Ask the MPN Expert – Dr. Pemmaraju
“Ask the Expert” session with MPN specialist Dr. Naveen Pemmaraju from The University of Texas MD Anderson Cancer Center.
Andrew: And greetings from near San Diego, Carlsbad, California. I’m Andrew Schorr from Patient Power. Welcome to this patient empowerment network program, and thanks to Incyte Corporation for helping make it possible. They have no editorial control. I’m a myelofibrosis patient, have been for several years, so I’m vitally interested in this. Welcome to our MPN community, and welcome to one of our favorite experts joining us from MD Anderson Cancer Center in Houston. There’s Dr. Naveen Pemmaraju. You can see behind his desk there all the working on the cures of tomorrow, but Naveen, thank you so much for being with us.
Dr. Pemmaraju: Thanks for having me, Andrew. My pleasure.
Andrew: Okay. Let’s get right started. We’ve gotten all sorts of questions in. If you have a question, send it to MPN@patientpower.info, but we’ve gotten a lot already and I’ll start to buzz through them over the next 30 minutes. This question is from Cynthia and she says, “I was diagnosed with ET (Essential Thrombocythemia). I’m JAK2 positive,” so she has that JAK gene. “When I was 66 years old,” now she’s 68, I’m about to be 68 as well, “What markers on my blood work, asides platelets, are important for my doctor to watch? What indicates a need for another bone marrow biopsy?”
Dr. Pemmaraju: Well, thanks, Andrew. And thanks to the question from Cynthia out there. This is very important. This is what we talk about day-to-day, week-to-week in the clinic. There are a couple of perimeters outside of the platelets. One, I would say the most important for us to watch are the other of the big two. That’s your hemoglobin number, also known as anemia; if it’s too low, or polycythemia, if it’s too high, and then the white blood cell count is also very important. Again, if too high, or too low, it can tell us what’s going on.
With ET, the key thing is it can transform, or change into any of the other MPNs. For example, PV (polycythemia Vera), myelofibrosis, or – and I hate to mention it, but it does happen five, maybe seven percent of our patients, where the disease can go to Acute Myeloid Leukemia, AML. So, distinct blood count changes, either too high, or too low, can give us clues if the MPN is changing, or in fact, going to AML.
And so, the answer for a repeat bone marrow is based on that, which is, let’s look together, patient and provider to see if there are subtle or avert changes in the blood counts that are markedly different from the previous visit, rather than having a pre-prescribed, every three months, or every six months type of a deal.
Andrew: But, Naveen, with all you’re doing now with sophisticated testing, do you still have to poke us in the hip, or couldn’t they just do it from our arm?
Dr. Pemmaraju: I wish, Andrew. I think this is very important. I think with the juxtaposition, you have this sophisticated gene panel testing, JAK2 CALR, MPL, and yet we’re still sticking a needle in people’s backs in a very painful procedure. Nothing still has overmatched as the gold standard, the bone marrow aspiration biopsy. So, for now, we’re – pun intended, I guess – stuck with this procedure. But your point is a good one. For example, with bone marrow transplant, can you believe it nowadays, they’ve moved from not having to exclusively do it from bone marrow source to peripheral blood, so I think you’re on the right track and we need to work on different ways of accessing this important information.
Andrew: Okay. One thing about bone marrow biopsy, it doesn’t have to be painful. It’s uncomfortable, but it doesn’t have to be painful if you have somebody experienced doing it.
Dr. Pemmaraju: I wanna emphasize how right that is because at least here, at our center at MD Anderson, as you know, we have a team that is dedicated to doing it many, many people, many repetitions doing it, so there might be local discomfort, but a lot of our patients do not experience pain. I’m glad you brought that up.
Andrew: Right. And that’s been my experience both there, and at other major centers. Okay. Here’s a question from Denise. Denise says, “I have PV and I’m trying to improve my health by making smoothies containing large amounts of dark green vegetables, such as spinach, kale, and watercress. I’ve been warned by some members of our community that these foods will increase iron and raise the hematocrit, putting me at risk. Is that true? And should people with PV avoid these foods that are high in vitamin K?”
Dr. Pemmaraju: Well, this is an important question and I remember five to 10 years ago we would say things like, “Well, we don’t really know the answer,” or you know, “Diet doesn’t really have anything to do.” But now with more and more understanding of the total therapy for patients and approach to the whole body, I think this is an important question. So, yes, iron levels do matter. Too low, then you’re iron deficient. (That can definitely happen in our patients.) Too high, potentially may fuel the fire, if you will, for polycythemia Vera.
So, I think iron levels are important to watch and certainly can be increased by what our question is being asked about. But there’s another aspect, too, that some of the medications that we prescribe and take. One example is Coumadin, or Warfarin that a lot of our patients know, which is a high-level blood thinner. It’s an anticoagulant. And man, oh, man, that is exquisitely dependent on the vitamin K pathway. So sensitive, that in some patients in some cases even salad consumption, or spinach, so healthy foods because of the vitamin K level in them can alter this level. It’s called the INR. And so, it’s something we have to watch out for.
So, not only in terms of iron metabolites, but also drug-to-drug interactions. So, it is always best to mention these things when we’re going on new medications.
Andrew: Right. Talk to your doctor.
Dr. Pemmaraju: Talk to your doctor.
Andrew: What you’re doing –
Dr. Pemmaraju: Everything.
Andrew: – what you’re eating. Yeah. Okay. Here’s a question from Sally. Sally says, “I have ET with the MPL mutation. So, I have JAK, but there’s also MPL. I believe, not much is know about my mutation. Can you shed light on it, or me and our community here today?”
Dr. Pemmaraju: Yeah, great question. So, when I look at these mutations as the big three, I go back to the time of William Dameshek, who hypothesized in the ‘50s and ‘60s that MPNs would be a unified group of diseases; ET, PV, and MF. And now, 67 years later, we’ve proven that. So, JAK2, we’ve known about since 2005. The most common, most major recurring mutation, fifty to 60 percent of patients of myelofibrosis. Then in 2013, 2014 the CALR mutation was elucidated. Can you believe, that’s only been four, five years. That’s the second most common. But there’s a third of the big three. That’s the least common, the MPL; MPL mutation.
That’s a mutation in something called the thrombopoietin receptor (TPO), which is in charge of helping to stimulate and make platelets. So, in terms of MPN patients, it does make sense and it has something to do with platelets, and that axis. It is the least common; by far the less common of these three, so I would say maybe something to the point of three to seven percent of our patients will have it.
Up until recently, we didn’t know if it had any prognostic significance, but our Italian colleagues published a very nice paper in Blood a few years ago, independent of the IPSS risk, that I’m sure we’ll talk about later. That if you just take patients with myelofibrosis, not ET and PV, you can stratify our patients based on the mutation risk. And not everyone knows about this.
For example, in this scoring, CALR mutation alone is the best prognosis for our patients. JAK2, or MPL is what’s called an intermediate prognosis, and the so-called triple negative, if you don’t have any of these big three, the implication being that you likely have something else, like ASXL1, then those patients tend to have the worst prognosis. So, MPL helps us to diagnose and confirm an MF diagnosis, and it also may have prognostic significance in our modern era.
Andrew: Okay. I don’t want people to freak out because this is a moving target as they learn and say, “Oh, my god. I have triple negative…
Dr. Pemmaraju: That’s right.
Andrew: Right. Okay? Because there’s progress going on all the time.
Dr. Pemmaraju: Well said.
Andrew: This is what they’re learning now. Okay. Now. Here’s the big one and you mentioned it. You said, a small percentage of us with myelofibrosis have the risk of progressing to AML. I know there been a lot of new drugs now either approved, or in development for AML. And some that help people who have secondary AML.
Dr. Pemmaraju: Oh, yes.
Andrew: Right? But tell us about the risk of progression, and then what do you do about it?
Dr. Pemmaraju: Right. So, that’s a great topic, and as you know, you’ve been doing this for so long now. This has often been a very not great part of the conversation, but it’s an exciting time for our patients based on the research I’m about to share. So, the first part is progression to AML, which we touched on earlier. We do have an objective prognostics scoring system. Actually we have so many scoring systems now that many of our patients are starting to see them.
But the IPSS, or International Prognostics Scoring System, was first developed by our colleague, Cervantes et al, this is right before 2010, so ’07 to ’09. That one is supposed to be applied at diagnosis and based on five of these risk factors, we can prognosticate, or tell which of our patients are at a higher risk for AML. And so, a lot of our viewers ask that. So, it is true. Age – over a certain age, white count of 25,000, circulating blasts, constitutional symptoms, and anemia made up that original five.
Since that time, there are dynamic scoring systems, DIPSS, DIPSS+ and others that include, or modify as some of those risk factors. So, we can tell, at least based on a textbook impression, who has a higher likelihood of going to AML. Once our patients go to AML, there’s a lot of hope now. There have been four – count them – four new FDA approvals for AML in just the last 12-24 months. They apply to different segments of AMLs, two of them are targeted therapy, so one drug called Midostaurin hits the FLT3 inhibitor, one drug hits the IDH1 and 2. Actually those are two separate drugs.
The drug you were referring to had a code name CPX-351, or VYXEOS, and it does have an approved label for so-called secondary, or therapy-related AML. Although I will caution our viewers that – MPN patients, specifically, we’re not included in those early data sets. They were more geared towards patients with MDS leading to AML, but the principle is there for us.
And then finally there’s another drug called Gemtuzumab or Mylotarg. So, you have four FDA approvals, ongoing clinical trials with combination therapy, excitement and ongoing investigation for CAR-T cells, optimizing stem cell transplant, and then combining possibly MPN drugs with AML drugs in a clinical trial setting. So, I think this is actually a very, very important time to talk about AML in all of our MF and MPN sessions.
Andrew: Okay. Just one brief question, and – if someone like me, where I’m on Jakafi myself, but if that sort of poops out, or that, or another medicine is not working for me, and I’m developing AML, do you feel now it’s a more hopeful time than it’d had been previously?
Dr. Pemmaraju: I do, Andrew, and you know me. I used the word ‘hope’ very seriously and very carefully. Before with AML – and I mean, just five to seven years ago, it was not as hopeful of a time for us, as researchers, and for our patients. Not just because of the FDA approvals. That obviously is very encouraging and applies to a lot of our patients, but also because of the funding, the research, and the ideas for combination chemotherapies, and the emergence of these immune therapies. I think it’s a hopeful time for all of us involved with AML.
And specifically as you were mentioning this secondary, or post-MPN, or post-MDS AML, which is largely been an urgent unmet medical need.
Andrew: Okay. And just to everybody understands, AML, Acute Myeloid Leukemia, so it’s acute and as has been in the past a five alarm fire and now they’re developing medicines for that. All right. Let’s go on. Bonnie has a question. “I have myelofibrosis and my only symptom is that my spleen is enlarged. I’m on Hydroxyurea, but hesitant to switch to Jakafi or Ruxolitinib. Assuming no real discomfort and just moderate weight loss and stable blood counts, does an enlarging spleen itself cause problems?” And also, I guess the bigger question, Naveen is, is there a penalty for waiting if there is a treatment that might line up with what you got?
Dr. Pemmaraju: You’re right on. Yeah. This is very, very serious, important topic. So, for the first part of the question, the spleen itself being enlarged can in fact cause some really, really big problems for a lot of our patients. It is true, as the questioner’s asking, that one can have mild splenomegaly. So, a spleen that’s slightly enlarged, not yet causing physical symptoms of early satiety, which means getting full fast, or physical discomfort, but a lot of patients do have that. So, yes, a big spleen alone can cause not only local problems, but also systemic. Because again, it’s a disease of cytokines; messengers and proteins that are being scattered all throughout the body, causing the body to feel flu-like symptoms, or fatigue.
Now, the studies for Ruxolitinib are very specific. These are two Phase 3 studies, they are called Comfort 1 and 2, published in the New England Journal five six years ago now. And they did include patients with intermediate to, or high-risk disease. Or intermediate to high-risk disease, shall we say. And although the spleen itself doesn’t come out in the scoring system, some position is that it should be patients with more advanced, or higher scoring diseases than say someone with lower risk disease.
So, with the trial data that we have we know a couple of things. 1) The drug got approved in those more advanced patients. 2) There was early crossover that was allowed. So, one of the comfort studies, Andrew, was as you know, randomize to placebo. So, no active therapy, and one was best available therapy. Even with the early crossover allowed to the Ruxolitinib, both are not showing overall survival benefit. Translated into more layman’s terms, what that means is, it does appear, maybe, possibly, that if you got the drug at the beginning early on, there looks to have been some long-term benefit.
We won’t know that until further studies are done, and those studies are being planned. Those are called ‘early intervention’ studies, so people at a lower, earlier stage, low risk, Intermediate 1, and I think we’ll all be eager to see how that benefits our patients.
Andrew: Okay. Great. So, the penalty for waiting – right now it appears there could be a penalty. In other words, it could be better to get on it. Don’t wait. If you and your doctor agree, there’s a therapy for you.
Dr. Pemmaraju: I think that’s exactly the resource position to take, which is I think that – I believe that there are a subset of our patients who exactly fit what you said. They are symptomatic, out of proportion to the risk scores that are available. The spleen is highly enlarged, although they have lower intermediate risk by IPSS. And that’s exactly the are of investigation for myself, and our colleagues. And even in the clinic there might be some role to assessing patients as you said like that. So, it shows you the limitation of these text book scoring systems and how much research we have left to do.
Andrew: Okay. Well, you know more than you did before, so, I –
Dr. Pemmaraju: Well said.
Andrew: – I’m happy about that. Okay. So, here’s a question from Jane. She says, “I have myelofibrosis, but it’s not progressing, and I’m CALR negative.” So, that’s one. “I’m JAK negative.” That’s two. “And I’m waiting to hear if I’m actually triple negative, as you said, which would be JAK, CALR, and MPL. Are there medicines to slow progression for me?”
Dr. Pemmaraju: Well, that’s the ultimate question. Isn’t it? So, the first concept is this triple negative. And if our viewers have heard that before you have, that was borrowed from the breast cancer literature, which was a similar sentiment, which is having the top three markers negative. And just in that case, as in RMF, the supposition is the same, that that means that you have a higher risk disease.
But going from negative to positive, what it does mean now with the new sequencing and molecular studies that are coming out, is that it really looks like 90 percent, maybe even close to a 100 percent of patients, have some form of a molecular driver. And those other mutations you’re going to start to hear about are becoming common; ASXL1, TP53, EZH2, IDH, etc. etc. So, triple negative may mean that we don’t have those big three, but there might be something else that’s driving the MF, and it means that it’s a higher risk to progress to AML and for some patients to not do as well.
But this questioner brings up a very good point. What the textbook risk score says does not have to imply to each individual patients. So, just because the finding is that, okay. Triple negative patients as a population may do worse, it may not apply to that individual patient. So, in this person’s case, maybe they’ve been diagnosed very, very early. That’s a good thing. Maybe the driver mutations and the triple negative matter, which is what I think. So, ASXL1 mutation vs. some other ones.
And then finally, each patient is different. Everyone’s case is different. You have other co-morbidities, other underlying drivers of disease. So, I think that’s the good point. But, we do have to say, at least for right now, I like your phrase ‘of a moving target’. The understanding that if you are this triple negative disease in this classical sense, should mean that you are a higher risk at some point to progress, as compared to others in your group, and so, possibly closer monitoring and observation is necessary.
Andrew: Right. And see an MPN specialist. Because what if there’s a drug in development that’s an AS – What is it? AS –
Dr. Pemmaraju: ASXL1.
Andrew: Inhibitor. And that’s driving your bus. Right? Maybe you wanna be in that trial. [
Dr. Pemmaraju: Absolutely right. Clinical trials are important for all of our patients with any rare cancers, or any cancers in general.
Andrew: Right. Okay. Let’s go on. I just wanna take this question from Susan. It really rang true for me. Susan writes, “Is it common for an ET patient to experience numbness in the scalp, ears, and face? I’m currently on 1,500 milligrams of Hydrea daily.” And I wonder if you can broad this out because I was telling you before the program, I’m getting every once in a while – I wake up with a little prickliness. Not itchy, and I go back to sleep, but is that related to my MPN? So, she has scalp questions, is it the MPN, ET whatever? Is it the medicine?
Andrew: This is coming up in my clinic on a weekly basis. The short answer is, yes. It’s always due to the MPN. And I’m here to tell you why. This is an underappreciated part of what we do as healthcare providers in patients. For anyone who’s ever filled out the Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score:, developed by Ruben Mesa, his colleagues, now shortened down to a nice, nifty 10 ques – sheet. You know, actually, peripheral neuropathy is one of those 10 questions. Do you have numbness and tingling? So, even though we don’t talk about it, that’s our fault, peripheral neuropathy is a thing. It’s a common aspect of the MPN.
No. 2 is – and you brought this up to me nicely as well, is some of the mediations that we prescribe at the chemotherapeutic level can also cause nerve damage and neuropathy. JAK inhibitors either as a class, or some of these individual ones, both FDA approved in clinical trials have been associated with either a central, or peripheral neuropathy. So, I think that’s another big aspect.
And then finally, I hate to say it, but these drug-to-drug interactions of all of these medicines can cause that. When you factor that, plus vitamin deficiencies, thyroid deficiencies, iron abnormalities, restless leg syndrome, our patients have a host of reasons to have neuropathy. Usually this is an intermittent phenomenon, a come and go phenomenon. When it starts to become more of a permanent phenomenon and progressive, that’s a big concern, and that would really require a separate neurologic work up.
True, there are some chemotherapy drugs that can cause that, but I would say that would necessitate a multi-disciplinary approach; neurologists and all of this kind of thing.
Andrew: Okay. You used the name of a drug that people take. Is a blood thinner, Coumadin. Somebody may take diabetes medicines, I also have Chronic Lymphocytic Leukemia and take medicines for that. Okay. So, if we’re developing some of this and we have an MPN, which of the many doctors we have doo we go to first – do we go to you as our MPN specialist? Do we start there?
Dr. Pemmaraju: Yes. Absolutely. I think the phrase and the motto of every MPN expert that you’ll meet (and you and I know all of them now) is, ‘Tell us everything.’ Because I will tell you what. Now that we have more understanding – not full understanding yet, but more understanding of the biology of these diseases, it turns out that a lot of things that are happening are due to MPN.
One example I’ll give you, Andrew, our colleague and friend, Claire Harrison has pioneered this phrase called, ‘presenteeism’. Presenteeism. Not absenteeism, as we learned when we were younger. The concept that our patients with MPN are there, they’re here at work, with their loved ones, they’re at dinner, but they’re not really there. That’s also a question on the questionnaire; inability to concentrate. Subtle, subtle, subtle, but this is part of the MPN process. We’re not talking about it enough, but programs like this will get the message out there. So, tell your MPN doctor everything because more than likely they know it’s part of the MPN.
Andrew: I gotta tell my wife. I’ve been married 33 years.
Dr. Pemmaraju: This is all recorded, so you can tell her.
Andrew: All right. Esther, where are you? Okay. No. Let’s go on. So, Heather sent in this question. “My local hematologist, oncologist will only give me a phlebotomy after my hematocrit is over 51. What is the standard marker? I have PV and I’m really struggling with symptoms.”
Dr. Pemmaraju: I actually have data to share with you and your viewers. So, before four years ago, we did use to do it either based on convention, symptom burden, or a pre-designed abstract number. But now we have data. So, our Italian colleagues, Barbui and colleagues published in the New England Journal about four years ago a very nice paper that starts to answer this question. They randomize patients with P. Vera to two groups. They called it a liberal group, where you could get phlebotomies at any number essentially just like what’s being asked here, and then a more stringent group, which they came up with the hematocrit goal of 45 and below. Or below 45.
And the trial was actually stopped early because it showed a four-fold decrease in cardiovascular morbidity and mortality. That means, four times less chance of people having cardiac events or cardiac deaths in the stringent phlebotomy group. That is when you put the goal below 45. Yes, it’s only one study, but it’s with several hundred patients with P. Vera in a nice controlled situation. So, that has become a lot of us – for us, the de facto of standard of care.
So, I would advise, if you’re a higher risk patient with P. Vera, the so-called triple therapy approach, where you’re doing, you know, baby aspirin if you qualify. The phlebotomy goal of 45 and below, and then of course, cytoreductive therapy if you need it in the higher-risk situation. So, 45 and below, it should be validated, we should do more studies here in the States, but that’s something that I think we can use with high-level data.
Andrew: Okay, thanks. Here’s a question we got in from Kimberley. She says, “My daughter is 22, she was diagnosed in 2013 with ET, and she’s been on Hydroxyurea, but is decided she no longer wants to take the med. What should she be aware of, or cautious about, given that she’s no longer taking it?”
Dr. Pemmaraju: Ugh. Well, this is an area that’s very dear to me and very important to my research. With our group here, with Dr. Serge Verstovsek and my colleagues, we just published a paper on our experience with adolescents and young adults with MPN, or AYA. As its own separate field, AYA cancer has become a very important understanding that really didn’t exist, in my opinion, 20 years ago. But our patients are not always older patients. So, young patients can get MPN, too. Yes, patients in their teens and twenties can get them just like this questioner.
So, this is a type of patient that I’m seeing quite commonly in the clinic. Couple of points to say. One is, who can blame her? Who wants to take a life-long, indefinite oral chemotherapy that may or may not have short-term and long-term side effects? In our study what we found is, approximately 10 percent of our patients met this definition. The NCCN gives it, I think, age 16 to 39. So, younger than 40. And out of those patients, I was surprised to see that a good seven percent had a thrombotic event. That means a blood clot, either at the time of diagnosis just prior to, or just after. Well, that’s a pretty good clip, and that would be more than the general population than what you would expect.
The problem with the young patient with MPN has several issues. One is, what about at the time of fertility and pregnancy? Two, what about at the time of surgical procedures? I’m talking about routine things, such as dental and other care. And then three, as they start to transition into their older adult years. So, in this patient’s case, this is a very difficult thing. We don’t have many drugs. We have Hydroxyurea, we have Interferon, which possibly might be better for a younger patient. If someone has myelofibrosis, there’s no age requirements. So, if you qualify, then the JAK inhibitor, as a class.
But this is just one of those in-between, vulnerable populations, and we really don’t have great treatments for in general, an AYA cancer, and specifically here. And so, the main thing that we would say to this person is, really, really close follow-up early on with an MPN expert, as you always advocate. Two, is at the time of fertility planning, pregnancy in our family planning is to have high-risk maternal-fetal experts involved early on. (I think, this is something important.) And three, really cautious planning in and around surgical procedures, looking for bleeding and blood clots. I think those are some basic guidelines for anyone to follow.
Andrew: Well, great advice for mom and daughter. I wanted to post this, just a quick question from Caroline who lives in the United Kingdom is diagnosed with primary myelofibrosis four years ago at age 49. And she said, “I’ve tried to find others with myelofibrosis of a similar age, but so far no luck.” So, is being diagnosed at her age, age 49 with myelofibrosis, unusual?
Dr. Pemmaraju: There you go. That’s perfect. So, that also goes along with our “Young people get MNPs as well.” This was a disease – first of all a disease, now we recognize it as a cancer that was thought to be 60, 70, 80, 90 and older. And now we realize that there’s a significant subset of our populations diagnosed in their teens, twenties, thirties, and forties. So, we definitely want our question – our viewer to know, no, you’re not alone at all. Please, see our paper that we just put out there and several other of my colleagues, including Brady Stein and others.
Two is, my goodness. Not only you’re not alone, but I actually believe – and I know you know this too – that a lot of rare cancers are sometimes are under diagnosed and underappreciated. It does require expert bone marrow, expertise, someone to identify it, someone to do a bone marrow. And lastly, for this patient looking for other patients, I would refer them to sources, such as this one. Patient Power, support groups on Facebook, we have a Twitter feed, as you know, a grassroots Twitter, that’s investigators initiative called #MPNSM (myeloproliferative neoplasm on social media).
So, there are lots of different ways for this person to connect with not only younger patients with the disease, but also as a support group, virtually. And I think platforms, such as Patient Power, have frankly revolutionized the way people have obtained information, have communicated with each other, and specifically for a patient like this in the UK, who is not able to connect with me. And when there are people all over the world waiting to talk to her.
Andrew: Right. I wanna call at our friends in the United Kingdom, MPN Voice.
Dr. Pemmaraju: Oh, yes.
Andrew: It’s Claire Harrison, who you mentioned, wonderful, devoted.
Dr. Pemmaraju: Outstanding.
Andrew: She’s an expert, out of London, helps run it. So, please, connect with them. Okay, here is a question from Erin, as we’re getting near the end of our program. “Can ET ever cause systemic inflammation? And is that what causes symptoms? The inflammation.”
Dr. Pemmaraju: Yes, yes, and yes. So, inflammation, I think, used to be a word that may have been potentially, if I may say, a wastebasket term, but now is a very specific term. So, now we know that a lot of our hematologic disorders and malignancies lead to a high level of inflammation. That means tissue damage. Tissue injury. That’s what inflammation means. There are some conditions that the patient does not even have a blood cancer diagnosis, but has a molecular mutation, that’s called CHIP (clonal hematopoiesis of indeterminate potential), and those patients appear to have a higher likelihood of cardiovascular disease and death. That’s New England Journal of Medicine. The likely pathway is inflammation.
In our patients with MPN, even the quote on quote, earlier stages, such as ET and PV. This is a disease of cytokines and inflammation. So, high levels of abnormal messengers and signals. So, yes, inflammation is part of the disease, patients have a higher rate of cardiovascular events and death. That’s inflammation. And then of course, the bone marrow milieu itself, as it progresses to myelofibrosis has an up ramp, if you will, of cytokines and inflammation. Last part of it is the therapies that we’re working on are trying to either target inflammation itself, or to bring down that level.
Andrew: Okay. I wanna see if – Here’s a – one that just popped in as we get near the end of our program. Roger says, “Are there any drugs being studied that improve anemia in patients with a low hemoglobin?” What’s the easiest way to find out about clinical trials if you live out of the state, or out of the country where this trial may be –?
Dr. Pemmaraju: Yes. Your best resource to look that up is run by the Federal Government, the NH, it’s called clinicaltrials.gov, that’s dot G-O-V. This is an outstanding website, well curated, updated as quickly as they can, and it has a nice search function. You can search by investigator, disease type, condition, and there’s even a box for ‘other’ where you can type in something like ‘myelofibrosis’.
There are several drugs in development. These drugs are known as Luspatercept and Sotatercept, for example. And they’re a class of drugs that are anemia targeting in myelofibrosis and myelodisplastic syndrome. So, the answer is, yes. And you can find out these types of clinical trials either online at this website, or at other websites. But this is an important, urgent, unmet medical need that we are working on, and there are active clinical trials for patients to enroll on.
Andrew: Well, okay. And the last thing I would ask you about – and this always comes up, Naveen, but I wanna hear what you have to say is somebody we have people with ET, we have people with PD, MF, and we talked at one end about acute myeloid leukemia. What do we know about progression now? So, if I’m sitting there with ET, am I necessarily going to go onto PV, or MF? Or anywhere along the line, and how do we know?
Dr. Pemmaraju: We do know a little bit more. So, the answer is no. So, a lot of our patients do stay in the chronic phase, as you’re asking. So, if you’re ET, or PV – and our European colleagues have really done these nice population studies, where the majority – the vast majority of patients with ET and PV are expected in the modern era to have normal life expectancies as long as you’re mitigating in some bleeds, clots, and these type of events.
But for the minority, who don’t have a normal life expectancy, you’re talking about progression to AML, which is a minority of all these. Right? Maybe 5-7 percent of cases at the most. There are some things we have identified. One is that there are some dynamic acquisition of molecular mutations that are happening at the time of progression. And what I mean by that is, there are new injuries to the DNA that people appear to be picking up. So, two important studies our colleague, Raajit Rampal showed that the acquisition of TP53 mutation, which is the guardian of the genome present in 50 (five, zero) percent of human cancers. That looks like it’s more common when ET and PV are trying to take off to AML.
Another study by our Mayo colleagues just published in Blood Advances showed that other mutations, such as PTPN11, or RUNX1, just to name some particular ones, and then we’ve known about ASXL-1 now for a while. So, rapidly change in blood counts in concert with new molecular mutations, and then a baseline if you have high-risk mutations. That seems to be a way for us to predict who might transform faster than others.
Now, that’s an addition to the traditional risk factors that you and I have already discussed, the IPSS risk, or etc. So, there are some ways that we can monitor. A lot of these may be in the research setting. Some are ready for the clinic, but there are some ways now.
Andrew: Okay. So, ladies and gentlemen, I hope this program is been worthwhile for you. Remember that the big meeting of Dr. Pemmaraju and his colleagues from around the world with thousands of hematologists is this the American Society of Hematology meeting, which once again, will be, yay, near me, in San Diego.
Dr. Pemmaraju: Very good.
Andrew: Esther and I’ll just drive over. And the Patient Power team will be there, the Patient Empowerment Network team will be there. So, we’re there for you. So, look for more programs as we go through the fall, and certainly in December, when this meeting happens. And that’s where a lot of the research that Dr. Pemmaraju talks about is presented.
Dr. Pemmaraju: Right.
Andrew: And then we’ll have more news. So, we’re living with these long-term conditions, thank god for most all of us, and it’s a moving target, as I’ve described. I wanna thank you for joining the Patient Empowerment Network program, for sponsoring this program. We thank Incyte Corporation for its support, and Dr. Naveen Pemmaraju from M.D. Anderson, and the Leukemia Department there, thank you for being a partner in this, and just explaining things, and your passion. And Naveen, again, back to your whiteboard back there. Figure it out.
Dr. Pemmaraju: It’s all there. Yes, sir, Andrew.
Andrew: It’s all there. Figure it out. Okay? All right. Thank you so much for being with us from around the world. We love it. We’ve got a community. This is what it’s all about and we’ll have future ask the expert programs. I’m Andrew Schorr near San Diego. Thanks to the Patient Empowerment Network for making all this happen. Remember, knowledge can be the best medicine of all.