One may be better for you than another one. You know how that goes. Number two category of excitement is combination therapy. Well, we've never had that opportunity. We've only had one pill to give in the clinic and that's worked fine. Now, whether people want to know about it or not, it's coming. The era of combination therapy to patients with MF.

So that's the so-called add-on or add-back, Ruth, where you're on your JAK inhibitor, say for three months or so, but you're not seeing the maximum benefits that other patients are having. So now you're starting to have a suboptimal response or even a failing one. Spleen starting to get big, even though you're deriving some benefit. So now we and others are adding in a second agent, whether it's the Bcl-xL agent navitoclax, the bromodomain agent, PI3-kinase, hypermethylator, you name it.

The concept here is two-fold. Can I improve your outcomes as a patient by adding a second drug, so it reduces your spleen, improve quality of life, improve your survival? And then two, how much toxicity am I introducing into your body and into your life when you were doing just fine with just the JAK inhibitor? So those are in phase two, heading into phase three studies, Ruth, and we'll have readouts on a lot of these in the next couple of years.

And finally, a third bucket. If that wasn't exciting enough, is just completely beyond JAK inhibitor, combination therapies, brand new pathways that our lab colleagues have discovered, old drugs that we're repurposing into MPNs. Brand new pathways and drugs that nobody's even heard of. Very exciting. One of those drugs, just to name one, is the imetelstat, the telomerase inhibitor, which may not be on people's radar, but that's heading into a phase three randomized trial in the relapse setting with overall survival, Ruth, overall survival as the primary endpoint, which marks a sea change in the field.

So basically, the review, there is new JAK inhibitors are coming. Combination therapies are being actively investigated for more advanced patients, and then completely beyond JAK inhibitors, brand new pathways. All of this brings me, on behalf of our patients and caregivers, hope and new pathways that I just didn't have to think about five years ago, Ruth. They just didn't exist five years ago. It's exciting.

Ruth Fein: It's very exciting. Very exciting. So, before we get to some more hopeful messages, I'll just add my two cents, that I'm on one of those combination therapies. And just yesterday, I named my new theme. That zero is my hero. And that's because, I will share with you that I had a bone marrow biopsy last week and I got the results, and I've moved from being an intermediate two myelofibrosis, skipped past one, and I'm now at zero, as in no evidence of fibrosis in my bone marrow. So, zero is my hero.

Dr. Pemmaraju: Wow.

Ruth Fein: And that’s my call out for people to consider trials.

Dr. Pemmaraju: Right.

Ruth Fein: Because without them, we don't get all the great news we're getting.

Dr. Pemmaraju: Well said, Ruth. Awesome. Thank you for sharing that.

Ruth Fein: Yeah. Thank you. So, before we do close and sign off, and this has been such an informative program on myelofibrosis, I'd like to end with a few words about how we change the conversation around MPNs. And that's something very special to me. And I know that it's on your radar and a mission of yours as well, Dr. Pem.

So as you're telling us there's a lot of hope around MPNs that wasn't there just a few years ago, let alone a decade ago. And I believe that that's true for all of the MPNs, but would you leave us with your own perspective on this groundbreaking path that we're headed toward? And let's put it into the patient perspective. So, what are you able to tell a patient when you sit with them today with ET or PV or either MF and their fear is progression, probably progression to myelofibrosis? What can you tell them now that you couldn't have said just a few years ago?

Dr. Pemmaraju: So important. It's so inspiring to me to even be here with you and thinking about this with your patient journey, with your own advocacy, and then now you're educating other people out there. I think of two things here to leave our viewers with. One is, the patient experience should be intertwined and front and center with the journey of the bone marrow blood sample, with the journey of the healthcare team member, with the journey of the science. And right now, I feel that a lot of times these are all separate journeys, Ruth. Doctor comes in, and I've done this before, if any of my patients are on, oh, I'm so excited about this lab result. But meanwhile, the patient feels miserable. Or “Hey, congratulations, your spleen size went down,” but then you've got two transfusions a week.

So there's a little bit of a disparate language of communication. And that bridge, I think, must be ... And it's a tough disease, as you and I both know, but I think we have to think about that. So, endpoints that matter to a scientist can sometimes be different that matter to the doctor that matter to the nurse that matter to the patient that may matter to the patient caregiver. So, let's all get on the same page there. And for that, I was really inspired. If you don't mind me mentioning this beautiful New York Times piece that you wrote, I think just came out a few months ago. And you know this, I reached out to you and we've now since met, which is a great honor for me. Just so everyone out there knows that.

But you wrote so movingly about this, that the patient journey with the C word is so weird and different. And then when you have a rare disease like you do and our folks out there. What I leave people with is, you now have a whole field of doctors, such as myself, Ruben Mesa, Srdan Verstovsek, who can pronounce the name of your disease, who don't have to Google it, and who actually have dedicated their life. It's not just my career. This is a calling. This is what I do for my life. And so, you've got teams of people and now we're starting to all know each other. We're starting to collaborate rather than compete. We're starting to reach out. Social media online has helped that.

So the message out there is no matter how rare a disease you personally have, or your loved one, nowadays, it almost doesn't matter. Because if you have a disease of N of a hundred versus N of a hundred thousand, and that mattered before, I want everyone out there to know, in terms of hope, that there's likely somebody out there who's working on your exact pathway or your exact disease and likely nowadays we're all linking up. Whereas before we didn't.

You see, Ruth, the way I look at it is, it doesn't matter how rare a disease is, if your mom, your sister, your brother, or your son or daughter has it, it's a disease. It's what you're facing. It's your life, it's Tuesday. And so, know that we're all out there fighting every single day to be able to make breakthroughs. Sometimes they come incrementally, sometimes huge sweeps as you heard here, but make no difference about that.

And then finally, I would say Field of Dreams, that movie, the baseball movie, where they said, "If you build it, they will come." Rare diseases are only rare to people outside of that world. To the people who are treating it, researching it, having it, dealing with it, that's what we have. That's what we have in front of us. So, we're going to move full steam ahead with gusto and hope and collaboration and think about the patient first. That's where it's all about. Think about the patient in your clinic. Then the discoveries will come, Ruth.

Ruth Fein: Thank you. That was so brilliant that I'd love to leave it there, but I'm going to push you just one more step, because that was exactly what as a patient you want to hear. And it's very encouraging and very hopeful, but the one thing I'd like you to address that you will address differently than our community oncologists and hematologists in most cases is the idea that we have a chronic cancer, and a "chronic," in quotes, is very different than the type of cancer that you can cut out and radiate out and get rid of and move on with your life. So how do you deal with the fear? As I did say in that New York Times article, people hear the C word, and they don't hear anything after that. How do you deal with that portion?

Dr. Pemmaraju: Yeah, that's very real. I think our estimates are that in that first visit, what I call the shocker visit or the information overload, I think my patients, and I pride myself on my communication skills, I think they only take in about five to 10%. Because after you hear bad news, everything else kind of goes over. So, I've given people three tips and I'd like to give that to our viewers here. Tip number one, if you can, not everybody has this, not everybody has this. And in the pandemic, we had to limit people, but if you can have a person with you, a neighbor, a friend, a cousin, somebody on the phone, on the iPhone, in the visit when it's safe, I think that helps. It shields some of that information overload. Have a second brain there. Have an advocate for you. Not everyone has that, but if you can, that's important.

Number two, repetition. The fear is real. That's a real, actual, helpful mechanism. It heightens the senses. It tells the person, oh my God, this is real. And then the other shutting down, it's just basically an allocation of resources and energy to face the scary thing. Well, that's what it is. So, repetition. So, repetition among the patient, the doctor, the providing team follow-up visits, telephone call visits, Epic, MyChart messages. Usually, most people aren't going to think of the question in the five minutes in the doctor's office. We know that. It's later that night after you finished dinner, you're like, oh man, I forgot to ask that. Well, don't live in isolation when there's five different ways to get in touch with your doctor. And there's ways to repeat that information.

Then finally, third, this may surprise some people out there, but I encourage everybody to Google. Use the internet, use social media, get out there. You should recognize that you're an N of one, so your case may be different from the next person, next person. And you should not take general information, make it specific to you, but you should research your disease. See what's out there, but don't just keep it an isolation. Bring that now to your clinic visit and say, “Hey, I saw this on my Facebook MPN support group. What do you think about this?” Or “Hey, I saw this on social media. This guy, Dr. Pem was tweeting about this agent.”

And so I think in that way, there's a community out there that you can tap into, even if you don't have people in your local area. So those are the ways to approach. So, accept the fear, accept it. It is there. Turn it into action and then make that action part of your daily routine and your weekly routine. Ruth?

Ruth Fein: So wise words from one of our MPN super-specialist superheroes. Thanks so much, Dr. Naveen ... I knew I'd mess up. Dr. Naveen Pemmaraju. He's of MD Anderson at the University of Texas. To our audience, if you have new questions for your doctor based on today's program, make a reminder, as Dr. Naveen said, make a note to self, bring the information with you. It can help you with your healthcare decisions and ultimately improve your care.

So one more note, Patient Power is piloting a new clinical trial finder tool. And this information on how to use the tool is in our MPN newsletter, which we hope you're already receiving. If not, you can sign up for it at patientpower.info. The information is also on the Patient Power Facebook page, and you can follow Patient Power on Instagram and on Twitter. That's all from here in beautiful Saratoga Springs, New York today. Take care. Be well. And remember that knowledge can be the best medicine of all.

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