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Novel Therapies and Clinical Trials for Myelofibrosis | Updates and Innovations

What’s the latest in higher risk myelofibrosis novel therapies and clinical trials? Expert Dr. Michael Grunwald from Levine Cancer Institute discusses JAK inhibitors and other research updates along with proactive patient advice for clinical trials.

[ACT]IVATION TIP

“…it is okay and, in fact, encouraged for patients to ask about clinical trials, especially if patients have access to a clinical trial center where they might be able to be treated on a clinical trial.”

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Transcript:

Lisa Hatfield:

Dr. Grunwald, can you discuss novel therapies and current clinical trials for lower risk and higher risk myelofibrosis?

Dr. Michael Grunwald:

We’re in an exciting time in myelofibrosis because we’ve already had some new therapies introduced into the clinic in recent years and there are a number of ongoing trials that are very exciting. Some of these trials look at agents in combination with JAK inhibitors or four currently approved JAK inhibitors for myelofibrosis, ruxolitinib (Jakafi) being the oldest one. And many of these trials that are ongoing will combine a novel agent.

So there’s pelabresib (CPI-0610), which is from a class of medicines called BET inhibitors, which has shown very good efficacy in reducing spleen size when it’s combined with ruxolitinib in the treatment of newly diagnosed patients with myelofibrosis. We also have navitoclax, which is an apoptosis inhibitor or a cell death inhibitor that’s been used in combination with ruxolitinib (Jakafi) and has had promising results presented in terms of spleen reduction. There’s selinexor (Xpovio), which is a drug approved for another blood disease, multiple myeloma, and that’s being combined in trials with ruxolitinib.

And then navtemadlin as well, which is from a group of drugs called MDM2 inhibitors. Then we have drugs being looked at as a single agent. So there’s an agent called imetelstat (Rytelo) that was recently approved for a cousin of myelofibrosis called myelodysplastic syndrome or MDS, and now it’s being evaluated in myelofibrosis.

We have ropeginterferon alfa-2b (Besremi), which is approved for another MPN polycythemia vera and it’s being looked at in myelofibrosis as well. Something really exciting to me is the CALR mutant inhibitors. So many patients with myelofibrosis will have CALR mutations. Probably around 30 percent of myelofibrosis patients have that mutation. And there are some strategies being developed to try to target that mutation and kill myelofibrosis cells by targeting it. There’s a naked antibody that’s in clinical trials. There is something called a bispecific antibody that is targeting the mutation, but also trying to bring immune cells or T cells close to the tumor cells so that there’s good tumor killing by the immune system.

And finally there’s a vaccine in development to try to target this mutation. There’s also a medicine called bomedemstat (MK-3543) that’s being tested in multiple myeloproliferative neoplasms and it’s been looked at as a single agent, and I believe it’s going to be looked at as a combination with a JAK inhibitor as well. Most of those therapies are targeting intermediate and high risk MF patients. That’s where a lot of the clinical trial action is. The ropeginterferon alfa-2b study is looking at lower risk patients. And then, there are some strategies to try to improve anemia in myelofibrosis, and those strategies can also include some patients toward the lower end of the risk spectrum.

For example, there’s a drug that’s been approved for myelodysplastic syndrome to help anemia since 2019, I think it’s been, 2019 or 2020. And that’s luspatercept (Reblozyl) it’s being tested for anemia in myelofibrosis. And I think that might be a drug that would be appropriate for some patients with lower risk disease who happen to have some anemia. My [ACT]IVATION tip for this question is that it is okay and, in fact, encouraged for patients to ask about clinical trials, especially if patients have access to a clinical trial center where they might be able to be treated on a clinical trial.


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Myeloproliferative Neoplasm News and Research Updates

Myeloproliferative Neoplasm News and Research Updates from Patient Empowerment Network on Vimeo.

Dr. Lucia Masarova, a myeloproliferative neoplasm (MPN) specialist and researcher, discusses the latest updates from a recent MPN Congress. Some of the highlights include new learnings in hematopoiesis, JAK inhibitor comparisons, interferon therapy, and the potential for combination treatments in the future.

Dr. Lucia Masarova is an MPN Specialist and Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Masarova.

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Advances in Research | Emerging MPN Therapies on the Horizon

Advances in Research | Emerging MPN Therapies on the Horizon 


Transcript:

Katherine Banwell:

Dr. Masarova, you were in New York recently for the MPN congress. Can you share some highlights from that meeting? 

Dr. Lucia Masarova:

Yeah. Sure. That was a very interesting and very loaded conference full of experts and great data. I really liked the overall excellent update of all the therapies that currently exist in the MPN space, including polycythemia vera, essential thrombocythemia, myelofibrosis. So, really a broad breadth of JAK inhibitors, their current sequencing, combinations, interferon update. I very much like also the focus of the novel therapies, which actually talked about, for example, the development of the antibody against mutant calreticulin, PIM inhibitors, and a couple others. They are very promising in the space. 

There were also very, very relevant clinical data. I think I really, really enjoyed the radiation in hematopoiesis topic. It spurred lots of discussions in the room. And also, fantastic talks about clonal hematopoiesis and its role in patients with myeloproliferative neoplasms and cancers.  

Overall, very great data on artificial intelligence because that will be a very needed tool, but also a very worrisome tool, at this point, until you learn how to use it to help our patients. But that showed a very promising effect and ability for us to, for example, predict thrombosis risk in polycythemia vera patients or to distinguish patients with ET versus prefibrotic myelofibrosis, which is still subject to lots of basically subjective analysis from hematopathologist.  

And also, the poster section was quite striking and really excellent. You could walk around and see so many interesting data. The match and direct comparisons of JAK inhibitors, particularly the latest approved, momelotinib (Ojjaara), as it compared to safety data which do currently exist in fedratinib (Inrebic) or pacritinib (Vonjo). 

Katherine Banwell:

When it comes to MPN research and emerging treatment options, what are you excited about specifically? 

Dr. Lucia Masarova:

There is a lot of excitement in the field currently, and it really depends how we put these patients in, as I would call, boxes, but I don’t like the term. We have these less aggressive diseases, such as polycythemia vera and essential thrombocythemia.  

Where I’m really excited about the role of interferon, with the approval of ropeginterferon (Besremi), or ropeginterferon in United States as well as Europe, we have opened a door for learning how can we do better.  

It is approved for polycythemia vera patients. There are currently clinical trials running in essential thrombocythemia patients, within patients with prefibrotic myelofibrosis. That’s an agent that has an ability to go after the disease clone and hopefully, hopefully eradicate or prevent it. Especially, especially exciting in the terms of preventing it for progression.  

Then iron metabolize modifier, hepcidin mimetics, other agents impacting this. It’s very important we finally learn how iron plays the role in these patients and how we can actually improve. Very important area in helping patients requiring phlebotomies and hopefully, hopefully altering the whole disease outcome in the long-term. 

For myelofibrosis we live in an era of JAK inhibitors. We are so excited to have four currently approved and we’re looking forward to the combinations where we have now safer and less cytopenic agents that have a role in anemia or thrombocytopenia and hopefully will be able to be combined with others. 

So, we could even move the field more into other hematologic malignancies, where in myeloma we use five, six, seven, eight drugs. For myelofibrosis, we still have one. So, I think we have still a lot to do. 

And then non-JAK inhibitor combination. Non-JAK inhibitor, a compounds or mechanism of action really tailored to the disease pathogenesis. Calreticulin, excellent topic, which I’m saying maybe in couple years we will be really classifying myeloproliferative neoplasm calreticulin-mutated, but also JAK2-mutated, and we will not be calling them one because hopefully we will find a tool to eradicate calreticulin and to really be able to offer ultimate – what I call ultimate cure.  

So, that’ll be something really exciting to come and all of these investigators in MPN fields are so eager to see what – whether the preclinical data we have seen are going to stand in our patients. And that would be really fantastic.   

Advances in Research | Emerging MPN Therapies on the Horizon

Advances in Research | Emerging MPN Therapies on the Horizon from Patient Empowerment Network on Vimeo.

The pace of research in myeloproliferative neoplasms (MPNs) is advancing rapidly, but what do patients need to know? MPN specialist and researcher Dr. Naveen Pemmaraju shares an update on the latest research and his optimism for the future of MPN care.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.

 

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Transcript:

Katherine Banwell:

Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?  

Dr. Pemmaraju:

Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers. Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib.  Hopefully, we’ll have that approved by the end of the year. 

 [Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.] 

And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib (Gleevec) medicine, hopefully, we have seven to 10 choices for our patients.  

Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies. And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go.

But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.   

An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example.

And so the concept here is, can you now hit the myelofibrosis in a completely different pathway? And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, Phase I and II. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol (Danocrine), steroids, growth factor shots, blood transfusions.  

But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.   

Common MPN Symptoms | What Are They and How Are They Managed?

Common MPN Symptoms | What Are They and How Are They Managed? from Patient Empowerment Network on Vimeo.

Managing the symptoms associated with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) can be frustrating, which is why communication with one’s healthcare team is so important. Dr. Naveen Pemmaraju provides an overview of common symptoms and shares advice for management.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju

 

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Increased MPN Symptoms | What Does It Mean for Patients?


Transcript:

Katherine Banwell:

I’d like to move on to common MPN symptoms now. Let’s start with myelofibrosis. What are the symptoms associated with this particular MPN?  

Dr. Pemmaraju:

Excellent question. So, for the myelofibrosis, generally thought to be our most advanced of the MPNs, can be low risk, intermediate to high risk. We’ll focus our comments here on intermediate to high risk, the more advanced MF. This is important because not only what I’m going to tell you is sort of a subjective list of symptoms, but because of the work of my great friend, Ruben Mesa, who pioneered the MPN symptom burden, we’ve actually been able to, as he and I say, quantify the unquantifiable.  

So, take subjective information and turn it into objective. For example, we know that among the three MPNs, PV, ET, and MF, that fatigue is by far the most common symptom that our patients report. It’s a fatigue that’s more than the general feeling tired at the end of the day. It’s sometimes a wiped-out fatigue. Some of our patients will have pruritus or itching. Many of our patients will have early satiety, which means getting full too early because either the spleen is too big, decreasing the appetite. Bone pain and neuropathy can happen in our MF patients. Brain fog and decreased concentration, huge issue among a lot of our patients. And finally, because of the low blood counts, if a myelofibrosis patient is anemic, they can have those issues. So, fatigue, shortness of breath, even chest pain and palpitations. If the platelets are too low, or too high for that matter, bleeding or clotting.  

So, the problem with myelofibrosis, it ranges the gamut from the low-risk patients, who can be treated maybe even as a PV or ET observation or not as advanced treatment paradigm, all the way to intermediate high risk where patients are cachectic, losing weight, not feeling well, drenching night sweats. And all of these can be captured on not only the scoring systems but also the symptom burden scales. And to be honest with you, this is the majority of what our patients are feeling outside of the blood counts and outside of the objective information. So much so to the point, Katherine, where a patient can present with these symptoms solely, without ever having a blood count or a bone marrow or anything, and then it leads to the work of it.  

Katherine Banwell:

Oh, wow. Wow, fascinating – what about symptoms for polycythemia vera?   

Dr. Pemmaraju:

Yeah, so this is a great theme that you’ve got going here, which is know your body. If you know your body, then you’re able to tell what’s abnormal or normal. p. vera can be a bit more subtle.  

Oftentimes patients with p. vera can have a normal life expectancy and the longer term series in Europe show that it’s basically about the same life expectancy as the general population or slightly lower. But that doesn’t tell the whole story. Patients with p.  vera can have an unbelievable symptom burden, either from the hyperviscosity of the hematocrit, the blood level being too high or the cytokine storm, that I mentioned, that makes people feel not well. So fatigue, brain fog, feelings of sluggishness, feeling too full, those are common in p. vera.  

The treatments are aimed at trying to make that better. So, phlebotomy to bring the hematocrit down below 45 can make you feel a little bit lighter, a little bit better, decrease the brain fog. If you’re using either the standard treatments of Hydrea or interferon, and then, of course, the baby aspirin to prevent clots, heart attacks, stroke. The newer agents in p. vera include the ropeginterferon that we mentioned earlier, clinical trials, such as the PTG-300 that I’m a part of, that try to really keep the blood levels normal all the time.   

And so hopefully help to improve the quality of life, decrease the chance of having a clot, and also hopefully try to make patients feel better from these aspects.   

Katherine Banwell:

What about essential thrombocythemia or ET? 

Dr. Pemmaraju:

ET, again, just like PV, you can have a lot of patients who are either incidentally diagnosed or not too much of a symptom burden. But again, here, the blood counts don’t tell the story. You can have “low risk ET” which is defined as less than 60 or no prior blood clots. So, you can be 43 years old, diagnosed with ET, your blood counts aren’t that high, but yet you’re still feeling overwhelming fatigue, itching. You’re seeing flashing things in your eyes called scotomas. You’re having small nerve or vascular issues called erythromelalgias. It’s a very elusive and difficult disease, particularly for our young patients. So, in ET, again, the same set of symptoms can happen. This fatigue, itching, the brain fog, concentration, bleeding, and or clotting.  

And so again, the goal of therapy is to mitigate those. If you’re young, a lot of patients are either observed or baby aspirin. If you’re older than 60 or have high risk features, then again, cytoreductive therapy. The other aspect I should mention is you can start out with one of these, and it transforms into the other. That’s called clinical or phenotypic shifts. You can start out as an ET, go to PV. You can start out as PV and go to myelofibrosis. You can start out as myelofibrosis and go to acute myeloid leukemia. So, that’s why follow-up, even over years, decades, is important, preferably with an expert team, because you never know when one of these things wants to transform. And then your side effect, or I should say your symptom profile therefore changes with that transformation. 

Common MPN Treatment Side Effects | Strategies for Management

Common MPN Treatment Side Effects | Strategies for Management from Patient Empowerment Network on Vimeo.

When starting treatment for myelofibrosis (MF), polycythemia vera (PV), or essential thrombocythemia (ET), what side effects might one expect? MPN specialist Dr. Naveen Pemmaraju provides an overview of MPN treatments, common issues patients may experience, and strategies for managing these side effects.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.

 

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Increased MPN Symptoms | What Does It Mean for Patients

Increased MPN Symptoms | What Does It Mean for Patients?


Transcript:

Katherine Banwell:

What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.  

Dr. Pemmaraju:

Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib  (Jakafi), the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib (Ojjaara), which is under regulatory review at this time.  

[Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.] 

So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.  

I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p. vera.

As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.  

Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.  

Katherine Banwell:

What about interferon? What are some common side effects?  

Dr. Pemmaraju:

Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular interferon, which was multiple times a week dosing. Then the pegylated interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.  

So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.  

The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days. So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team.

If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.  

I would say also, Katherine, that these later forms of the interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches. 

Katherine Banwell:

What about Hydrea (hydroxyurea)?   

Dr. Pemmaraju:

Yeah, so hydroxyurea, we also have to mention that.  

One of the workhorse medicines of our field. We use it in all the MPNs.  

Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.  

And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well-tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.  

I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.  

So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.   

Katherine Banwell:

With all the testing, yeah.  

Dr. Pemmaraju:

Exactly, right.  

Katherine Banwell:

You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?  

Dr. Pemmaraju:

Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth. So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.  

Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.  

But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later. And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams.

Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable. 

Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows. 

PODCAST: Thriving With an MPN | Managing Symptoms and Treatment Side Effects

 

In this podcast, MPN specialist Dr. Naveen Pemmaraju, discusses strategies for managing symptoms and treatment side effects for people living with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Pemmaraju also shares advice for communicating with your healthcare team and provides an update on the latest MPN treatment and research.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.

Transcript:

Katherine Banwell:

Hello and welcome. I’m your host, Katherine Banwell. Today’s program is a continuation of our Thrive Series and we’re going to discuss coping with MPN symptoms and managing treatment side effects. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.  

Let’s meet our guest today. Joining me is Dr. Naveen Pemmaraju. Dr. Pemmaraju, welcome. Would you please introduce yourself?  

Dr. Pemmaraju:

Oh, thank you, Katherine and team. Just an honor to be here. 

I’m Naveen Pemmaraju, a professor of leukemia at MD Anderson Cancer Center in Houston. And I also serve as one of our executive directors for the MD Anderson Cancer Network, and I specialize in MPNs and rare leukemia. So, happy to join you once again, Katherine.   

Katherine Banwell:

Thank you so much for being with us today, taking time out of your schedule. Well, Dr. Pemmaraju, when it comes to living and thriving within an MPN, managing disease symptoms and treatment side effects is a big part of that. How can symptoms and side effects impact life with an MPN?  

Dr. Pemmaraju:

Katherine, I’m glad you asked about that because I think before we get into the science and the pathobiology and all these complex things, it really starts with the patient. And as you and your team and others have really noted, the MPN for many of our patients, it is a chronic, often lifelong journey. And we really need to reemphasize in this modern era, the patient-centered experience and the caregiver experience.  

And so I would emphasize a few things. One is that our MPNs are oftentimes so-called invisible diseases to other people. So, this phrase that just really is tough for us to hear for our patients and our loved ones, oh, you don’t look that you’re sick. You don’t look like you have cancer. So, it emphasizes the internal part of the internal medicine, that’s one. Number two, it reminds you that you cannot tell on the external what kind of a war, a cytokine war that is going on inside of a patient. And so even though the blood counts are normal, the spleen is okay, the treatment paradigm is going okay, we don’t know what’s really going on. So, that’s why our great friend and colleague Ruben Mesa invented and pioneered the MPN symptom burden to really nail down what’s going on.  

And then third is our treatments, Katherine, our treatments, while overall halting or stopping or helping the MPN can then introduce a whole other round of toxicity, side effects, and so we need to manage that.  

So, both the disease itself and the treatments, two separate entities, and that’s what we need to be monitoring in the clinic.  

Katherine Banwell:

All right, well, thank you for that. As we get into the discussion, Dr. Pemmaraju, it’s important to note that some of the issues we’ll be talking about today are symptoms of the MPN, and others may be treatment-related side effects. So, let’s start with side effects. What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.   

Dr. Pemmaraju:

Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib, the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib, which is under regulatory review at this time.  

So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.   

I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p.- vera.

As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.  

Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.  

Katherine Banwell:

What about interferon? What are some common side effects?  

Dr. Pemmaraju:

Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular Interferon, which was multiple times a week dosing. Then the Pegylated Interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.  

So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.  

The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these Interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days.

So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team. If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.  

I would say also, Katherine, that these later forms of the Interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches. 

Katherine Banwell:

What about hydrea 

Dr. Pemmaraju:

Yeah, right. Yeah, so hydroxyurea, we also have to mention that.  

One of the workhorse medicines of our field. We use it in all the MPNs.  

Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.  

And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.  

I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.   

So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.  

Katherine Banwell:

With all the testing, yeah.  

Dr. Pemmaraju:

Exactly, right.  

Katherine Banwell:

You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?  

Dr. Pemmaraju:

Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth.

So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.  

Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.  

But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later.

And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams. Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable. 

Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows.  

Katherine Banwell:

Thank you for that Dr. Pemmaraju. I’d like to move on to common MPN symptoms now. Let’s start with myelofibrosis. What are the symptoms associated with this particular MPN?  

Dr. Pemmaraju:

Excellent question. So, for the myelofibrosis, generally thought to be our most advanced of the MPNs, can be low risk, intermediate to high risk. We’ll focus our comments here on intermediate to high risk, the more advanced MF. This is important because not only what I’m going to tell you is sort of a subjective list of symptoms, but because of the work of my great friend, Ruben Mesa, who pioneered the MPN symptom burden, we’ve actually been able to, as he and I say, quantify the unquantifiable.  

So, take subjective information and turn it into objective. For example, we know that among the three MPNs, PV, ET, and MF, that fatigue is by far the most common symptom that our patients report. It’s a fatigue that’s more than the general feeling tired at the end of the day. It’s sometimes a wiped-out fatigue. Some of our patients will have pruritus or itching. Many of our patients will have early satiety, which means getting full too early because either the spleen is too big, decreasing the appetite. Bone pain and neuropathy can happen in our MF patients. Brain fog and decreased concentration, huge issue among a lot of our patients.

And finally, because of the low blood counts, if a myelofibrosis patient is anemic, they can have those issues. So, fatigue, shortness of breath, even chest pain and palpitations. If the platelets are too low, or too high for that matter, bleeding or clotting.  

So, the problem with myelofibrosis, it ranges the gamut from the low-risk patients, who can be treated maybe even as a PV or ET observation or not as advanced treatment paradigm, all the way to intermediate high risk where patients are cachectic, losing weight, not feeling well, drenching night sweats. And all of these can be captured on not only the scoring systems but also the symptom burden scales. And to be honest with you, this is the majority of what our patients are feeling outside of the blood counts and outside of the objective information. So much so to the point, Katherine, where a patient can present with these symptoms solely, without ever having a blood count or a bone marrow or anything, and then it leads to the work of it.   

Katherine Banwell:

Oh, wow. Wow, fascinating. What about symptoms for polycythemia vera?  

Dr. Pemmaraju:

Yeah, so this is a great theme that you’ve got going here, which is know your body. If you know your body, then you’re able to tell what’s abnormal or normal. p. vera can be a bit more subtle.  

Oftentimes patients with p. vera can have a normal life expectancy and the longer term series in Europe show that it’s basically about the same life expectancy as the general population or slightly lower. But that doesn’t tell the whole story. Patients with p.  vera can have an unbelievable symptom burden, either from the hyperviscosity of the hematocrit, the blood level being too high or the cytokine storm, that I mentioned, that makes people feel not well. So fatigue, brain fog, feelings of sluggishness, feeling too full, those are common in p. vera.  

The treatments are aimed at trying to make that better. So, phlebotomy to bring the hematocrit down below 45 can make you feel a little bit lighter, a little bit better, decrease the brain fog. If you’re using either the standard treatments of hydrea or Interferon, and then, of course, the baby aspirin to prevent clots, heart attacks, stroke. The newer agents in p. vera include the ropeginterferon that we mentioned earlier, clinical trials, such as the PTG-300 that I’m a part of, that try to really keep the blood levels normal all the time.  

And so hopefully help to improve the quality of life, decrease the chance of having a clot, and also hopefully try to make patients feel better from these aspects.  

Katherine Banwell:

What about essential thrombocythemia or ET? 

Dr. Pemmaraju:

ET, again, just like PV, you can have a lot of patients who are either incidentally diagnosed or not too much of a symptom burden. But again, here, the blood counts don’t tell the story. You can have “low risk ET” which is defined as less than 60 or no prior blood clots. So, you can be 43 years old, diagnosed with ET, your blood counts aren’t that high, but yet you’re still feeling overwhelming fatigue, itching. You’re seeing flashing things in your eyes called scotomas. You’re having small nerve or vascular issues called erythromelalgias. It’s a very elusive and difficult disease, particularly for our young patients. So, in ET, again, the same set of symptoms can happen. This fatigue, itching, the brain fog, concentration, bleeding, and or clotting.  

And so again, the goal of therapy is to mitigate those. If you’re young, a lot of patients are either observed or baby aspirin. If you’re older than 60 or have high risk features, then again, cytoreductive therapy. The other aspect I should mention is you can start out with one of these and it transforms into the other. That’s called clinical or phenotypic shifts. You can start out as an ET, go to PV. You can start out as PV and go to myelofibrosis. You can start out as myelofibrosis and go to acute myeloid leukemia. So, that’s why follow-up, even over years, decades, is important, preferably with an expert team, because you never know when one of these things wants to transform. And then your side effect, or I should say your symptom profile therefore changes with that transformation.  

Katherine Banwell:

Well, it’s obvious that there’s some symptom overlap along with this.  

Dr. Pemmaraju:

Right. 

Katherine Banwell:

And so I’m wondering what the strategies are for managing these. Let’s start with fatigue first.  

Dr. Pemmaraju:

Let’s do that.  

Katherine Banwell:

How do you manage that?  

Dr. Pemmaraju:

This is one of the tougher parts of what we do. I’m glad you’re pinning me down to say it because really this is the majority of what we need to be talking about in the clinic. I’m going  to just be honest, you know, with all the scientific breakthroughs and everything, some of these are limited. The fatigue, this is some of the strategies I use and some of the experts in the field. I think one is managing the underlying disease. So, as you mentioned, if you have high-risk, intermediate to high-risk myelofibrosis, one of the great findings of our field is the JAK inhibitor class generally helps to improve symptom burden.  

So, that is the splenomegaly, the fatigue, the pruritus. Maybe not so much the itching, but some of these other things. So, I think treating the underlying disease, that’s okay. Number two is many clinics, Onc centers around the country are starting to open up a supportive care or fatigue center clinic. So, I am referring several of my patients there, we’re talking about diet, nutrition, exercise. We used to never talk about these things. Ruben Mesa has found that doing yoga and meditation can genuinely actually help the pathobiology to reduce the cytokine storm and improve the fatigue and quality of life. 

Dr. Angela Fleischman, our colleague at UC Irvine, has done work suggesting that possibly an antioxidant diet such as the Mediterranean diet can help the overall general fatigue, well-being, wellness. And then of course I mentioned earlier, but I’ll mention here too, sometimes fatigue is outside of the MPN. Have you had your TSH or thyroid checked? What about your vitamin D levels? How are you doing on these PCP general checks? Things that may be contributing to the life and the happiness.

And finally, let me make a plug for mental health. I don’t know how much we were emphasizing before the COVID pandemic, but after, the last three or four years have been tough. Healthcare providers, caregivers, patients themselves, mental health checkup, that can also be contributing to fatigue, not getting out of bed, in addition to the organic medical problems. So, let me advocate a multifactorial approach, scientifically summed up as treating what you can with the underlying MPN, fine, treating the side effects and symptoms of the MPN, as you said. 

And then, other, which can be a huge bucket, particularly as we get older, to not forget about that. Again, checking the thyroid level. And then when you’re on these different treatments, you can personalize it. Interferon, obviously, has its own separate set of side effects and then of course the other agents. So, I think that may be the best way to approach it. Maybe a three-bucket approach. The MPN itself, and then the treatment itself, and then the other, something like that.  

Katherine Banwell:

Yeah, yeah. And as you’ve mentioned, it’s all going to be personalized and individualized, because what’s going to work for one person is not necessarily going to work for another.  

Dr. Pemmaraju:

Hear, hear, well said to that. You know, you think you make a great diagnosis in the clinic, someone’s having fatigue, they’re on therapy for your MPN. You check the TSH, it’s wildly abnormal. Okay, you refer them to endocrine. Six months later, the thyroid level is completely normal now on thyroid medicine. And yet, the fatigue, brain fog, everything is still not clear.  

The MPN is under good control. What gives? That’s the difficult part of these diseases. So, I really love what you said about the personalization and to keep looking and keep trying.   

Katherine Banwell:

What might an increase in symptoms mean? Does it mean that the disease is progressing or that maybe it’s time to change therapies?   

Dr. Pemmaraju:

Yeah, possibly. So, with all this objective evidence, there’s different buckets of disease progression. And some of them are objective and obvious, rising spleen, increasing blasts, or leukemia cells in the peripheral blood. The start of transfusion dependency for either anemia or platelets that weren’t there before. Sometimes, there are obvious things that you can point to, but there are a couple of scenarios where it’s not as obvious. You just named one. One is increasing symptom burden profile. You see, sometimes you have to think about, is it the sequela of the treatment itself or is it disease progression?  

I’ll give an example. If you start on an Interferon product and the dose is too high, you may be feeling not so great from the Interferon. But maybe in that case, a simple dose reduction was the answer because then you’re still getting the anti-disease activity, less side effects and all that. So, I’ll answer your question by saying possibly, but it can’t be the whole story. So, increasing symptoms is a harbinger, it’s a red flag. In the clinic, it means pause. Workup, is this a subject of the treatment itself? Is it because the disease is progressing? Do we need to do a restaging and workup, whether that means a bone marrow biopsy, whatever that means?

Or again, let’s put that other in there. What about the other comorbidities? Do you have class one heart failure, that’s now class three and you’re retaining fluid? And that’s why you’re short of breath and you actually need an echo and a cardiologist and an evaluation of your diuresis. So, I think that’s important, but the key is don’t blow it off, right? So, increasing symptom in MPN is telling you something isn’t right, and we need to check it out.  

Katherine Banwell:

Right, and for the patient, tell your healthcare team about it.  

Dr. Pemmaraju:

Communicate always. I think what we see is people are so proper and so compassionate and so kind and collegial, and that’s beautiful. But actually in the MPNs and all these rare blood cancers where so little is known and so little is obvious, communication is the key.  

Katherine Banwell:

Yeah. I’d like to make some time now to answer questions from the audience.  

Dr. Pemmaraju:

Great. 

Katherine Banwell:

And here are a few we received prior to the program. Stephanie writes, I have ET and I’m not being treated. Do you have advice for the watch and wait period? I’m anxious about the disease changing and don’t know what I’m waiting for. So, before you answer the question, Dr. Pemmaraju, would you define this term, watch and wait?  

Dr. Pemmaraju:

I will. And to Stephanie and everyone out there, this is a great question. I will say half the folks I talk to actually call it watch and worry, okay. Some people call it watch and wait, and as Stephanie’s saying, some people call it watch and worry.   

Yeah, the concept is threefold. One is that there are many cancers, many cancers, including blood cancers, that can be caught so early on that they don’t require treatment. A lot of patients with CLL, chronic lymphocytic leukemia, ET, as Stephanie mentioned, in the solid tumor. It’s very common to be diagnosed with a prostate cancer that’s low grade, early stage that can be observed. Number two is in ET, there is a science behind it.   

What we found in our studies, and they can be updated over time and you’ll see those, the traditional is that if you’re below the age of 60 and/or you’ve had no blood clot, thrombotic event, that’s considered low risk. And the treatment can be observation, perhaps adding in a baby aspirin to prevent against blood clots if there’s no contraindication. Now what’s magic about that age 60, obviously as you know, it’s not magic. It’s more of a statistical, continuous variable algorithm that says around that time, the risk of blood clots goes up. And so then you’d consider cytoreductive therapy at that point. Now there’s exceptions to that.

Many of our young patients are on therapy, but there’s usually some reason for that. Some high-risk feature, wildly uncontrolled blood counts, for example, symptom burden, some other high-risk features. So, it’s a suggestion. It’s a guideline, not an absolute. And then the third part of it is, the what do you do in that time? And that’s the frustrating thing. And I think that’s what Stephanie’s getting to.  

Again, that’s why I said the watch and worry versus watch and wait. Some of it is, how are you feeling outside of this? Some patients take it as a great news. Hey, you have this blood cancer, that’s not good news. But the good news is it’s probably not going to be active for a long time, we can, “just watch it.” But some people, as Stephanie is saying, take it the opposite way. What do you mean I got a blood cancer? I got something lurking in my body. You’re telling me it’s there, you know it’s there. And so what’s up with that? And the concept there is that some of these situations like low-risk ET, we found that if you treat too early, too aggressively, you can actually do harm.  

Katherine Banwell:

Oh. 

Dr. Pemmaraju:

So, that’s the key. These chemo drugs are not benign as you had me discuss earlier. They have toxicity, side effects, short-term, long-term. So, it’s a risk-benefit thing. If the risk far outweighs the benefit, as in the younger patient with no symptoms, no high-risk features, observation is okay. But at some point, when it turns, that’s the threshold.  

So, really the key is, if we believe these are stem cell blood cancer disorders, we need to be thinking about and designing therapies with minimal to no toxicity. Something that actually modifies the disease early on and something that leads to long-term outcomes. And we don’t have that yet in ET. We’re working on that in PV and myelofibrosis. So, stay tuned for that. And then finally, let me also add, this is an important point, not everybody gets it. This watch and wait versus watch and worry. So, I’m glad Stephanie brought that up because it’s not always good news, uniformly, when you tell someone, good news is you don’t have to do anything bad news, there’s something there.  

Katherine Banwell:

Right. Jess wrote in with this question. I’ve been experiencing bone pain and neuropathy. Is there anything that can eliminate or reduce these symptoms?  

Dr. Pemmaraju:

Great question, and it ties into our earlier question about the MPN symptom burden. On the original MPN-10 scale that Ruben and others pioneered, you will see both of those. You will see the bone pain, neuropathy.  

Now there’s been, you know, different narrowing down of these questionnaires and things, but in general, our patients do have these and that’s across the board. So, not only myelofibrosis but also our patients with PV and ET. These are among the most frustrating, I would say. Again, as you would expect, if you are advanced enough and you’re getting treatment, you hope that the treatment itself, whether it’s the Interferon or the JAK inhibitors or whatever you’re doing, clinical trial, hopes to alleviate those. But it doesn’t all the time.

Then the second issue is, these are likely the result of a cytokine storm or increased cytokines, these protein messengers that are abnormally high in our patients with MPNs. There’s varying unsatisfying things that people do. Sometimes we give antihistamines for people with bone pain. So that’s these over-the-counter sinus allergy medicines. Interestingly, the Claritins and the Zyrtecs, these type of medications, that can sometimes help in MPN bone pain. And then also for the neuropathy, these common neuropathy drugs that everybody knows, the gabapentins and all of these drugs are used frequently.  

There’s no doubt in my clinic and everybody else’s, but the varying levels of success. So, I think it speaks to the fact that these two are kind of from the MPN itself. And treating the underlying MPN is still usually your best strategy, using these, borrowing these medications, from the other aspects.

And then finally, my other plug here, which has kind of been a theme here, hopefully it resonates, and it doesn’t sound generic or unnecessary, is these things can sometimes be something else. Okay, bone pain and neuropathy can be something else. So, we do have cases of people having frequent falls, really serious stuff. In those cases, I refer those patients to a neurologist. Nerve conduction studies right, very advanced studies in the couple of cases that are so severe that it’s beyond thinking that it’s just due to the MPN.   

Katherine Banwell:

Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?  

Dr. Pemmaraju:

Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers.

Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib. Hopefully, we’ll have that approved by the end of the year. And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib Gleevec medicine, hopefully, we have seven to 10 choices for our patients.  

Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies.

And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go. But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.  

An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example. And so the concept here is, can you now hit the myelofibrosis in a completely different pathway?

And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, phase one and two. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol, steroids, growth factor shots, blood transfusions.  

But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.   

Katherine Banwell:

Yeah. Well, Dr. Pemmaraju, as we close out our conversation, I wanted to end with a question that we usually start within our Thrive Series. In your experience, what does it mean to thrive with an MPN?  

Dr. Pemmaraju:

Well, I really love that phrase so much because it’s meaningful to me.  

You know, you’re talking about something that resonates with me and my patients, which is not just living with the MPN, but you’re talking about thriving with an MPN. That’s so resonant to us. I think really, I would go for three parts to that.  

One is that it’s an acknowledgment or a complete understanding of the disease. So, not denial, the opposite of denial, whatever that is, Katherine. So, understanding as much as you can about the disease which is, I encourage people to Google, look up on the internet. I just, what I want you to do is couple that with talking about it in context with your provider. I think the worry that people have is you’re at your home midnight, you’re Googling stuff, it may or may not be right.

So, anyway, so just do that, but then bring the information to the next visit. So, fully understanding and learning as much as you can in your own way. Number two is to be able to have a quality of life that is not just living with the disease, but actually being successful at your relationships, your work, whatever it is that brings you meaning and joy in life. And that sometimes has to do with the MPN paradigm, sometimes has to do with the other stuff we said.  

But I think, doing that, not despite the fact that you have the MPN, but acknowledging it with that, right? And then I think the third aspect is, if you have some way or some platform to be able to express yourself with the MPN because it’s such a rare disease, we think maybe only four out of 100,000 people worldwide get these. A lot of patients, not for everybody, by the way, but a lot of patients are thriving on support groups. 

It used to be you have to be in person, that’s very difficult to do with rare diseases. But now online, social media, a lot of different ways to get involved. Whether someone’s an introvert or an extrovert, whether someone wants to be private or public, all those things are hugely important, so it’s a personal decision. But for many, they want to get out there, and it’s not necessarily this scientific information exchange, although that’s good. But the support and encouragement and comradery of talking to other patients about what we’re talking about.  

It is, in fact, a little bit more facile to do it with the more common diseases, breast cancer, all of these things. And it’s much more difficult, social media online has opened that up. So, to me, I think that’s a kind of mix that I’ve been seeing in my patients. And that leads to empowerment. It leads to taking control of the things that can be controlled, leaving the things that can’t be controlled to what needs to happen. And then an understanding and anticipation of things that may happen in the next few visits, in the next few years. I think that’s how people can thrive with these MPNs. 

Katherine Banwell:

Yeah. And that’s a hopeful message to leave our audience with Dr. Pemmaraju. Thank you so much for joining us today.  

Dr. Pemmaraju:

Well, thank you, Katherine, and hats off to you and the team for not only keeping the advocacy and information going but during this pandemic time, becoming an essential source of information for our patients and getting the word out there. So, thank you.  

Katherine Banwell:

Yeah, thank you. And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today.  

Thriving With an MPN | Managing Symptoms and Treatment Side Effects

Thriving With an MPN | Managing Symptoms and Treatment Side Effects from Patient Empowerment Network on Vimeo.

In this webinar, MPN specialist Dr. Naveen Pemmaraju, discusses strategies for managing symptoms and treatment side effects for people living with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Pemmaraju also shares advice for communicating with your healthcare team and provides an update on the latest MPN treatment and research.

Dr. Naveen Pemmaraju is Director of the Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. Learn more about Dr. Pemmaraju.

 

Related Programs:

Are There Predictors That an MPN May Be Progressing

Are There Predictors That an MPN May Be Progressing?

Understanding and Managing Common MPN Symptoms and Side Effects

Understanding and Managing Common MPN Symptoms and Side Effects

Thriving With an MPN: Advice for Setting Goals and Making Treatment Decisions

Thriving With an MPN | Advice for Setting Goals and Making Treatment Decisions


Transcript:

Katherine Banwell:

Hello and welcome. I’m your host, Katherine Banwell. Today’s program is a continuation of our Thrive Series and we’re going to discuss coping with MPN symptoms and managing treatment side effects. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.  

Let’s meet our guest today. Joining me is Dr. Naveen Pemmaraju. Dr. Pemmaraju, welcome. Would you please introduce yourself?  

Dr. Pemmaraju:

Oh, thank you, Katherine and team. Just an honor to be here. 

I’m Naveen Pemmaraju, a professor of leukemia at MD Anderson Cancer Center in Houston. And I also serve as one of our executive directors for the MD Anderson Cancer Network, and I specialize in MPNs and rare leukemia. So, happy to join you once again, Katherine.   

Katherine Banwell:

Thank you so much for being with us today, taking time out of your schedule. Well, Dr. Pemmaraju, when it comes to living and thriving within an MPN, managing disease symptoms and treatment side effects is a big part of that. How can symptoms and side effects impact life with an MPN?  

Dr. Pemmaraju:

Katherine, I’m glad you asked about that because I think before we get into the science and the pathobiology and all these complex things, it really starts with the patient. And as you and your team and others have really noted, the MPN for many of our patients, it is a chronic, often lifelong journey. And we really need to reemphasize in this modern era, the patient-centered experience and the caregiver experience.  

And so I would emphasize a few things. One is that our MPNs are oftentimes so-called invisible diseases to other people. So, this phrase that just really is tough for us to hear for our patients and our loved ones, oh, you don’t look that you’re sick. You don’t look like you have cancer. So, it emphasizes the internal part of the internal medicine, that’s one. Number two, it reminds you that you cannot tell on the external what kind of a war, a cytokine war that is going on inside of a patient. And so even though the blood counts are normal, the spleen is okay, the treatment paradigm is going okay, we don’t know what’s really going on. So, that’s why our great friend and colleague Ruben Mesa invented and pioneered the MPN symptom burden to really nail down what’s going on.  

And then third is our treatments, Katherine, our treatments, while overall halting or stopping or helping the MPN can then introduce a whole other round of toxicity, side effects, and so we need to manage that.  

So, both the disease itself and the treatments, two separate entities, and that’s what we need to be monitoring in the clinic.  

Katherine Banwell:

All right, well, thank you for that. As we get into the discussion, Dr. Pemmaraju, it’s important to note that some of the issues we’ll be talking about today are symptoms of the MPN, and others may be treatment-related side effects. So, let’s start with side effects. What are the most common issues associated with the main MPN treatment classes? Let’s start with JAK inhibitors.   

Dr. Pemmaraju:

Oh, very nice. Yeah, that’s exactly the way I think about it too. So, with our JAK inhibitors, we now have 10 years since the approval of the ruxolitinib, the first in class. And now we have two more approved agents which are known as fedratinib (Inrebic) and pacritinib (Vonjo), and hopefully a fourth agent, momelotinib, which is under regulatory review at this time.  

[Editor’s Note: Momelotinib (Ojjaara) was approved by the U.S. Food and Drug Administration (FDA) on Sept 15, 2023 for the treatment of intermediate- or high-risk myelofibrosis, in adults with anemia.]

So, we have a whole class of drugs. They have some similarities and then some differences, but in general, the JAK inhibitor class are well-tolerated drugs, but each of them has some side effects.   

I’d like to go through them just as a top-line overview. It’s very important. Number one for the ruxolitinib agent, the one that’s been around longest. This one is usually well-tolerated as we said, but you do have to look out for a few things. Non-melanoma skin cancers can be increased in some of our patients, so the importance of dermatology and skin evaluations. Some infections such as viral herpes, zoster, and shingles, so we need to be aware of that. And then weight gain, weight gain is something that we’re seeing more over time as we appreciate the drug, particularly as we move it into earlier lines of therapy, such as p.- vera.

As I look at the other agents, the fedratinib already carries an FDA black box warning for an encephalopathy syndrome, thought to be Wernicke’s encephalopathy, which can affect the brain. But really an encephalopathy syndrome, which means we have to check thiamine levels and replace them and be aware of that. That’s vitamin B1 and also GI side effects with that agent. And then finally, the pacritinib agent has a few toxicity and side effects.  

Again, all these are on the package label insert, well-known. Some GI side effects, particularly in the first few months, including diarrhea, and we need to watch out for bleeding and these kinds of effects, especially in the opening days and weeks of the agent. So, again, JAK inhibitors, well-tolerated class, oral medicines, but can have some notable side effects that we have to follow together in the clinic.  

Katherine Banwell:

What about interferon? What are some common side effects?  

Dr. Pemmaraju:

Yeah, great. So, the interferon class, which actually now is a class of drugs. We started out as let’s call it the regular Interferon, which was multiple times a week dosing. Then the Pegylated Interferon, which went down to once a week. And then now we have the ropeginterferon (Besremi), which is the recently approved agent in p. vera, which is every two weeks spaced out to every month.  

So, as you said, in this class of drugs, what’s old is new again. These drugs have actually been around longer than the JAK inhibitors, interestingly. You do have to be mindful. These are a very serious set of drugs. We usually set aside a good amount of time to talk about the side effects, and they are many historically.  

The main ones include psychiatric neurological side effects. So, it can cause a depressed mood, change in the mood, even depression. Hugely important, so everyone needs to be aware of that, including the caregivers. It can cause autoimmune side effects, so such as thyroid, liver, these type of side effects. And then finally, of course, any of these Interferons can cause a flu-like profile, you know, not feeling well, particularly in the beginning days.

So, we usually try to mitigate it with lots of education to the patient, the caregiver, remind all members of the team. If you can, maybe even start at a low dose and escalate up, which is what we’re trying to do in the clinic. And then really close monitoring for stuff that you can monitor, the thyroid, the liver, the mental side effects, as we said. Usually most of our patients over time, most of them do get used to the drug. So, there is some kind of an immune component to it, but you can have side effects at any time.  

I would say also, Katherine, that these later forms of the Interferon continue to improve. And so we’re seeing either less and less side effects or at least better managed, better tolerated, more understanding of these. So, a great class of drugs. And I should also say that our colleagues around the world are starting to combine the two classes of drugs for patients with myelofibrosis. And so we need to be paying attention to those combinatorial approaches. 

Katherine Banwell:

What about hydrea 

Dr. Pemmaraju:

Yeah, right. Yeah, so hydroxyurea, we also have to mention that.  

One of the workhorse medicines of our field. We use it in all the MPNs.  

Again, an older class of drugs such as the Interferons that have been around prior to the JAK inhibitors. Used in a variety of diseases, both benign and malignant, used in sickle cell anemia. Historically has been used in both blood and solid tumor cancers, but we use it very commonly in MPNs. Almost all of our viewers are familiar. Hydroxyurea is not a benign drug. It is a chemotherapeutic agent. You know, you have to handle it with care.  

And so it’s got a few side effects. It can cause some fatigue in some patients. One of the more notable classical side effects is an ulcer formation, either in the mouth area or in the lower extremities, such is in the feet, so, you know, grossly visible. It can cause some fever and not feeling well in some patients. I will say again, a lot of these drugs are generally well tolerated. Most of our patients are 60, 70, 80, and older, but you can certainly have those side effects. A lot of these drugs, Katherine, can affect the skin.  

I did mention that earlier. So, ruxolitinib, even the interferons, hydrea, they can all cause skin lesions, maybe some of them associated with non-melanoma skin cancer, such as squamous cell and basal cell. So, one amazing part of the practice has been close association with our dermatology colleagues, not something I would have expected 10, 15 years ago. And that’s been a helpful part of the practice.   

So, I think it’s a point where I can emphasize that, in addition to having us as the MPN or blood cancer team, Katherine, the pandemic has reminded us the importance of primary care team as well. So, it’s really two teams, someone checking the cholesterol, cancer screenings, skin checkups, mammogram, PSAs. And then in coordination with your MPN team and then everyone working together, so colonoscopies, et cetera. So, just a plug there, especially the last three, four years where people have gotten behind to make sure that we’re keeping up with that part of the deal as well.  

Katherine Banwell:

With all the testing, yeah.  

Dr. Pemmaraju:

Exactly, right.  

Katherine Banwell:

You mentioned a couple of treatment side effects and how they’re managed, but in general, across the board, are treatment side effects managed in the same way, in similar ways?  

Dr. Pemmaraju:

Now, that’s a great question. So, here I’ve given you this nice list, kind of academic version of the list, but boy, no, right. And all my patients and everyone out there knows that there’s some varied practices. You know, the varied practices are not only, as you say, across the country and across the world, but also even in our own clinics, patient to patient. The MPNs have humbled and taught us that one person’s MPN can be starkly different from the next, so on and so forth.

So, I’m not just talking about the difference between PV, ET, myelofibrosis, and systemic mastocytosis. I’m talking about one person’s MF is completely different than the other. I think there are a couple of things I didn’t mention. So, pruritus, or itching is one of the great symptoms really. It’s not a side effect usually, but it’s a symptom of the MPN. There are some ways to treat that in the clinic.  

Fatigue really has no great way to treat it. Usually when you introduce one of the JAK inhibitors that can improve. On the side effects side, as we were mentioning, a lot of these are unsatisfying things. The flu-like symptoms of the interferon, the weight gain of the JAK inhibitor. So, I think what you’re saying is so correct, and let me admit it, I’m going to be the first to admit it, there’s not really a good standard playbook.  

But on the other hand, I think personalization. As we’ve always said, in our rare disease space, if you have a disease, it’s not rare to you. It’s what you have, it’s what your spouse is dealing with, your loved one, your mother with you. And so, I would advocate here that there’s a personalized playbook there. I would say that there are three guiding principles though. One is when you have side effects of a medicine, the first thing to do is let your healthcare provider team know. I know that sounds obvious, but here I am in the clinic and sometimes we don’t find out until later.

And so some of that is because the patient says to themselves, let’s tough it out. Or they may not know, or they may not be able to, or it may not be easy to communicate with our healthcare teams. Two is when you’re evaluating, every patient’s case is different. This is not specific advice, as you said, at the top of the hour here. But in a general sense, you really need to evaluate if the side effect is peculiar or particular to just that patient case, so idiosyncratic, unpredictable, notable. 

Or, is it a general expected sort of something that you thought could already happen and then go with it from there? And then finally, the concept of dose interruptions, dose reductions, treatment holidays, something very important. So, basically a lot of different ways you can go, but no standard or uniform playbook in our MPN field, as you and the team well knows.  

Katherine Banwell:

Thank you for that Dr. Pemmaraju. I’d like to move on to common MPN symptoms now. Let’s start with myelofibrosis. What are the symptoms associated with this particular MPN?  

Dr. Pemmaraju:

Excellent question. So, for the myelofibrosis, generally thought to be our most advanced of the MPNs, can be low risk, intermediate to high risk. We’ll focus our comments here on intermediate to high risk, the more advanced MF. This is important because not only what I’m going to tell you is sort of a subjective list of symptoms, but because of the work of my great friend, Ruben Mesa, who pioneered the MPN symptom burden, we’ve actually been able to, as he and I say, quantify the unquantifiable.  

So, take subjective information and turn it into objective. For example, we know that among the three MPNs, PV, ET, and MF, that fatigue is by far the most common symptom that our patients report. It’s a fatigue that’s more than the general feeling tired at the end of the day. It’s sometimes a wiped-out fatigue. Some of our patients will have pruritus or itching. Many of our patients will have early satiety, which means getting full too early because either the spleen is too big, decreasing the appetite. Bone pain and neuropathy can happen in our MF patients. Brain fog and decreased concentration, huge issue among a lot of our patients.

And finally, because of the low blood counts, if a myelofibrosis patient is anemic, they can have those issues. So, fatigue, shortness of breath, even chest pain and palpitations. If the platelets are too low, or too high for that matter, bleeding or clotting.  

So, the problem with myelofibrosis, it ranges the gamut from the low-risk patients, who can be treated maybe even as a PV or ET observation or not as advanced treatment paradigm, all the way to intermediate high risk where patients are cachectic, losing weight, not feeling well, drenching night sweats. And all of these can be captured on not only the scoring systems but also the symptom burden scales. And to be honest with you, this is the majority of what our patients are feeling outside of the blood counts and outside of the objective information. So much so to the point, Katherine, where a patient can present with these symptoms solely, without ever having a blood count or a bone marrow or anything, and then it leads to the work of it.   

Katherine Banwell:

Oh, wow. Wow, fascinating. What about symptoms for polycythemia vera?  

Dr. Pemmaraju:

Yeah, so this is a great theme that you’ve got going here, which is know your body. If you know your body, then you’re able to tell what’s abnormal or normal. p. vera can be a bit more subtle.  

Oftentimes patients with p. vera can have a normal life expectancy and the longer term series in Europe show that it’s basically about the same life expectancy as the general population or slightly lower. But that doesn’t tell the whole story. Patients with p.  vera can have an unbelievable symptom burden, either from the hyperviscosity of the hematocrit, the blood level being too high or the cytokine storm, that I mentioned, that makes people feel not well. So fatigue, brain fog, feelings of sluggishness, feeling too full, those are common in p. vera.  

The treatments are aimed at trying to make that better. So, phlebotomy to bring the hematocrit down below 45 can make you feel a little bit lighter, a little bit better, decrease the brain fog. If you’re using either the standard treatments of hydrea or Interferon, and then, of course, the baby aspirin to prevent clots, heart attacks, stroke. The newer agents in p. vera include the ropeginterferon that we mentioned earlier, clinical trials, such as the PTG-300 that I’m a part of, that try to really keep the blood levels normal all the time.  

And so hopefully help to improve the quality of life, decrease the chance of having a clot, and also hopefully try to make patients feel better from these aspects.  

Katherine Banwell:

What about essential thrombocythemia or ET? 

Dr. Pemmaraju:

ET, again, just like PV, you can have a lot of patients who are either incidentally diagnosed or not too much of a symptom burden. But again, here, the blood counts don’t tell the story. You can have “low risk ET” which is defined as less than 60 or no prior blood clots. So, you can be 43 years old, diagnosed with ET, your blood counts aren’t that high, but yet you’re still feeling overwhelming fatigue, itching. You’re seeing flashing things in your eyes called scotomas. You’re having small nerve or vascular issues called erythromelalgias. It’s a very elusive and difficult disease, particularly for our young patients. So, in ET, again, the same set of symptoms can happen. This fatigue, itching, the brain fog, concentration, bleeding, and or clotting.  

And so again, the goal of therapy is to mitigate those. If you’re young, a lot of patients are either observed or baby aspirin. If you’re older than 60 or have high risk features, then again, cytoreductive therapy. The other aspect I should mention is you can start out with one of these and it transforms into the other. That’s called clinical or phenotypic shifts. You can start out as an ET, go to PV. You can start out as PV and go to myelofibrosis. You can start out as myelofibrosis and go to acute myeloid leukemia. So, that’s why follow-up, even over years, decades, is important, preferably with an expert team, because you never know when one of these things wants to transform. And then your side effect, or I should say your symptom profile therefore changes with that transformation.  

Katherine Banwell:

Well, it’s obvious that there’s some symptom overlap along with this.  

Dr. Pemmaraju:

Right. 

Katherine Banwell:

And so I’m wondering what the strategies are for managing these. Let’s start with fatigue first.  

Dr. Pemmaraju:

Let’s do that.  

Katherine Banwell:

How do you manage that?  

Dr. Pemmaraju:

This is one of the tougher parts of what we do. I’m glad you’re pinning me down to say it because really this is the majority of what we need to be talking about in the clinic. I’m going  to just be honest, you know, with all the scientific breakthroughs and everything, some of these are limited. The fatigue, this is some of the strategies I use and some of the experts in the field. I think one is managing the underlying disease. So, as you mentioned, if you have high-risk, intermediate to high-risk myelofibrosis, one of the great findings of our field is the JAK inhibitor class generally helps to improve symptom burden.  

So, that is the splenomegaly, the fatigue, the pruritus. Maybe not so much the itching, but some of these other things. So, I think treating the underlying disease, that’s okay. Number two is many clinics, Onc centers around the country are starting to open up a supportive care or fatigue center clinic. So, I am referring several of my patients there, we’re talking about diet, nutrition, exercise. We used to never talk about these things. Ruben Mesa has found that doing yoga and meditation can genuinely actually help the pathobiology to reduce the cytokine storm and improve the fatigue and quality of life. 

Dr. Angela Fleischman, our colleague at UC Irvine, has done work suggesting that possibly an antioxidant diet such as the Mediterranean diet can help the overall general fatigue, well-being, wellness. And then of course I mentioned earlier, but I’ll mention here too, sometimes fatigue is outside of the MPN. Have you had your TSH or thyroid checked? What about your vitamin D levels? How are you doing on these PCP general checks? Things that may be contributing to the life and the happiness.

And finally, let me make a plug for mental health. I don’t know how much we were emphasizing before the COVID pandemic, but after, the last three or four years have been tough. Healthcare providers, caregivers, patients themselves, mental health checkup, that can also be contributing to fatigue, not getting out of bed, in addition to the organic medical problems. So, let me advocate a multifactorial approach, scientifically summed up as treating what you can with the underlying MPN, fine, treating the side effects and symptoms of the MPN, as you said. 

And then, other, which can be a huge bucket, particularly as we get older, to not forget about that. Again, checking the thyroid level. And then when you’re on these different treatments, you can personalize it. Interferon, obviously, has its own separate set of side effects and then of course the other agents. So, I think that may be the best way to approach it. Maybe a three-bucket approach. The MPN itself, and then the treatment itself, and then the other, something like that.  

Katherine Banwell:

Yeah, yeah. And as you’ve mentioned, it’s all going to be personalized and individualized, because what’s going to work for one person is not necessarily going to work for another.  

Dr. Pemmaraju:

Hear, hear, well said to that. You know, you think you make a great diagnosis in the clinic, someone’s having fatigue, they’re on therapy for your MPN. You check the TSH, it’s wildly abnormal. Okay, you refer them to endocrine. Six months later, the thyroid level is completely normal now on thyroid medicine. And yet, the fatigue, brain fog, everything is still not clear.  

The MPN is under good control. What gives? That’s the difficult part of these diseases. So, I really love what you said about the personalization and to keep looking and keep trying.   

Katherine Banwell:

What might an increase in symptoms mean? Does it mean that the disease is progressing or that maybe it’s time to change therapies?   

Dr. Pemmaraju:

Yeah, possibly. So, with all this objective evidence, there’s different buckets of disease progression. And some of them are objective and obvious, rising spleen, increasing blasts, or leukemia cells in the peripheral blood. The start of transfusion dependency for either anemia or platelets that weren’t there before. Sometimes, there are obvious things that you can point to, but there are a couple of scenarios where it’s not as obvious. You just named one. One is increasing symptom burden profile. You see, sometimes you have to think about, is it the sequela of the treatment itself or is it disease progression?  

I’ll give an example. If you start on an Interferon product and the dose is too high, you may be feeling not so great from the Interferon. But maybe in that case, a simple dose reduction was the answer because then you’re still getting the anti-disease activity, less side effects and all that. So, I’ll answer your question by saying possibly, but it can’t be the whole story. So, increasing symptoms is a harbinger, it’s a red flag. In the clinic, it means pause. Workup, is this a subject of the treatment itself? Is it because the disease is progressing? Do we need to do a restaging and workup, whether that means a bone marrow biopsy, whatever that means?

Or again, let’s put that other in there. What about the other comorbidities? Do you have class one heart failure, that’s now class three and you’re retaining fluid? And that’s why you’re short of breath and you actually need an echo and a cardiologist and an evaluation of your diuresis. So, I think that’s important, but the key is don’t blow it off, right? So, increasing symptom in MPN is telling you something isn’t right, and we need to check it out.  

Katherine Banwell:

Right, and for the patient, tell your healthcare team about it.  

Dr. Pemmaraju:

Communicate always. I think what we see is people are so proper and so compassionate and so kind and collegial, and that’s beautiful. But actually in the MPNs and all these rare blood cancers where so little is known and so little is obvious, communication is the key.  

Katherine Banwell:

Yeah. I’d like to make some time now to answer questions from the audience.  

Dr. Pemmaraju:

Great. 

Katherine Banwell:

And here are a few we received prior to the program. Stephanie writes, I have ET and I’m not being treated. Do you have advice for the watch and wait period? I’m anxious about the disease changing and don’t know what I’m waiting for. So, before you answer the question, Dr. Pemmaraju, would you define this term, watch and wait?  

Dr. Pemmaraju:

I will. And to Stephanie and everyone out there, this is a great question. I will say half the folks I talk to actually call it watch and worry, okay. Some people call it watch and wait, and as Stephanie’s saying, some people call it watch and worry.   

Yeah, the concept is threefold. One is that there are many cancers, many cancers, including blood cancers, that can be caught so early on that they don’t require treatment. A lot of patients with CLL, chronic lymphocytic leukemia, ET, as Stephanie mentioned, in the solid tumor. It’s very common to be diagnosed with a prostate cancer that’s low grade, early stage that can be observed. Number two is in ET, there is a science behind it.   

What we found in our studies, and they can be updated over time and you’ll see those, the traditional is that if you’re below the age of 60 and/or you’ve had no blood clot, thrombotic event, that’s considered low risk. And the treatment can be observation, perhaps adding in a baby aspirin to prevent against blood clots if there’s no contraindication. Now what’s magic about that age 60, obviously as you know, it’s not magic. It’s more of a statistical, continuous variable algorithm that says around that time, the risk of blood clots goes up. And so then you’d consider cytoreductive therapy at that point. Now there’s exceptions to that.

Many of our young patients are on therapy, but there’s usually some reason for that. Some high-risk feature, wildly uncontrolled blood counts, for example, symptom burden, some other high-risk features. So, it’s a suggestion. It’s a guideline, not an absolute. And then the third part of it is, the what do you do in that time? And that’s the frustrating thing. And I think that’s what Stephanie’s getting to.  

Again, that’s why I said the watch and worry versus watch and wait. Some of it is, how are you feeling outside of this? Some patients take it as a great news. Hey, you have this blood cancer, that’s not good news. But the good news is it’s probably not going to be active for a long time, we can, “just watch it.” But some people, as Stephanie is saying, take it the opposite way. What do you mean I got a blood cancer? I got something lurking in my body. You’re telling me it’s there, you know it’s there. And so what’s up with that? And the concept there is that some of these situations like low-risk ET, we found that if you treat too early, too aggressively, you can actually do harm.  

Katherine Banwell:

Oh. 

Dr. Pemmaraju:

So, that’s the key. These chemo drugs are not benign as you had me discuss earlier. They have toxicity, side effects, short-term, long-term. So, it’s a risk-benefit thing. If the risk far outweighs the benefit, as in the younger patient with no symptoms, no high-risk features, observation is okay. But at some point, when it turns, that’s the threshold.  

So, really the key is, if we believe these are stem cell blood cancer disorders, we need to be thinking about and designing therapies with minimal to no toxicity. Something that actually modifies the disease early on and something that leads to long-term outcomes. And we don’t have that yet in ET. We’re working on that in PV and myelofibrosis. So, stay tuned for that. And then finally, let me also add, this is an important point, not everybody gets it. This watch and wait versus watch and worry. So, I’m glad Stephanie brought that up because it’s not always good news, uniformly, when you tell someone, good news is you don’t have to do anything bad news, there’s something there.  

Katherine Banwell:

Right. Jess wrote in with this question. I’ve been experiencing bone pain and neuropathy. Is there anything that can eliminate or reduce these symptoms?  

Dr. Pemmaraju:

Great question, and it ties into our earlier question about the MPN symptom burden. On the original MPN-10 scale that Ruben and others pioneered, you will see both of those. You will see the bone pain, neuropathy.  

Now there’s been, you know, different narrowing down of these questionnaires and things, but in general, our patients do have these and that’s across the board. So, not only myelofibrosis but also our patients with PV and ET. These are among the most frustrating, I would say. Again, as you would expect, if you are advanced enough and you’re getting treatment, you hope that the treatment itself, whether it’s the Interferon or the JAK inhibitors or whatever you’re doing, clinical trial, hopes to alleviate those. But it doesn’t all the time.

Then the second issue is, these are likely the result of a cytokine storm or increased cytokines, these protein messengers that are abnormally high in our patients with MPNs. There’s varying unsatisfying things that people do. Sometimes we give antihistamines for people with bone pain. So that’s these over-the-counter sinus allergy medicines. Interestingly, the Claritins and the Zyrtecs, these type of medications, that can sometimes help in MPN bone pain. And then also for the neuropathy, these common neuropathy drugs that everybody knows, the gabapentins and all of these drugs are used frequently.  

There’s no doubt in my clinic and everybody else’s, but the varying levels of success. So, I think it speaks to the fact that these two are kind of from the MPN itself. And treating the underlying MPN is still usually your best strategy, using these, borrowing these medications, from the other aspects.

And then finally, my other plug here, which has kind of been a theme here, hopefully it resonates, and it doesn’t sound generic or unnecessary, is these things can sometimes be something else. Okay, bone pain and neuropathy can be something else. So, we do have cases of people having frequent falls, really serious stuff. In those cases, I refer those patients to a neurologist. Nerve conduction studies right, very advanced studies in the couple of cases that are so severe that it’s beyond thinking that it’s just due to the MPN.   

Katherine Banwell:

Dr. Pemmaraju, as a researcher, what are new and emerging therapies on the horizon in MPN care?  

Dr. Pemmaraju:

Well, Katherine, I’m glad you asked because I’m proud to tell you here, at the end of 2023, that we’ve now entered a new golden era of therapies for MPNs. Your group, and others, have led the way in advocating, but for so many years, honestly, we didn’t have many breakthroughs or new medicines. And now we literally have something we’re hearing about once a month. I think this golden era is divided into four buckets, Katherine, and that’s why I’m so excited for our patients and their caregivers.

Number one is novel JAK inhibitors. So, beyond the approved ruxolitinib, fedratinib, and now pacritinib, we have a fourth one that’s under consideration, that’s called momelotinib. Hopefully, we’ll have that approved by the end of the year. And there are actually other drugs around the world. So, not just in the U.S. and North America that are being developed as a further JAK inhibitor. So, just like we’ve seen in CML with the TKIs for BCR-ABL after the imatinib Gleevec medicine, hopefully, we have seven to 10 choices for our patients.  

Number two is the combinatorial approach of a JAK inhibitor plus something else. And that’s a field that I’m personally very involved in and helping to lead. The concept there is you take the known workhorse drug, the JAK inhibitor, use it as the backbone, and then add in the second agent. We started to do those studies in patients who were already starting to lose a response and we added in the second agent, those were called suboptimal studies.

And then now we’re moving those drugs into the frontline setting in international global randomized studies. So, stay tuned, let’s see how those go. But the concept is, can you take a new agent, whether it’s a BET inhibitor, a bromodomain inhibitor, a Bcl-xL inhibitor, PI3 Kinase, et cetera, and combine it with the JAK inhibitor? The third bucket that’s even more exciting to many people is that of novel agents standing alone by themselves. Now you’ve had either a JAK inhibitor or some other therapy for your myelofibrosis. That didn’t work for whatever reason. Now you’re looking for a completely new strategy.  

An explosion of research, not just in the lab, which we’ve had for the last 10 years, but over the last three or four years, amazingly, even despite the COVID pandemic. I would say dozens, really dozens of trials that are what you would consider beyond or non-JAK inhibitor therapy. Some of them include telomerase inhibition, with the imetelstat agent, for example. And so the concept here is, can you now hit the myelofibrosis in a completely different pathway?

And the answer clearly is yes. And those results have been tested now in the lower stages, the earlier stages, phase one and two. And you’re starting to see those drugs enter into the phase two and phase three. We eagerly await those results if there can be a viable beyond JAK inhibitor. And then finally, if that wasn’t exciting enough, there’s a fourth bucket, which is thinking about specifically the anemia myelofibrosis. We’ve never really historically done that. We’ve had older drugs, danazol, steroids, growth factor shots, blood transfusions.  

But now here you see both pharmaceutical interest, as well as academic interest, in developing agents that either specifically target the anemia of MF or both, the MF and the anemia. And that could be a game changer for our patients in the next five years. So, Katherine, a wealth of exploding research that I’m personally very excited about that gives me and our field hope, momentum, and enthusiasm going into 2024.   

Katherine Banwell:

Yeah. Well, Dr. Pemmaraju, as we close out our conversation, I wanted to end with a question that we usually start within our Thrive Series. In your experience, what does it mean to thrive with an MPN?  

Dr. Pemmaraju:

Well, I really love that phrase so much because it’s meaningful to me.  

You know, you’re talking about something that resonates with me and my patients, which is not just living with the MPN, but you’re talking about thriving with an MPN. That’s so resonant to us. I think really, I would go for three parts to that.  

One is that it’s an acknowledgment or a complete understanding of the disease. So, not denial, the opposite of denial, whatever that is, Katherine. So, understanding as much as you can about the disease which is, I encourage people to Google, look up on the internet. I just, what I want you to do is couple that with talking about it in context with your provider. I think the worry that people have is you’re at your home midnight, you’re Googling stuff, it may or may not be right.

So, anyway, so just do that, but then bring the information to the next visit. So, fully understanding and learning as much as you can in your own way. Number two is to be able to have a quality of life that is not just living with the disease, but actually being successful at your relationships, your work, whatever it is that brings you meaning and joy in life. And that sometimes has to do with the MPN paradigm, sometimes has to do with the other stuff we said.  

But I think, doing that, not despite the fact that you have the MPN, but acknowledging it with that, right? And then I think the third aspect is, if you have some way or some platform to be able to express yourself with the MPN because it’s such a rare disease, we think maybe only four out of 100,000 people worldwide get these. A lot of patients, not for everybody, by the way, but a lot of patients are thriving on support groups. 

It used to be you have to be in person, that’s very difficult to do with rare diseases. But now online, social media, a lot of different ways to get involved. Whether someone’s an introvert or an extrovert, whether someone wants to be private or public, all those things are hugely important, so it’s a personal decision. But for many, they want to get out there, and it’s not necessarily this scientific information exchange, although that’s good. But the support and encouragement and comradery of talking to other patients about what we’re talking about.  

It is, in fact, a little bit more facile to do it with the more common diseases, breast cancer, all of these things. And it’s much more difficult, social media online has opened that up. So, to me, I think that’s a kind of mix that I’ve been seeing in my patients. And that leads to empowerment. It leads to taking control of the things that can be controlled, leaving the things that can’t be controlled to what needs to happen. And then an understanding and anticipation of things that may happen in the next few visits, in the next few years. I think that’s how people can thrive with these MPNs. 

Katherine Banwell:

Yeah. And that’s a hopeful message to leave our audience with Dr. Pemmaraju. Thank you so much for joining us today.  

Dr. Pemmaraju:

Well, thank you, Katherine, and hats off to you and the team for not only keeping the advocacy and information going but during this pandemic time, becoming an essential source of information for our patients and getting the word out there. So, thank you.  

Katherine Banwell:

Yeah, thank you. And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today.  

Understanding MPN Treatment Options | What’s Available for MF, PV, and ET?

Understanding MPN Treatment Options | What’s Available for MF, PV, and ET? from Patient Empowerment Network on Vimeo.

How are myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) treated? Dr. Raajit Rampal reviews the available therapies for each of the MPNs. 

Dr. Raajit Rampal is a hematologist-oncologist specializing in the treatment of myeloproliferative neoplasms (MPNs) and leukemia at Memorial Sloan Kettering Cancer Center in New York City. Learn more about Dr. Rampal.

 

Related Programs:

MPN Essential Testing | How Results Impact Care & Treatment Options

MPN Essential Testing | How Results Impact Care & Treatment Options

Thriving With an MPN: Advice for Setting Goals and Making Treatment Decisions

Thriving With an MPN | Advice for Setting Goals and Making Treatment Decisions

Understanding and Managing Common MPN Symptoms and Side Effects

Understanding and Managing Common MPN Symptoms and Side Effects


Transcript:

Katherine Banwell:

So, what are the types of treatments available for MPNs?  And let’s start with myelofibrosis or MF. 

Dr. Raajit Rampal:

If we had had this discussion five years ago, it would be pretty simple, and it would take a minute or two. And that’s completely changing and that’s amazing, and it’s good for all of our patients.  

Right now, for patients with MF, it depends on what the issue is. If the issue is symptoms or spleen, JAK inhibitors are our first line of therapy. Three approved JAK inhibitors are currently available, two on the first side ruxolitinib (Jakafi) and fedratinib (Inrebic). And pacritinib (Vonjo) can be used for patients with really low platelet counts.  

There is a fourth JAK inhibitor that we expect to be, hopefully, approved in June of this year, momelotinib. So, the landscape is about to complete broaden in terms of just JAK inhibitors. 

But beyond the JAK inhibitors themselves, there are a number of late stage clinical trials that are combining JAK inhibitors with agents that work through a different mechanism that don’t work through inhibition of the JAK pathway. So far, these drugs have all shown promise in early phase trials. Now, the definitive Phase III trials are being done. We have to wait and see what the data tells us. But if these are positive trials, this could completely alter the landscape of MPN. 

Katherine Banwell:

There’s also transplants available, right? 

Dr. Raajit Rampal:

Correct. Transplants for more advanced patients, which comes with some major risks. And so, that has to be thought of very carefully in terms of the risks and benefit. But it is a potentially curative strategy. 

Katherine Banwell:

Let’s turn to polycythemia vera or PV. What types of treatments are available? 

Dr. Raajit Rampal:

It’s really quite a range. So, there are things like phlebotomy and aspirin, which has been the mainstay of therapy for many years. There are drugs like hydroxyurea (Hydrea), interferons, JAK inhibitors. So, ruxolitinib is approved in certain settings for treating polycythemia vera. So, the landscape is broad. There are a lot of questions going on right now with polycythemia vera with regards to how it should best be treated. Is the mainstay of phlebotomy and aspirin really what we should be doing or should we be giving patients treatment earlier on. 

And there is some data to suggest that. There is this drug called ropeginterferon (Besremi) that’s FDA-approved for polycythemia, which was compared in the study to phlebotomy and aspirin.  

And at least the data suggests that there may be better control of the disease and less progression possibly, and it’s a small number of patients, by treating patients earlier. Whereas we would have just given phlebotomy and aspirin. So, it’s something to consider. There are drugs in clinical trials as well that look promising one of which is called rusfertide, which actually works by changing the way iron is used by the body. 

Iron is a key component to hemoglobin and it is, of course, a key component to polycythemia in the sense that we phlebotomize patients to make them iron deficient and that’s how we control the disease. But this is a pharmacological way to do that. So, that drug is now in Phase III trials. So, that may also alter the landscape of treatment of PV in the near future.  

Katherine Banwell:

Finally, how is essential thrombocythemia treated? 

Dr. Raajit Rampal:

So, in some cases, with absolutely nothing as we had talked about a moment ago. There is some thought that in really, really low-risk patients. Maybe you don’t need to do anything except observe them. Whereas most patients are on an aspirin. And beyond that, we have drugs like interferon, pegylated interferon, and hydroxyurea and anagrelide, all of which can be utilized. It’s not entirely clear if there is one distinct first line treatment that is the best but these drugs are all active. JAK inhibitors have been studied in this setting. And to date, the data hasn’t led to their approval but, certainly, people have studied it.   

Katherine Banwell:

Dr. Rampal, how can you tell if a treatment is effective? Are there signs that you look for? 

Dr. Raajit Rampal:

Well, I think it’s a couple of things.  

One, are we meeting the treatment goals in terms of are we controlling blood counts with ET or PV? That’s one of the first principles in management. And with regards to MF, the same thing. Are patients’ symptoms being controlled? Is the spleen being adequately controlled? And then, there’s the symptom burden because just because the blood counts are being controlled, patients may still have symptoms, in which case, they are not being adequately treated. And then, we have to do our best to try to find a treatment strategy that does control their blood counts but also does control their symptoms. So, there is the blood count perspective but there is the symptom perspective as well. 

Managing Life With an MPN | What You Need to Know

MPN expert Dr. Raajit Rampal shares advice for making treatment decisions for patients with essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Rampal also reviews tips and tools for managing symptoms and side effects and provides an update on new and emerging MPN therapies.
 
Dr. Raajit Rampal is a hematologist-oncologist specializing in the treatment of myeloproliferative neoplasms (MPNs) and leukemia at Memorial Sloan Kettering Cancer Center in New York City. Learn more about Dr. Rampal.
 
 

Related Programs:

Thriving With an MPN | Tips for Managing Worry and Anxiety

Thriving With an MPN | Tips for Managing Worry and Anxiety

How Can You Thrive With an MPN? Advice for Navigating Care. 

How to Treat PV-Related Itching

How to Treat PV-Related Itching 


Transcript:

Katherine Banwell:

Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today’s webinar is a continuation of our Thrive series. And we’re going to discuss how to manage life with an MPN.  Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.  

Let’s meet our guest today. Joining me is Dr. Raajit Rampal. Dr. Rampal, welcome. Would you please introduce yourself.    

Dr. Raajit Rampal:

Hi. Thank you so much for having me. I’m Raajit Rampal from Memorial Sloan Kettering Cancer Center where I focus on myeloproliferative neoplasms. 

Katherine Banwell:

Thank you so much for being with us today. 

Dr. Raajit Rampal:

My pleasure.  

Katherine Banwell:

As we do with each of the webinars in our Thrive series, let’s start with this question. In your experience, what do you think it means to thrive with an MPN? 

Dr. Raajit Rampal:

It’s a great question, right. I think taking a step back, when we think about our patients with MPNs, one of the questions I always have for patients are what are your goals. And inevitably and invariably, people want two things. They want to live longer and they want to live better. And so, I think that thinking about thriving with an MPN to me is about how do we minimize the impact of an MPN in someone’s life. And that means a couple of things. One that means how do we deal with symptoms or things that are causing medical problems. 

But two, how do we deal with the anxiety of a diagnosis? In many cases in my experience, that can be just as detrimental to somebody’s well-being as the actual physical symptoms of the disease.  

Katherine Banwell:

When it comes to choosing therapy for polycythemia vera essential thrombocythemia, or myelofibrosis, it’s important to work with your healthcare team to identify what is going to work best for you. So, to begin, would you define shared decision making and why is this critical to properly managing life with an MPN? 

Dr. Raajit Rampal:

Yeah. Shared decision-making, to me, is really about the physician or whoever is on the healthcare team providing the patient all of the information needed to make a good decision. That means what are we trying to do? What is the medication or invention going to accomplish? What are the side effects because there are always side effects.  

And what do we think that’s going to do or how is that going to impact the patient’s life? Where things get nuanced is that patients come to us because we have expertise. There are two extremes. One extreme is that the physician says this is the medication you should take. End of discussion. The other extreme though is also not helpful, which is to say to a patient here are five choices. Here are the side effects. You pick one. Our job is to lay out those side effects and the benefits but then, also help guide a decision. 

Katherine Banwell:

What are treatment goals and how are they determined?  

Dr. Raajit Rampal:

It depends on the disease to a large extent. Now, when we’re dealing with ET and PV, the primary goal of our interventions is to reduce the risk of a clotting event or bleeding event. And that usually involves controlling the blood counts in some cases, not in all patients with ET. 

Sometimes aspirin is all we do. Myelofibrosis is a little bit more complicated because it depends on what the problem is. Not all myelofibrosis patients have the same challenges. Some have anemia that needs treatment. Some have a big spleen. Some have symptoms and some have nothing and they just need observation. So, it’s a bigger list with MF patients. But I think the first part of the discussion always is defining what the goal needs to be. 

Katherine Banwell:

What factors are considered when choosing therapy for ET, PV, and MF? 

Dr. Raajit Rampal:

I think a couple of things. One is what medication we think is going to benefit the patient best. That has to take into account the individual, their willingness to take certain medications, for example, pills versus interferon injection. Some people have an aversion to self-injection, which we have to take that into account. What are the other medical conditions that the patient is dealing with? 

And the reality is, in some cases, it’s cost because these medications, depending on a patient’s insurance, can have quite a different spread in terms of cost. Unfortunately, that is something we have to take into account. 

Katherine Banwell:

Let’s talk about what sort of tests should be done following an MPN diagnosis. Can you tell me about those? 

Dr. Raajit Rampal:

Yeah. Fundamental to the MPN itself, the things that we really want to know is, in most cases, a bone marrow examination is needed because that will tell us really what the disease is that we’re dealing with. It will tell us about the genetics. I strongly believe we have to be comprehensive in our genetic assessments because that does prognosticate and sometimes gives us an opportunity in terms of treatment. Chromosomal analysis. These are the basic bread and butter hematology tests we want to do from the bone marrow to really understand what the patient’s disease is. 

Beyond that, I think that particularly in patients with PV and ET, it’s important that we partner with their primary care physicians to make sure that they’ve had, for example, testing for diabetes, a recent lipid profile, any cardiovascular tests, particularly measurements of blood pressure because these things are all important in terms of an ET or PV patient’s risk of having a blood clot. So, there are, again, things that are within hematology realm but then, there are other general health things that become really important in somebody who is diagnosed with PV or ET. 

Katherine Banwell:

How often should lab tests of blood work be done? 

Dr. Raajit Rampal:

It really depends on the patient. For some patients with PV, for example, they need to have their blood checked every three weeks because they’re having frequent phlebotomies. Whereas some patients with ET could probably go forward to six months between blood tests.  

So, it depends on the individual. 

Katherine Banwell:

How can results of biomarker testing affect treatment choices for patients with MPNs? 

Dr. Raajit Rampal:

 question. The genetics are becoming increasingly important in our treatment decisions. So, let’s take a simple example, which is patients with ET. Calreticulin and JAK2 and MPL are the three most common mutations that we see. But they have very different invocation. So, somebody could have a calreticulin-mutated ET and based on them having that calreticulin mutation and no other factors like no history of clotting, that patient may never need to go on a medication aside from aspirin. And even early on, it’s debatable whether or not some of these patients really need aspirin at all. 

Whereas somebody who had a JAK-2 mutant ET, our guidelines and data suggests that that person, once they reach a certain age, should probably be on medication. So, that’s kind of perhaps one of our more clearcut examples of a genetic biomarker telling us how to approach treatment. 

And then, it gets more nuanced from that and more exciting and interesting in the sense that there are mutations, for example, that occur in myelofibrosis and in patients whose disease is progressing towards leukemia, such as IDH mutations. And these are things that are now targetable with FDA-approved drugs.  

And there are now clinical trials combining JAK inhibitors and IDH inhibitors for patients who have more advanced disease who have these IDH mutations. So, you go from on one end, these genomic markers being of prognostic significance and now, on the other hand, we’re getting to a point where, in some cases, they might tell us how to best treat a patient. 

Katherine Banwell:

Dr. Rampal, should all patients diagnosed with MPN’s undergo molecular testing? 

Dr. Raajit Rampal:

I strongly believe that. I think that we’ve learned so much that these tests have prognostic value. 

And in some cases, it may suggest a slightly different diagnosis. I definitely think that should be the case. 

Katherine Banwell:

What should patients be asking once they have the results? 

Dr. Raajit Rampal:

What does it mean? That’s the most basic and fundamental question. It’s one thing to get a list of mutations. But the real bread and butter question is what does this mean to the disease and my prognosis and my treatment?  Those are the key questions.  

Katherine Banwell:

So, what are the types of treatments available for MPNs?  And let’s start with myelofibrosis or MF. 

Dr. Raajit Rampal:

If we had had this discussion five years ago, it would be pretty simple, and it would take a minute or two. And that’s completely changing and that’s amazing, and it’s good for all of our patients.  

Right now, for patients with MF, it depends on what the issue is. If the issue is symptoms or spleen, JAK inhibitors are our first line of therapy. Three approved JAK inhibitors are currently available, two on the first side ruxolitinib (Jakafi) and fedratinib (Inrebic). And pacritinib (Vonjo) can be used for patients with really low platelet counts.   

There is a fourth JAK inhibitor that we expect to be, hopefully, approved in June of this year, momelotinib. So, the landscape is about to complete broaden in terms of just JAK inhibitors.  

But beyond the JAK inhibitors themselves, there are a number of late stage clinical trials that are combining JAK inhibitors with agents that work through a different mechanism that don’t work through inhibition of the JAK pathway. So far, these drugs have all shown promise in early phase trials. Now, the definitive Phase III trials are being done. We have to wait and see what the data tells us. But if these are positive trials, this could completely alter the landscape of MPN. 

Katherine Banwell:

There’s also transplants available, right? 

Dr. Raajit Rampal:

Correct. Transplants for more advanced patients, which comes with some major risks. And so, that has to be thought of very carefully in terms of the risks and benefit. But it is a potentially curative strategy.  

Katherine Banwell:

Let’s turn to polycythemia vera or PV. What types of treatments are available? 

Dr. Raajit Rampal:

It’s really quite a range. So, there are things like phlebotomy and aspirin, which has been the mainstay of therapy for many years. There are drugs like hydroxyurea (Hydrea), interferons, JAK inhibitors. So, ruxolitinib is approved in certain settings for treating polycythemia vera. So, the landscape is broad. There are a lot of questions going on right now with polycythemia vera with regards to how it should best be treated. Is the mainstay of phlebotomy and aspirin really what we should be doing or should we be giving patients treatment earlier on. 

And there is some data to suggest that. There is this drug called ropeginterferon (Besremi) that’s FDA-approved for polycythemia, which was compared in the study to phlebotomy and aspirin.  

And at least the data suggests that there may be better control of the disease and less progression possibly, and it’s a small number of patients, by treating patients earlier. Whereas we would have just given phlebotomy and aspirin. So, it’s something to consider. There are drugs in clinical trials as well that look promising one of which is called rusfertide, which actually works by changing the way iron is used by the body. 

Iron is a key component to hemoglobin and it is, of course, a key component to polycythemia in the sense that we phlebotomize patients to make them iron deficient and that’s how we control the disease. But this is a pharmacological way to do that. So, that drug is now in Phase III trials. So, that may also alter the landscape of treatment of PV in the near future. 

Katherine Banwell:

Finally, how is essential thrombocythemia treated? 

Dr. Raajit Rampal:

So, in some cases, with absolutely nothing as we had talked about a moment ago. There is some thought that in really, really low-risk patients. Maybe you don’t need to do anything except observe them. Whereas most patients are on an aspirin. And beyond that, we have drugs like interferon, pegylated interferon, and hydroxyurea and anagrelide, all of which can be utilized. It’s not entirely clear if there is one distinct first line treatment that is the best but these drugs are all active. JAK inhibitors have been studied in this setting. And to date, the data hasn’t led to their approval but, certainly, people have studied it.  

Katherine Banwell:

Dr. Rampal, how can you tell if a treatment is effective? Are there signs that you look for? 

Dr. Raajit Rampal:

Well, I think it’s a couple of things.  

One, are we meeting the treatment goals in terms of are we controlling blood counts with ET or PV? That’s one of the first principles in management. And with regards to MF, the same thing. Are patients’ symptoms being controlled? Is the spleen being adequately controlled? And then, there’s the symptom burden because just because the blood counts are being controlled, patients may still have symptoms, in which case, they are not being adequately treated. And then, we have to do our best to try to find a treatment strategy that does control their blood counts but also does control their symptoms. 

So, there is the blood count perspective but there is the symptom perspective as well. 

Katherine Banwell:

How do you know when it’s time to change treatments? 

Dr. Raajit Rampal:

Well, I think really two things. One is if we aren’t meeting our goals like we just talked about. But the other aspect of that is if we are incurring toxicities that are just not tolerable to the patient and that’s a reason to change therapy always. 

Katherine Banwell:

Many patients, of course, worry about disease progression. Are there key predictors or tests for progression that patients should know about? 

Dr. Raajit Rampal:

This is a key area of investigation currently. I think one of the things that patients say to us so often when we meet them is what’s going to happen to me. And right now, we don’t have great prediction tools. We can say on a population level well, there is X percent of chance of progression at 15 years. That’s useful if you’re talking about a population. That’s not really useful if you’re talking to an individual. Because if I say to somebody there’s a 20 percent chance of your disease progressing to leukemia, it doesn’t really make a difference. That’s a meaningless statement because if you’re in the 20 percent who progress, it’s not a relevant statistic anymore.  

It’s sort of a binary thing. We’ve got to do better at developing this. This is something that the MPN Research Foundation is really heavily invested in in trying to identify predictive biomarkers. 

If we can do that, then perhaps what we can do is say to a patient this is really what we think your actual risk is. And then, the next step is asking the question if we intervene early, can we prevent that progression from occurring. So, that’s where I think we need to go. We aren’t there yet. 

Katherine Banwell:

What signs or symptoms do you look for that may indicate that the disease is progressing? 

Dr. Raajit Rampal:

The blood counts are often the canary in the coal mine regardless of the disease. They can tell us if ET or PV is progressing into MF or whether MF is progressing to more of a leukemic phase. Changes in symptoms sometimes can be a harbinger of disease progression. So, Patient 2, for example, is doing really well and now, he’s having drenching sweats and losing weight. So, those types of symptoms are a sign that physical findings is the size of the spleen if it’s increasing. 

All of those things together give us a hint about progression.  

Katherine Banwell:

Well, is there any way to prevent progression?  

Dr. Raajit Rampal:

That is the million dollar question. Again, that’s where we ultimately need to be. We want to be able to intervene to a point where patients don’t get that sick. It would be amazing if we’d come to the point where we can intervene early and nobody progresses to late stage MF. Nobody gets leukemia. And I think that’s a worthy goal. That’s not something that we should think is too lofty of a goal. That should be our ultimate goal here. And a number of groups are investigating this exact question. It’s complicated and it’s going to take time. But I think that’s a worthwhile investment. 

Katherine Banwell:

Let’s talk about MPN symptoms and treatment side effects. Here’s a question we received from a viewer before the program. How common is peripheral neuropathy in primary myelofibrosis? 

And what is the best treatment for it? 

Dr. Raajit Rampal:

Well, by itself, it’s not a very common symptom of MF by itself. Can it be a symptom? Sure. But there are also a number of things that can cause peripheral neuropathy. So, I’m not sure there’s a best treatment.   

But what needs to be done is a thorough investigation. There can be a number of causes. It could be nerve injury. It could be a deficiency in vitamins like B12. There are a lot of things that could cause it. So, that type of a symptom needs to be thought of in a broad way in terms of diagnosis.  

Katherine Banwell:

Jeff sent in this question. How could I manage the itching? Are there new treatments or strategies to live with itching? 

Dr. Raajit Rampal:

Very common thing. And it’s an interesting thing explaining to when we teach our trainees about this symptom, we have to impress on them the fact that itching is not the itching that everybody else experiences. 

This is a very profoundly different symptom. It’s debilitating for so many people. I have patients who go to the Emergency Room for that. That’s how terrible it could be. There are a lot of things that could be tried. JAK inhibitors, in my experience, work very well for itching but not in everybody. We use sometimes antihistamines that can work well. Sometimes, antidepressants can work well, not because they’re treating depression but because of other properties that they have. And sometimes, UV light therapy can be useful tool here, too. A lot of patients swear by it. 

 Katherine Banwell:

Another common side effect is fatigue. Do you have any advice for managing this symptom? 

Dr. Raajit Rampal:

Fatigue is the most common symptom across MPNs. And it is also one of the most difficult things to treat. Part of the issue is trying to figure out what does fatigue mean to the patient.  

When someone says they’re tired, does that mean they’re sleeping all of the time? Does that mean they don’t have get up and go? The first step is always understanding what does fatigue mean to the patient? And then, the second is trying to dissect that. In some cases, it’s related to anemia, in some cases, it’s not related to anemia and it’s just the disease itself.  

And in some cases, you have to think outside of the box about general medical issues like thyroid dysfunction that could be at play here. So, there isn’t one best fit. 

But the first test is always to dig deep. When someone says they have fatigue to dig deeper and try to figure out what is that really. 

Katherine Banwell: 

What other common symptoms do you hear about from patients? And what can be done about those?  

Dr. Raajit Rampal:

There are a lot of different things. It’s a spectrum. So, I think that itching and fatigue are very common. Feeling full early is, that’s a big thing, particularly in myelofibrosis patients.  

Bone pain, that’s another big one, particularly in myelofibrosis. There is not one therapy that is best for all. I think the JAK inhibitors, certainly, benefit many of these symptoms. But they don’t benefit everybody and not to the extent that makes it tolerable for everybody. So, often times, we struggle with this and try a lot of different things. But, again, I think one of the things to always remember is we don’t always want to say that this must be because of the MPN. Sometimes, symptom is arising because of another medical condition that’s going on concurrently. 

Katherine Banwell:

That’s good advice. Thank you. Let’s answer a few more audience questions we received. This one is from Calvin, “If your hematologist says you’re stable and responding well to Hydrea, should you still seek out a second opinion?” 

Dr. Raajit Rampal:

It’s never wrong to seek out a second opinion. I strongly believe that, especially when you’re dealing with a disease that’s rare like this. 

And even seeking out a second opinion, even if you’re under the care of an expert in the field is never a wrong thing. I think that no one person knows everything. And sometimes, people’s experience and perspective is different. So, I don’t think that’s a bad thing ever.  

Katherine Banwell:

As a follow-up to Calvin’s question, is it sufficient to just look at what the blood tests reveal? Or does having  bone marrow biopsy dictate what treatment you should follow? 

Dr. Raajit Rampal:

I think the bone marrow is important, particularly at initial diagnosis or when there is a change. The blood counts are the canary in the coal mine. So, they tell us is there something else going on that we’re not thinking about. And that’s when the bone marrow becomes important. So, I definitely think bone marrow is important at certain points in the disease.  

Katherine Banwell:

Sandra has this question, “Are there new treatments for polycythemia vera being researched beyond interferon?” 

Dr. Raajit Rampal:

Yeah. So, we talked about rusfertide as an example of this. And there are, certainly, other drugs that have been evaluated in this space. So, there is a lot of work going on for this disease, which is really encouraging. 

Katherine Banwell:

Carolyn sent in this question, “Is there a possibility of bone marrow fibrosis reversal in myelofibrosis without a stem cell transplant?” 

Dr. Raajit Rampal:

The answer is yes. So, even with JAK inhibitors, we see that about a third of patients will have a reduction in bone marrow fibrosis. And this is a key question being investigated with some of the newer therapies that are being introduced into the treatment of myelofibrosis. And, certainly, we’ve seen data to date that suggests that the fibrosis can be reduced if not potentially eliminated in some cases.  

Katherine Banwell:

Dr. Rampal, should all patients diagnosed with MPNs undergo molecular testing? 

Dr. Raajit Rampal:

I strongly believe that. I think that we’ve learned so much that these tests are prognostic value. 

And in some cases, it may suggest a slightly different diagnosis. I definitely think that should be the case. 

Katherine Banwell:

What should patients be asking once they have the results? 

Dr. Raajit Rampal:

What does it mean? That’s the most basic and fundamental question. It’s one thing to get a list of mutations. But the real bread and butter question is what does this mean to the disease and my prognosis and my treatment?  Those are the key questions. 

Katherine Banwell:

Andrew wants to know does Jakafi cause other mutations to develop? 

Dr. Raajit Rampal:

That’s a really good question. Right now, we don’t think the answer is necessarily yes. We have seen that in some patients where the disease has progressed on Jakafi, mutations have emerged. 

But the problem is that genetic testing has limits of detection. In other words, the mutation appears, it may not have just appeared or been caused by the drug but that it may have been below our limits of detection and actually grew while the patient was on therapy, which does not mean that the drug caused the mutation but that it was allowed to emerge during treatment with the specific drug. So, that is an area of investigation.  

Katherine Banwell:

Well, thank you, Dr. Rampal. And please continue to send in your questions to question@powerfulpatients.org and we’ll work to get them answered on future webinars.  

You mentioned earlier clinical trials. And I’d like to dig a little bit deeper. Where do these fit into the treatment plan? 

Dr. Raajit Rampal:

I think they should always be considered. None of the therapies that we have do we consider curative. And in many cases, standard therapy is fine given a patient’s clinical situation. In a case where standard therapy is not working or where we think that a patient’s prognosis is particularly challenging, or if they have mutations that may confer resistance to current therapies. 

I think in those scenarios, a trial should always be considered. 

Katherine Banwell:

So, if a patient is interested in possibly participating in a clinical trial, what kinds of questions should they be asking their healthcare team? 

Dr. Raajit Rampal:

All of these trials are different. I think the first thing is to discuss what’s the risk, what’s the benefit of any given trial or drug. What stage and development is it? What’s the evidence to support it? And what can I expect from it?   

Katherine Banwell:

What about cost? 

Dr. Raajit Rampal:

So, trials, in general, have two components. One is what we call standard of care meaning that things we would do normally for in the course of a patient’s treatment would be billed to a patient’s insurance as if they weren’t on a trial. 

Almost all trials, the study drug or any tests that are being done specifically with regards to the study drug are all covered by whoever is sponsoring the trial.  

Katherine Banwell:

How do patients find out about where the clinical trials are taking place? 

Dr. Raajit Rampal:

Usually, their physician should either, if they’re in a specialized center, they’ll have access there. But if they’re interested in trials and they’re being seen, for example, by a physician in the community who doesn’t necessarily specialize, asking for a referral to a major center where that MPN expertise is not an unreasonable approach to that. There is also clinicaltrials.gov where patients can go look for ongoing trials for their particular diagnosis.  

Katherine Banwell:

So, if patients want to learn more about MPNs, what sort of resources would you recommend? 

Dr. Raajit Rampal:

The thing I always say to patients is the internet is a very dangerous place for a variety of reasons. We have to, I think, do a good job of communicating to patients what are the resources. And the ones that I always point patients to are, for example, the MPN Advocacy International, the MPN Research Foundation, The Leukemia & Lymphoma Society, and the American Cancer Society. Those are sources of information that are vetted by physicians. 

Some of that information is specifically for patients. Those, to me, are good sources for patients to read.  

Katherine Banwell:

Dr. Rampal, as we close out our conversation, I wanted to get your thoughts on where we stand with progress and MPN care. Are there advances in research and treatment that make you hopeful? 

Dr. Raajit Rampal:

Without a doubt. I think I’ve seen more progress in the last three years than I’ve seen in the last 10 years. And we have so many new drugs coming forward, new questions that we’re trying to answer, tough questions as you alluded to. The question about prognosis but also intervening early to prevent progression of disease. These are things that are difficult questions that we are trying to dig into now. So, I think we should be optimistic. We are seeing so many excellent developments. We’ll have to see how far they’re going to take us. I don’t think we know the answer to that. But this is an exciting time.  

Katherine Banwell:

Dr. Rampal, thank you so much for joining us. 

Dr. Raajit Rampal:

My pleasure.  

Katherine Banwell:

And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for being with us today.   

Advances in Myelofibrosis Research

Advances in Myelofibrosis Research from Patient Empowerment Network on Vimeo.

What are the recent developments in the study and advancement of myelofibrosis treatment? MPN researcher Dr. Gabriela Hobbs discusses ongoing clinical trials for new JAK inhibitors, BET inhibitors, and anemia therapies, among others.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia, and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Hobbs.

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Transcript:

Katherine:

What about myelofibrosis, Dr. Hobbs? What advances are being made in the care of patients with this more advanced MPN? 

Dr. Hobbs:

Yeah. So, in myelofibrosis, I would say it is almost difficult to keep track of how many clinical trials are currently open. So, in 2011, we had ruxolitinib approved, or Jakafi. That was the first JAK inhibitor. Since then, we’ve had two more JAK inhibitors approved, fedratinib (Inrebic) and most recently pacritinib (Vonjo). And we’re currently awaiting the fourth JAK inhibitor to be approved, and that’s called momelotinib.   

And in addition to the JAK inhibitors, there are lots of other clinical trials underway right now that are either alone – a drug by itself or a drug in combination with ruxolitinib.  

So, there are several Phase III studies. And the reason why that’s important is that after Phase III we usually see a drug approval. So, we can expect, hopefully in the next couple of years, to see many more drugs available on the market to treat patients with myelofibrosis. Some of those include agents that block different pathways within a cell. And that includes a drug called parsaclisib. There’s a drug called pelabresib (CPI-0610), which is a BET inhibitor.  

There’s another drug called navitoclax (ABT-263), which is a cousin of venetoclax (Venclexta), which is a drug that we’ve been using a lot in leukemia. So, there’s lots of different drugs that are being used in combination with ruxolitinib. There’s also a drug called luspatercept (Reblozyl) that’s also been approved for myelodysplastic syndromes. And I suspect that that’ll be approved as well to help patients with anemia. So, really, there’s lots of drugs that are being studied right now. And I think the question that we’re all asking is, well, how are we going to use all of these different drugs? So, I look forward to seeing the results of those studies.  

Katherine:

Mm-hmm. Will some drugs work better for some patients and others not? 

Dr. Hobbs:

That is such a good question. And so, what I’m hoping to see is exactly that. I’m hoping to see that for patients, for example, with anemia, perhaps we’re going to be using luspatercept and momelotinib. Perhaps we’re going to see that patients with certain mutations may respond better to certain medications like the BET inhibitors or navitoclax or the PI3 kinase inhibitor, parsaclisib. But as of now, we don’t have enough information.  

We haven’t seen enough results of these studies to start to be able to know, you know, what is the patient that’s going to do better with two drugs versus one drug? And so, I think that over the next couple of years we’re going to start to have answers to those questions.  

Advances in Polycythemia Vera Research

Advances in Polycythemia Vera Research from Patient Empowerment Network on Vimeo.

What are the recent developments in the study and advancement of care for patients with polycythemia vera (PV)? Dr. Gabriela Hobbs reviews recently approved PV treatments as well as those currently in clinical trials.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia, and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Hobbs.

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Transcript:

Katherine:

There was recently an interferon approved for use in patients with PV. What other studies are showing promise for patients with PV?   

Dr. Hobbs:

Yeah. So, we as a community, there’s been a lot of excitement about this new interferon that was approved, the ropeginterferon (Besremi) study. And there are still some ongoing studies utilizing ropeginterferon to see if we can use it differently.  

Because currently the way that that drug is approved is that it has to be titrated up very slowly to get to the maximum dose. So, that’s something that is still ongoing. In addition, there’s a new drug that’s being studied called Rusfertide (PTG-300) from a company called Protagonist. And this drug has been very interesting. It acts through iron metabolism.  

And so far in preliminary results, it has shown that a lot of the participants that receive this medication no longer need phlebotomy. And I think what’s exciting about this is that phlebotomy is a very archaic way of treating patients.  

And I hope that we can stop utilizing it. So, it’s nice to have a compound that’s specifically asking that question. And the other thing to keep in mind is that this drug has been used in combination with other drugs, which is really reflective of how participants or patients show up to clinics.  

Some patients are not going to be on any medications. Some patients may be on hydroxyurea (Hydrea).  

Some patients may be on an interferon. Some patients may be on ruxolitinib (Jakafi). And these trials allow participants to be on a variety of different medications. So, that’s an exciting new compound. 

Advances in Essential Thrombocythemia Research

Advances in Essential Thrombocythemia Research from Patient Empowerment Network on Vimeo.

Are there new treatment developments for patients with essential thrombocythemia (ET)? Dr. Gabriela Hobbs shares an update on ET therapies in clinical trials and discusses when it might be appropriate for a patient to join a clinical trial.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia, and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Hobbs.

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Transcript:

Katherine:

Let’s talk about ET for a moment. Is there any research being done to help better manage this condition? 

Dr. Hobbs:

Yeah. I would say that of the three MPNs, ET is certainly the one that has the least amount of drugs that are being currently studied for this group. But that doesn’t mean that there isn’t any research. Ropeginterferon (Besremi), which was recently approved in polycythemia vera, is now being studied in essential thrombocythemia.  

So, I would expect in the next couple of years, if those trials are successful, to have ropeginterferon as a therapy to offer patients.  

There is also a clinical trial that we have at our site. We’re using ruxolitinib or Jakafi for patients with ET that have symptoms of their disease to see if it can help them in the same way that it can help PV or myelofibrosis patients. So, there’s definitely some research going on in ET. But probably less than for PV and myelofibrosis.  

Katherine:

Mm-hmm. While ET is typically well-managed, what patient type might benefit from joining a trial? 

Dr. Hobbs:

It really depends on what the patient is experiencing. I think there are some patients that really are very asymptomatic and can expect to have an excellent outcome with their disease. But they can also participate in research, for example, by participating in a tissue bank and offering a sample of their blood or if they have a bone marrow by offering some bone marrow if there’s extra.  

Because that can really help to understand the disease biology, if a patient is going to progress from ET to myelofibrosis.  

So, we can learn a lot from that. But then there are maybe some ET patients that need to be on a medication to reduce their blood counts or a cytoreductive agent.  

And that’s a patient that could ask about participation in a clinical trial. For example, the ropeginterferon study or, like I mentioned, there may be some patients that maybe are already on a medication, and their blood counts aren’t well-controlled on the first drug that was used. 

So, before considering switching to a second-line agent or a second medication, that could inquire with their clinician if there’s a clinical trial available for second-line use. Or those patients that have a lot of symptoms with ET, they could potentially be eligible for a study that addresses just symptoms.  

Expert Perspective | Promising MPN Research

Expert Perspective | Promising MPN Research from Patient Empowerment Network on Vimeo.

What’s the latest in promising MPN research news? Dr. Angela Fleischman shares an update about treatment research and discusses the importance of clinical trial participation.

Dr. Angela Fleischman is a physician scientist and assistant professor in the Department of Medicine at the University of California, Irvine. Learn more about Dr. Fleischman.

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Transcript:

Dr. Fleischman:

My name is Angela Fleischman. I’m what’s called a physician scientist, meaning, I do research as well as see patients, and my focus for my entire career thus far has been on myeloproliferative neoplasms, specifically their role of inflammation in MPN. And I am at the University of California, Irvine in Southern California. So, nice to be here today. 

Katherine:

Well, thank you so much for joining us and taking the time. Let’s talk about the latest developments in the field. What MPN clinical trials are you excited about right now? 

Dr. Fleischman:

So, I would say, there’s a lot of new clinical trials in the field for myelofibrosis, which is the most severe form of myeloproliferative neoplasm. 

There tend to be more clinical trials because that’s a patient population in – I don’t want to say in more need, but they do have more need in terms of necessitating better treatments. 

Drugs that are quite far along in clinical trials – and in order for a drug to make it to market, one needs to go through multiple clinical trials to demonstrate the safety, as well as efficacy. Things like a BET inhibitor are very, very promising in moving forward in clinical trials. Other medications for other diseases, such as polycythemia vera, not anymore in clinical trials, but excitingly, newly FDA-approved, was ropeginterferon (Besremi) for polycythemia vera. 

So, that’s a real exciting development for polycythemia vera patients. 

And now, we have – outside of the context of clinical trials, because I want to talk about what’s actually available to patients now, we now have three JAK inhibitors available for myelofibrosis patients. And really, since 2011, we had only had one, and then, more recently, a second JAK inhibitor, but now, we have three. So, now we’re moving into an era where we can tailor a specific JAK inhibitor for a specific myelofibrosis patient, depending on what their particular needs are. So, I think that that’s very promising. And then, there are lots of clinical trials combining JAK inhibitors with new drugs. 

Katherine:

What do you want to leave MPN patients with, relating to clinical trial participation? 

Dr. Fleischman:

I would say that MPN patients today are the key to our future treatments. 

Without participation in clinical trials today, there’s going to be no new drugs for myeloproliferative neoplasms. They’re just not going to appear. We need to test them in patients before them actually coming to market, and before really knowing whether they work or not. So, I would say that the MPN patients today are the key to the future of MPN treatments.  

What Patients Should Know About Developing MPN Treatments and Research

What Patients Should Know About Developing MPN Treatments and Research from Patient Empowerment Network on Vimeo.

MPN expert Dr. Gabriela Hobbs provides an update on developments in myeloproliferative neoplasm (MPN) treatment and research. Dr. Hobbs explains how clinical trials and global research collaborations advance MPN care.

Dr. Gabriela Hobbs is a hematology-oncology physician specializing in the care of patients with myeloproliferative neoplasms (MPN), chronic myeloid leukemia and leukemia. Dr. Hobbs serves as clinical director of the adult leukemia service at Massachusetts General Hospital. Learn more about Dr. Gaby Hobbs.

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Transcript:

Katherine:

Hello and welcome. I’m Katherine Banwell, your host for today’s program. Today we’re going to discuss the advancements in MPN research through clinical trials. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you. Well, let’s meet our guest today. Joining me is Dr. Gabby Hobbs. Dr. Hobbs, welcome. Would you please introduce yourself? 

Dr. Hobbs:

Hi, how are you? Thank you so much for having me. My name is Gabby Hobbs. I’m the clinical director of the Adult Leukemia Service at the Massachusetts General Hospital in Boston. And I dedicate my clinical time and research efforts to the care of patients with Myeloproliferative Neoplasms.  

Katherine:

Thank you so much for taking the time to join us today.  

Dr. Hobbs:

Thank you.  

Katherine:

I’d like to start by discussing your role as an MPN researcher. You’re on the front lines for advancements in the field. What led you to there and why is it so important to you?  

Dr. Hobbs:

Many things in my life led me to becoming an MPN clinician. First, I wanted to be a clinical investigator since I was very little, and I read a Louis Pasteur book about – you know. And I was fascinated by the fact that you could be both a scientist and a clinician. And after that, I had phenomenal teachers and mentors. And I was really always drawn to patients with hematologic malignancies. I thought that that interaction was very intense and intimate.  

And I was honored to be a part of that interaction. And then from a research perspective and from a scientific perspective, I very clearly remember seeing when the first targeted therapy, Imatinib, was approved when I was an undergrad. And I just thought that was the most fascinating thing. And so, I’ve basically continued to feel that way as I’ve gone through my training and I’m thrilled to be able to have actually become an MPN clinician so many years later.  

Katherine:

With the American Society of Hematology or ASH meeting taking place this month, it demonstrates how researchers work together around the world to advance care.   

Can you share with the audience how this collaboration works?  

Dr. Hobbs:

Yeah. So, the American Society of Hematology meeting – or the ASH meeting – is really one of my favorite events of the year.  

And it really highlights what you said. It is such a positive environment, and it’s so exciting to use that opportunity to talk to my collaborators from across the globe. And I really think that that’s where the scientific community shines because really all of us are actually trying to figure out how to work together and overcome sometimes a lot of obstacles – bureaucratic obstacles, regulatory obstacles – to make sure that we can share data, do it the right way. But really we always have one thing in mind.  

And that is to be able to advance the care that we give our patients. And so, that collaboration and really that collaborative environment is always very positive. And I always come back home very energized from that. And then just seeing all my colleagues presenting all the wonderful things that they are working on and getting updates on their research is just an exciting environment.   

Katherine:

In your view, why is it essential to present and share data at these larger conferences like ASH? 

 Dr. Hobbs:

So, for many different reasons. I mean, there are many different ways of presenting data that can be done through just publishing a paper. But the nice thing about conferences – and especially large conferences – is that you really get an opportunity to present work in progress. And some of these research projects may not end up turning into bigger projects or they may not become bigger trials. But all of them have at least an opportunity to learn something from them, whether or not they worked or they didn’t work.  

Oftentimes when things are published in journals, especially the high-impact journals, we are seeing trials that had positive results. But sometimes we don’t see those smaller trials that never went anywhere. And so, having a forum when we can discuss work that’s ongoing, discuss about projects that are maybe having issues, all those things actually really help us to change our research questions or develop new research questions based on what’s working and also really what’s not working. And so, having this large forum to present all of that data, I think, is really, really important to helping us design future clinical trials and projects.  

Katherine:

Yeah. Well, this is a great way to begin our clinical trial discussion, Dr. Hobbs. This research all requires MPN patients to participate in clinical trials. So, what should be considered when deciding whether to join a trial? 

Dr. Hobbs:

What a great question. Many things need to be considered when joining a trial. And I think some patients are really eager to join a trial, and they just need to be aware that they may be either too healthy, or they may have other things going on that may not make them eligible.  

And that’s okay. There are actually many ways of participating in research, even if it’s not a clinical trial that requires a medicine. For example, we often can send patients to what’s called a tissue bank where they have patients just give a sample of blood.  

So, patients can participate in research in many different ways. When considering whether or not a patient should enroll in an actual clinical trial with a new medicine, I think it’s really important for the patients to be informed and to not be afraid to ask questions. First, what is a clinical trial? Second, what will this trial involve? Is this a drug that has never been given to people before, or is this a drug that has already undergone many different clinical trials? And this trial that’s being offered is a Phase III trial where the purpose of the study is to get the drug to be approved.  

So, I think learning about the risk of the study, how it’s been utilized. And also the other more practical things. What is the time commitment of this clinical trial? How often are you going to have to be going to the office because of the clinical trial? Because there’s certainly a big investment in the part of the patients in terms of their time. Participating in a clinical trial most of the time requires more time than not participating in a clinical trial. That’s not always the case. There are some studies that definitely don’t require that many visits.  

But most clinical trials will require at least something extra from the patient. And I think it’s really important to ask about that, to read the consent that’s given to the patients. Oftentimes these consents are very long.  

And so, they can be overwhelming. I personally find them overwhelming. And I review a lot of those consents. And so, I think taking a minute to really ask those questions, speaking to the research staff, and getting the clarification on that is really important.  

Like you said, it is impossible to approve new therapies and improve the care that we offer our patients without patients participating in the clinical trial. But that doesn’t mean that absolutely every single patient needs to participate in a clinical trial if it just doesn’t make sense for them. [14:17]  

Katherine:

There have been huge developments in the last 10 to 15 years in the field of MPN. So, I’d like to dig a little deeper. We hear about the common driver mutations in MPNs like JAK2, CALR, and MPL. How are these being studied , and what is being discovered? 

Dr. Hobbs:

Yeah. So, it’s amazing how in the last 15 years really so much has been discovered. You know. The JAK2 mutation was first published out in 2005 and calreticulin in 2013. So, those are relatively recent discoveries. And I think a lot of efforts has been put into learning about what these mutations are doing and how they lead to disease. And so, we have the JAK inhibitors, which block the signaling through a pathway called JAK-STAT. And all of these mutations will activate that pathway within cells.  

And so, many of the approved drugs, for example, ruxolitinib (Jakafi), fedratinib (Inrebic), and pacritinib (Vonjo), work on blocking that pathway.  

But since then we’ve also learned that there are other mutations and other pathways that are likely involved in the development of myeloproliferative neoplasms and also their progression. And so, what we’re seeing now is that many of the clinical trials that are being conducted don’t just target the JAK-STAT pathway or the pathway that’s influenced by these main mutations.  

But also block other pathways to try to really block all the variant expression of signaling in the myeloproliferative neoplasms. And so, we’re trying to attack it by many different angles.  

Katherine:

Yeah. Is there a possibility of specific targeted therapies at MPNs similar to those in AML such as FLT3 inhibitors? 

Dr. Hobbs:

Absolutely. So, similarly to AML, we know that we have mutations in similar types of genes called tyrosine kinases. So, these are enzymes that are turned on and always active. And so, I think there is definitely hope that we can develop some targeted agents. For example, ruxolitinib or the other JAK inhibitors are similar. They’re tyrosine kinase inhibitors where they block an enzyme, specifically the JAK2 enzyme.  

But I think that we can definitely do better and develop more specific inhibitors, for example, a molecule that just blocks the JAK2 mutation and not just every JAK2 molecule in every cell. Similarly to AML, there are mutations, for example, in enzymes called IDH.  

And we have IDH inhibitors for AML. And there are some studies that are using IDH inhibitors for MPN. So, I think we’re going to continue to see more targeted therapies specific to the mutations that occur in MPN.  

Katherine:

Yeah. Let’s talk about ET for a moment. Is there any research being done to help better manage this condition? 

Dr. Hobbs:

Yeah. I would say that of the three MPNs, ET is certainly the one that has the least amount of drugs that are being currently studied for this group. But that doesn’t mean that there isn’t any research. Ropeginterferon (Besremi), which was recently approved in polycythemia vera, is now being studied in essential thrombocythemia.  

So, I would expect in the next couple of years, if those trials are successful, to have ropeginterferon as a therapy to offer patients. There is also a clinical trial that we have at our site.  

We’re using ruxolitinib or Jakafi for patients with ET that have symptoms of their disease to see if it can help them in the same way that it can help PV or myelofibrosis patients. So, there’s definitely some research going on in ET. But probably less than for PV and myelofibrosis.  

Katherine:

Mm-hmm. While ET is typically well-managed, what patient type might benefit from joining a trial? 

Dr. Hobbs:

It really depends on what the patient is experiencing. I think there are some patients that really are very asymptomatic and can expect to have an excellent outcome with their disease. But they can also participate in research, for example, by participating in a tissue bank and offering a sample of their blood or if they have a bone marrow by offering some bone marrow if there’s extra. Because that can really help to understand the disease biology, if a patient is going to progress from ET to myelofibrosis.  

So, we can learn a lot from that. But then there are maybe some ET patients that need to be on a medication to reduce their blood counts or a cytoreductive agent.  

And that’s a patient that could ask about participation in a clinical trial. For example, the ropeginterferon study or, like I mentioned, there may be some patients that maybe are already on a medication and their blood counts aren’t well controlled on the first drug that was used.  

So, before considering switching to a second-line agent or a second medication, that could inquire with their clinician if there’s a clinical trial available for second-line use. Or those patients that have a lot of symptoms with ET, they could potentially be eligible for a study that addresses just symptoms.  

Katherine:

Right. That’s really good news. I’m glad you talked about that.  

Dr. Hobbs:

Mm-hmm.  

Katherine:

There was recently an interferon approved for use in patients with PV. What other studies are showing promise for patients with PV?  

Dr. Hobbs:

Yeah. So, we as a community, there’s been a lot of excitement about this new interferon that was approved, the ropeginterferon study. And there are still some ongoing studies utilizing ropeginterferon to see if we can use it differently. Because currently the way that that drug is approved is that it has to be titrated up very slowly to get to the maximum dose. So, that’s something that is still ongoing. In addition, there’s a new drug that’s being studied called Rusfertide (PTG-300) from a company called Protagonist. And this drug has been very interesting. It acts through iron metabolism.   

And so far in preliminary results, it has shown that a lot of the participants that receive this medication no longer need phlebotomy. And I think what’s exciting about this is that phlebotomy is a very archaic way of treating patients.  

And I hope that we can stop utilizing it. So, it’s nice to have a compound that’s specifically asking that question. And the other thing to keep in mind is that this drug has been used in combination with other drugs, which is really reflective of how participants or patients show up to clinics.  

Some patients are not going to be on any medications. Some patients may be on hydroxyurea.  

Some patients may be on an interferon. Some patients may be on Jakafi. And these trials allow participants to be on a variety of different medications. So, that’s an exciting new compound.  

Katherine:

What about myelofibrosis, Dr. Hobbs? What advances are being made in the care of patients with this more advanced MPN?  

Dr. Hobbs:

Yeah. So, in myelofibrosis, I would say it is almost difficult to keep track of how many clinical trials are currently open. So, in 2011, we had ruxolitinib approved, or Jakafi. That was the first JAK inhibitor. Since then we’ve had two more JAK inhibitors approved, fedratinib and most recently pacritinib. And we’re currently awaiting the fourth JAK inhibitor to be approved, and that’s called momelotinib.   

And in addition to the JAK inhibitors, there are lots of other clinical trials underway right now that are either alone – a drug by itself or a drug in combination with ruxolitinib.  

So, there are several Phase III studies. And the reason why that’s important is that after Phase III we usually see a drug approval. So, we can expect, hopefully in the next couple of years, to see many more drugs available on the market to treat patients with myelofibrosis. Some of those include agents that block different pathways within a cell. And that includes a drug called parsaclisib. There’s a drug called pelabresib, which is a BET inhibitor.  

There’s another drug called navitoclax, which is a cousin of venetoclax (Venclexta), which is a drug that we’ve been using a lot in leukemia. So, there’s lots of different drugs that are being used in combination with Ruxolitinib. There’s also a drug called luspatercept (Reblozyl) that’s also been approved for myelodysplastic syndromes. And I suspect that that’ll be approved as well to help patients with anemia. So, really, there’s lots of drugs that are being studied right now. And I think the question that we’re all asking is, well, how are we going to use all of these different drugs? So, I look forward to seeing the results of those studies.  

Katherine:

Mm-hmm. Will some drugs work better for some patients and others not? 

Dr. Hobbs:

That is such a good question. And so, what I’m hoping to see is exactly that. I’m hoping to see that for patients, for example with anemia, perhaps we’re going to be using luspatercept and momelotinib. Perhaps we’re going to see that patients with certain mutations may respond better to certain medications like the BET inhibitors or navitoclax or the PI3 kinase inhibitor, parsaclisib. But as of now, we don’t have enough information.  

We haven’t seen enough results of these studies to start to be able to know, you know, what is the patient that’s going to do better with two drugs versus one drug? And so, I think that over the next couple of years we’re going to start to have answers to those questions.  

Katherine:

Yeah. I’d like to get specific about your research. What are you excited about right now? 

Dr. Hobbs:

A few different things. There’s a clinical trial that I’ve been leading for several years now that got somewhat delayed due to the pandemic that’s utilizing ruxolitinib before, during, and after transplantation for patients with Myelofibrosis.  

And that study is hopefully going to finish accrual in the next couple of months. So, I’m excited to see the results of that study. That study was presented at ASH of last year, the interim results of that study. And so far, we’ve seen exciting results. Patients have done well with transplant while receiving ruxolitinib.  

We’ve seen that patients that have undergone transplant and have received ruxolitinib have had very low rates of a complication of transplant called graft-versus-host disease.   

And that’s been very exciting, because we know that graft-versus-host disease is really very difficult to deal with after transplant. It can really impact quality of life. And so, that’s been exciting to see that we can help our patients to better tolerate this difficult treatment. On the complete opposite end of the spectrum, we’re treating patients that have low-risk essential thrombocythemia and polycythemia vera with ruxolitinib also to see if their quality of life can improve.  

We know that patients with ET and PV live with a lot of symptoms. And often times patients that are considered low-risk can still have a lot of symptoms. And therapies haven’t really specifically been studied just to improve symptoms. Really, therapies are usually used to reduce the risk of having blood clots.  

Katherine:

What about checkpoint inhibitors? You’ve done a study about that? Or it’s ongoing? 

Dr. Hobbs:

Yes. Great question. So, a few years ago we utilized a checkpoint inhibitor called Pembrolizumab for patients with advanced myeloproliferative neoplasms. And that study was open at Mass General and also at Mount Sinai. We were worried that it wouldn’t be well tolerated. But it was actually very well tolerated. But unfortunately patients didn’t have a response. And a group at MD Anderson utilized another checkpoint inhibitor, Nivolumab, for these patients. And similarly they also didn’t see a response.  

So, that was disappointing. However, I do think that there is a role for immunotherapy in patients with MPNs. I think that we probably need to think about utilizing the checkpoint inhibitors maybe earlier or maybe in combination with other agents. This has been done, for example, in solid tumors where two checkpoint inhibitors are sometimes utilized together. So, I think their area of investigation is still worth pursuing even though that was a disappointing result.  

Katherine:

Yeah. Yeah. Any other research that’s going on that you’re doing? 

Dr. Hobbs:

Yeah. We are looking forward to opening some clinical trials using different drugs in combination with ruxolitinib to offer different treatments to our patients up front. And so, instead of offering just single-agent JAK inhibitor, we can combine that with one of the new agents. And so, I’m looking forward to seeing how that’s going to work for my patients and to be able to offer them another treatment. I’m also thinking of developing a clinical trial for use in patients that have clonal hematopoiesis.  

So, patients that have this entity called CHIP where they have a JAK2 mutation but maybe don’t have overt disease. We know that they have a high rate of transformation to an actual MPN. So, we’re working to develop clinical trials for those patients with the hope of maybe preventing the MPN from ever happening. 

Katherine:

That’s great. We have some questions from the audience that were sent in prior to the program. Carl asks, “Are MPNs inherited? And why does one sibling develop an MPN and the other does not?”  

Dr. Hobbs:

Great question. So, historically, we’ve always said MPNs are very rarely inherited. Now that we’re able to test for JAK2 mutations more commonly, we have, I think over the last decades, probably found that there are more families where the MPNs kind of run in the family.  

Katherine:

Mm-hmm.  

Dr. Hobbs:

Generally speaking, it’s very rare for MPNs to run in the family. I would say less than 10 percent of the case. And this is why a sibling can have an MPN and one doesn’t, even if they’re identical twins.  

Katherine:

Is research being done to learn more about who may be at risk for developing an MPN? 

Dr. Hobbs:

So, over the list, there’s been a lot of attention placed on this entity called clonal hematopoiesis of indeterminate potential. And through those types of investigations, we’ve learned that people can actually live with a JAK2 mutation for many years, even decades, before they develop a myeloproliferative neoplasm. And so, indirectly, I think that type of research will help us understand why some people get the JAK2 mutation to begin with and what else needs to happen in a patient’s life for that person to develop an MPN.  

Because clearly there are many more people walking around with a JAK2 mutation than there are people with an actual MPN. So, there’s something else other than that JAK2 mutation that predisposes patients to then develop an MPN.  

Katherine:

Angela has another question. “What are the long-term effects of JAK inhibitors? And what happens when JAK inhibitors are no longer effective?” 

Dr. Hobbs:

Yeah. Great question. So, so far the patients that have been on JAK inhibitors for a long time don’t seem to have the development of additional toxicities that we didn’t know about. So, I’ll just comment on some of the things that we do know about. Weight gain is a common complaint that I have from patients, especially those that have polycythemia vera, because maybe they didn’t want to gain weight when they were put on a JAK inhibitor compared to the myelofibrosis patients who maybe had lost a lot of weight before being on a JAK inhibitor.  

There are certainly higher risk probably of developing infections with some of the JAK inhibitors. And we see, for example, shingles reactivation being a common one. And there’s the concern of development of skin cancers, which has been seen with some JAK inhibitors. But generally speaking, long-term use seems to be safe. That being said, ruxolitinib, which is the oldest one to be approved, has only been around since 2011, so we don’t have decades worth of experience to know.   

When JAK inhibitors stop working – to answer the second part of your question – until fairly recently we really didn’t have a whole lot to offer because there was only one JAK inhibitor. Now we have two others. We have fedratinib and also pacritinib. And we know from the studies that have been done with both of these agents that some patients that lose response to Jakafi, meaning that their spleen starts to grow or their symptoms start to come back, can be treated with these other JAK inhibitors.   

And many patients will, again, have control of their spleen and symptoms. Now losing response to a JAK inhibitor can come in many different ways. And so, some patients may also develop signs of having leukemia or progression of their disease to leukemia. And, unfortunately, for those patients, being on another JAK inhibitor doesn’t make sense. So, those patients may need to receive other types of medications or a stem cell transplant.   

Katherine:

Mm-hmm. Gary has two questions for you. The first is, “How useful is having a genetic panel done? Should all patients get molecular or genetic testing?” 

Dr. Hobbs:

Great question. And I think that it is very important to have genetic testing.  

And genetic testing involves more than just testing the JAK2 mutation. So, we know that the JAK2 mutation is the most common mutation in patients with MPN. But that being said, there are other mutations that also occur such as the calreticulin mutation and the MPL mutation. And so, I think having genetic testing that at least tests for those three mutations is very important so that we can actually help a patient know that they have an MPN. In addition to those three main mutations, many clinicians now have access to what’s called extended next-generation sequencing, where there’s a panel that tests for many different genes at the same time and can test for a variety of other mutations.  

And this is particularly relevant for patients with myelofibrosis. As we know that having other mutations, like, for example, mutations in IDH or ASXL1 and others, can increase the risk of that disease in terms of its risk of transforming to leukemia or how long a patient may live with their myelofibrosis. 

And so, I do recommend having extended next-generation sequencing done at least at diagnosis.  

When I generally think about repeating that, if there’s something that looks like it’s changing within the patient’s disease, to be honest, also on the flipside of that argument, sometimes this next-generation sequencing will mostly contribute to adding anxiety and will not necessarily directly impact how a patient is treated. And this is particularly true in patients with PV and ET, where we’ll sometimes order these tests, and we get a bunch of mutations back, but we don’t know what to do with that information yet.   

And so, as a researcher – not a clinician – as a researcher, I think it’s very important to have that information so that we can then do studies and understand the patterns of mutations and how that affects outcome. But as a clinician, and you as a patient, you need to really be aware of how that’s going to impact the patient in front of you and how that may impact you as a patient. Do you want to know if you have these mutations if nothing can be done about it? So, I would say, take a moment to reflect upon what I said and also to ask your clinician, how is this information going to help me? Do I need to have this information?  

Maybe you want to have it done so that it’s in your record. But maybe you don’t necessarily want to know those results. And everybody’s very different. And I think it’s absolutely wonderful to talk to my patients about all the information. But there may be some patients that really are just, like, do the test but don’t tell me the results, because I know that I’m just going to be very anxious knowing that I have something that I can’t do anything about. So, just take a minute to talk about it with your doctors. I think that’s really important.  

Katherine:

Yeah. Yeah. Here’s Gary’s second question. “Is allele burden a key predictor of progression?” And before you answer that, Dr. Hobbs, what does “allele burden” mean, and how does it impact progression? 

Dr. Hobbs:

Great questions. And I hope that in the next couple years I have a much better answer for you. So, maybe I’ll come back again and maybe we can talk about this again. So, allele burden – just simply put – is basically, like, how many of the stem cells in your bone marrow have that JAK2 mutation. And that’s a concept that’s not obvious. So, not all of a patient’s blood with an MPN has that JAK2 mutation. There are some stem cells that have the JAK2 mutation and produce JAK2-mutated blood. And then there are some stem cells that are normal that just make normal blood and don’t have a JAK2 mutation.  

And so, we can measure, what is a proportion of cells in the blood that has that JAK2 mutation? Now the next question should be very obvious and straightforward. But it really is not. So, what do we do with allele burden, and how do we measure that, and what does it mean if the allele burden goes up or it goes down? At this moment, we don’t necessarily know that. There have been some studies showing that maybe higher JAK2 mutation burden is maybe associated with progression or more with PV as opposed to ET.  

And we’d all like to think that lowering that JAK2 mutation level or that JAK2 allele burden has to be good and maybe will decrease progression or improve survival. We haven’t seen that yet. And so, I think we’re all really waiting to see, what does it mean to lower that JAK2 allele burden? And then how often should we be measuring that? But right now we really don’t know.  

Katherine:

Yeah. One more question for you. This one from Joseph. “I have PV and had adverse side effects from peginterferon alfa-2a (Pegasys). Is it likely that similar side effects would be experienced with Besremi?” 

Dr. Hobbs:

Good question. It’s hard to know. And it really depends on the severity of the side effects that you had and the type of side effect that you had. In my experience, ropeginterferon or Besremii is very well-tolerated compared to the other interferons that were available. But if you really had a severe side effect it may be difficult to consider trying it. But it’s worth considering it. I’ve definitely had patients that have gone from Pegasys to ropeginterferon without any difficulty. But just because you had a bad side effect to one doesn’t mean that you’ll have a bad side effect to the other.  

Katherine:

This is from Paul who lives in the United Kingdom. “How important is it to see an MPN specialist rather than a general hematologist? Right now I’m currently seeing a general hematologist who makes a note of my side effects but offers no coping strategies or solutions.” 

Dr. Hobbs:

Yeah. That is a great question. And one with not one answer. I would say that if you’re an MPN patient and you have a clinician that treats you that feels comfortable treating you or you feel heard and you’re being offered different ways of dealing with symptoms or side effects, etc., then perhaps you don’t have to go out of your way to find an MPN clinician. And participating in webinars like this or learning online may be sufficient to know how to advocate for yourself and how to monitor your disease. That being said, I do think that it’s nice for patients to at least have a one-time opinion with a specialist.  

And I would say that with the advent of virtual care, that has become increasingly more accessible. And so, if that’s something that’s available to you, that’s something you should consider. You know. Sometimes it’s very difficult to travel a long distance to meet with a specialist. But if you can avoid the travel by having a virtual visit, that often times can be very helpful in just knowing that you’ve met with somebody once. And then you can meet with that person periodically throughout your care can be very helpful. And I’ll tell you personally I see patients in the neighboring states to where I live.  

And I like to see those patients periodically or communicate with their local providers. And so, it just helps to offer care that’s very specialized in maybe areas of the country that don’t necessarily have access to specialized care. So, I would encourage patients to seek that out if that’s something that they’re interested in because it’s really become, I think, easier to access the specialists.  

Katherine:

Thank you for your thoughtful responses. And viewers please continue to send in your questions to question@powerfulpatients.org. Before we end the program, Dr. Hobbs, I’d like to hear why you’re hopeful about the future MPN care.   

Dr. Hobbs:

Thank you so much. Those are great questions. I feel very hopeful about the future of MPN. As we mentioned at the beginning of this webinar, the scientific community and the MPN community of clinicians and investigators, it’s such a nice example of how scientists can work together to improve the care of patients. That I always feel very inspired by my colleagues. And now that ASH is around the corner, I can tell you that I feel very hopeful for the future of MPNs because I know that we’re going to learn about a variety of different clinical trials that are showing promising results that are going to ultimately impact the way that we are able to treat our patients with MPN.   

And lastly, I feel very hopeful for the future of MPN because I know that the MPN community is very active. Patients participate in webinars like this, belong to different online groups, and are excellent advocates for themselves. I’ve seen firsthand in my clinic how when a drug gets approved, patients learn about new treatments online and come and ask for them. And so, I just feel very honored to be a clinician that is able to treat a group of patients that can advocate so well for themselves. And so, I definitely see lots of changes in the next couple years.  

Katherine:

This is from Paul who lives in the United Kingdom. “How important is it to see an MPN specialist rather than a general hematologist? Right now I’m currently seeing a general hematologist who makes a note of my side effects but offers no coping strategies or solutions.” 

Dr. Hobbs:

Yeah. That is a great question. And one with not one answer. I would say that if you’re an MPN patient and you have a clinician that treats you that feels comfortable treating you or you feel heard and you’re being offered different ways of dealing with symptoms or side effects, etc., then perhaps you don’t have to go out of your way to find an MPN clinician. And participating in webinars like this or learning online may be sufficient to know how to advocate for yourself and how to monitor your disease. That being said, I do think that it’s nice for patients to at least have a one-time opinion with a specialist.  

And I would say that with the advent of virtual care, that has become increasingly more accessible. And so, if that’s something that’s available to you, that’s something you should consider. You know. Sometimes it’s very difficult to travel a long distance to meet with a specialist. But if you can avoid the travel by having a virtual visit, that often times can be very helpful in just knowing that you’ve met with somebody once. And then you can meet with that person periodically throughout your care can be very helpful. And I’ll tell you personally I see patients in the neighboring states to where I live.  

And I like to see those patients periodically or communicate with their local providers. And so, it just helps to offer care that’s very specialized in maybe areas of the country that don’t necessarily have access to specialized care. So, I would encourage patients to seek that out if that’s something that they’re interested in because it’s really become, I think, easier to access the specialists.   

Katherine:

Mm-hmm. Dr. Hobbs, thank you so much for joining us today.  

Dr. Hobbs:

Thank you so much for having me.  

Katherine:

And thank you to all of our partners. To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today. 

What Is in the Treatment Pipeline for Patients With MPNs?

What Is in the Treatment Pipeline for Patients With MPNs? from Patient Empowerment Network on Vimeo.

What does the MPN treatment pipeline hold for patients? MPN expert Dr. Claire Harrison from Guy’s and St. Thomas’ Hospital in London shares insight about future treatments and the outlook for care.

See More from Best MPN Care No Matter Where You Live

Related Resources:

New Developments in MPN Treatment Landscape

MPN Treatment Strategies for Patients Who Have Failed Traditional Therapies

How Are MPN Treatments Changing for Low-Risk vs High-Risk Patients?


Transcript:

Dr. Nicole Rochester: 

Can you share a little about what’s in the robust pipeline of potential therapies for patients with MPN, what is it that you’re excited about? And is the future bright in this area?

Dr. Claire Harrison: 

I think the future is really bright from the point of view of de-escalating treatment as well as newer treatment, so I think it’s important to point that because all treatments have potential complications inside of it, so as we understand that some of these conditions may have very low risk for patients, it’s important to understand that, and de-intensify, I call that calreticulin (post ET?), I would also call out ET, essential thrombocythemia, which lacks a known driver mutation, so-called triple-negative ET, emerging data suggests that may have very low risk for patients, but what you all want to hear about, of course, is what’s new treatment-wise. 

So I think just to call out, I’m really excited that there will be a new trial this year for ET patients with Bomedemstat, which is an LSD-1 inhibitor, new target, new molecule. We’ve been testing it in myelofibrosis and we’ve tested it now in a bunch of patients with ET, and it seems to be very efficiently reducing the platelet count not affecting hemoglobin and patients appear to get a good benefit with regard to fatigue, which we know is the number one symptom for patients with MPN, so I’m excited about that because it’s been a long time since we’ve had a new treatment for patients with ET. And then for patients with PV, increasingly across the globe, the availability of this newer formulation of interferon, Besremi is becoming more available and the latest data with that agent suggests that it may be superior to standard therapy such as hydroxyurea, hydroxycarbamide in terms of clotting, et cetera, is really important.

Interestingly, and we may both have to think back to our med school days on this, we’ve been targeting the iron pathway for patients with PV. So I always tell my patients with PV, do not let anyone give you iron tablets without speaking to one of our team because that’s like putting oxygen on the fire, it’s like feeding the red cell production. So there is a new agent called Rusfertide PTG-300, which targets the iron pathway and allows iron to build up in the body, but it doesn’t allow it to get to the bone marrow and so, this is a new treatment for PV patients, which might reduce the need for iron removal by phlebotomy or venesection, and has been also shown to give symptomatic benefit, and then of course, there’s a bunch of new treatments for patients with myelofibrosis, that’s probably the busiest part of the portfolio at the moment. 

We’ve just seen positive data with me momelotinib, which is one of the fourth JAK inhibitors, very strong data from the MOMENTUM  study, good results in patients even with low platelet counts down to 25, and then I’m really excited to see strong data coming with navitoclax and pelabresib, which are other agents targeted at are the pathways in myelofibrosis. And then finally, in Denmark, they’ve been looking at vaccination strategies, and I know my patients are really interested in vaccination and gene editing. I don’t have anything new to say on gene editing), but I do have something new to say on vaccination.

So in Denmark, they’ve been looking at producing a vaccination against the calreticulin mutation, Nicole, because it’s expressed on the surface of the blood cells, so antibodies can find it. So this is ongoing, no positive result as yet, but it’s still ongoing and there are newer taking off with regards to vaccination structures, and I think that’s really exciting.