Tag Archive for: pacritinib

Myelofibrosis Symptoms and Side Effects | Why Speaking Up Is Vital

Dr. Naveen Pemmaraju emphasizes the importance of knowing your body and sharing all myelofibrosis symptoms and side effects with their healthcare team. 

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

Download Resource Guide

See More from Elevate Myelofibrosis

Related Resources:

Myelofibrosis Care | Impact of Diet & Lifestyle Modifications

Myelofibrosis Care | Impact of Diet & Lifestyle Modifications

Advice for Shared Decision-Making | Myelofibrosis Care and Treatment Goals

Advice for Shared Decision-Making | Myelofibrosis Care and Treatment Goals

Emotional Health | Why It’s Vital for Myelofibrosis Patients to Share Concerns 

Emotional Health | Why It’s Vital for Myelofibrosis Patients to Share Concerns

Transcript:

Katherine Banwell:

So, the symptoms of myelofibrosis as well as the side effects of certain medications can vary greatly among patients. 

Dr. Naveen Pemmaraju:

Yeah. 

Katherine Banwell:

Why is it critical for patients to share any issues they may be having with their care team?  

Dr. Naveen Pemmaraju:

Yeah, exactly what you said. So, those two concepts are tied. Since the disease is so rare and it’s so heterogeneous, not just patient to patient, but within the same patient over the journey of years, that is the reason. So, because of that, that’s why one has to communicate every single thing to the healthcare team. It’s interesting. Something that the patient may not believe is serious, the caregiver sometimes knows, right, team?  

So, sometimes the person who’s your loved one or caregiver, “Oh, you know, that’s not-quite-right.” Sometimes the patient knows obviously, and then sometimes the healthcare team may say, “You know, that’s not-quite-right.” I think the not-quite-right thing is the key because that is what supersedes or at least precedes lab testing, X-rays, imaging, and bone marrows, it has to be some provocation. So, what I try to tell people is you know your body best. So, you want to be in touch with yourself, with your body, and anything that isn’t right, don’t be the final judge on that.  

Push it up the chain, let your caregiver know, let your doctors know, let your team know, and let them help you decide. Sometimes it may be nothing, that’s fine. Sometimes it may be something. Sometimes it may be something outside of your MPN. That’s another key theme, I think, I mentioned here a couple of times. Anemia is a good example. So, lowering of the hemoglobin. It’s exactly what you just asked me. So, in addition to looking to see if it’s the disease progression itself, okay, fine.  

However, could it also be drug toxicities, as you mentioned? So, the JAK inhibitor may be causing the anemia or whatever. Then the third bucket is, could it be anemia of regular life stuff, iron deficiency anemia. Could it be a colon cancer or a polyp that’s hiding there? Could it be vitamin B12 deficiency, hemolysis, immune, or something destroying the red blood cells, etc., etc.? So, you make an awesome point, which is all of that can be alleviated or the ball can be started rolling, if you will, by mentioning it. So, the key is no shame, no silence, and mention everything.  

Katherine Banwell:

No silly questions.  

Dr. Naveen Pemmaraju:

No silly questions, that’s right.  

What Myelofibrosis Treatment Types Are Available?

Dr. Naveen Pemmaraju outlines available myelofibrosis therapies, such as JAK inhibitors, and discusses the role of clinical trials and emerging treatments for managing the disease.  

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

Download Resource Guide

See More from Elevate Myelofibrosis

Related Resources:

Myelofibrosis Symptoms and Side Effects | Why Speaking Up Is Vital

Myelofibrosis Symptoms and Side Effects | Why Speaking Up Is Vital

Emerging Treatments in Myelofibrosis Care

Emerging Treatments in Myelofibrosis Care

Myelofibrosis Care | The Impact of Test Results

Myelofibrosis Care | The Impact of Test Results

Transcript:

Katherine Banwell:

So, once all testing is complete and the patient has an accurate diagnosis, they’ll work with their doctor then on a treatment approach. You’ve touched on this a little bit, but  

What are the types of treatment available for people with myelofibrosis? 

Dr. Naveen Pemmaraju:

Yeah, thanks, Katherine. We’ll keep it general and standard of care. As you mentioned at the top, I’ll reiterate, that none of these are intended to be specific instructions for specific folks. However, in general, for the category of patients with myelofibrosis, in general, there’s not many treatments, unfortunately. As of 2024, we have only four standard JAK inhibitors. So, that’s this pathway we’re talking about, JAK-STAT. Interestingly, you don’t have to be JAK2V617F mutated. These are for the whole pathway.  

So, all patients with myelofibrosis, are intermediate to high risk. The first one, Katherine, is ruxolitinib (Jakafi), which has been around for more than a decade, and first in class JAK inhibitor. The second drug is fedratinib (Inrebic). The third is pacritinib (Vonjo), approved only in 2020 for those patients with less than platelets of 50. Then the myelofibrosis drug, momelotinib (Ojjaara), just approved not even a year ago, in September of 2023 for myelofibrosis with anemia. So, those four are considered as called JAK inhibitors.  

They are really the only targeted therapy class of drugs specifically approved in the MF space. Outside of that, there’s older and other drugs that me and others have used, if you will, so-called off-label or historical use, hydroxyurea  (Hydrea), interferon products such as pegylated interferon. Hypomethylators such as azacitidine (Vidaza) and decitabine (Dacogen), particularly in more advanced cases. Some of those drugs are borrowed from MDS and AML and have been around for decades.  

Then of course, finally, clinical trials. We really recommend folks, if they have the ability and feasibility, clinical trials, even in the first diagnosis setting. So, untreated, first therapy. These clinical trials, Katherine, are based on three factors. One is JAK inhibitor plus another agent. So, that’s kind of like a combination trial. Two is add-on agents. So, you’re already on the JAK inhibitor for a while, maybe it’s starting to not work. Then you add in a third agent.  

Then three is a completely novel agent beyond the JAK-STAT pathway. Then maybe we can even add a fourth one now as this is evolving in real-time, which is anemia-targeting drugs. Many of our patients have either transfusion-dependent or bad anemia. Some of the drugs that are being developed are specifically aimed at them. 

Elevate | What You Should Know About Your Role in Myelofibrosis Treatment and Care Decisions

How can you elevate your overall myelofibrosis care and treatment? Dr. Naveen Pemmaraju discusses the importance of engaging in myelofibrosis care decisions with your healthcare team, shares advice for setting treatment goals, and reviews factors that may impact therapy options. Dr. Pemmaraju also provides tips and resources for self-advocacy, including coping with emotional health.

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

Download Resource Guide

See More from Elevate Myelofibrosis

Related Resources:

What Are the Currently Approved Myelofibrosis Therapies?

What Are the Currently Approved Myelofibrosis Therapies?

Considering a Myelofibrosis Clinical Trial? Questions You Should Ask

Considering a Myelofibrosis Clinical Trial? Questions You Should Ask

Primary vs Secondary Myelofibrosis | What’s the DifferencePrimary vs Secondary Myelofibrosis | What’s the Difference?

Transcript:

Katherine Banwell:

Hello and welcome. I’m your host, Katherine Banwell. Today’s webinar is part of the Patient Empowerment Network’s Elevate Series to help myelofibrosis patients and care partners feel well-informed when making treatment decisions with their healthcare team. On today’s program, an expert will join us to share advice for accessing better overall care. 

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 us is Dr. Naveen Pemmaraju. Dr. Pemmaraju, it’s good to see you again. Welcome. Would you please introduce yourself?  

Dr. Naveen Pemmaraju:

Oh, thanks, Katherine, and to Jamie and the team. I’m Dr. Naveen Pemmaraju, a Professor of Leukemia at MD Anderson Cancer Center in Houston, Texas. I also serve as the director for our rare disease program focusing on BPDCN and, of course, MPNs. Also, I want to mention, I have another hat, which is executive director for MD Anderson Cancer Network for Cancer Medicine. Thanks, Katherine.   

Katherine Banwell:

Well, thank you so much for taking the time out of your day to join us. I’d like to start by discussing your role as a researcher. You’re on the front lines for advancements in the myelofibrosis field. What led you here, and why is it important to you?  

Dr. Naveen Pemmaraju:

Well, I think it’s an important question to start with and one that we need to evaluate and dynamically reevaluate over time. I think really for me, two major themes, Katherine, that brought me to this point. One is the absolute desire to be there for patients who don’t have a voice. So, that means giving voice to the voiceless. It’s something I’ve always been good at ever since I was a youth, which is advocating for those who may not be able to or cannot advocate for themselves.  

So, this is the rare disease thread. A lot of my colleagues were going into lung cancer, breast cancer, and colon cancer, very important. We need folks there. However, those were common diseases, largely elucidated. I was always drawn to the more difficult-to-treat diseases, esoteric, and rare, and I think that’s one component, which is the patient voice.  

The second aspect is scientific interest. Again, in the more common tumor types and diseases, there’s a lot already known. So, many of the researchers and research being done is either derivative from that knowledge, Katherine, a or kind of secondary. I wanted to put my efforts and my team’s efforts and frankly, my life effort into trying to figure out new science, new pathways, new breakthroughs, new ideas, and new concepts. I find that in the rare disease space, that’s where I can do that. So, both from the humanistic patient aspect and the science aspect.  

Katherine Banwell:

Well, it sounds like it’s a challenge to you as well.  

Dr. Naveen Pemmaraju:

I think that’s a great point. So, while it’s intellectually satisfying and very important to pursue this, and I love my patients, the clinic, and my team, you make a really good point. Every day when I wake up, it is the challenge that really drives you, which is to try to improve not only the lives of our patients but the quality of life.  

Try to improve the education barriers, which are many, and then the access barriers, not only here in the U.S., but all over the world. Social media has helped that, democratization of information, and platforms like yours right now to get the message out there to folks who need it the most. However, you make a good point. We have a lot of challenges and a lot of barriers, and that motivates me to get up in the morning every day. 

Katherine Banwell:

When it comes to choosing therapy, Dr. Pemmaraju, it’s important to work with your healthcare team to identify what is going to work best for you. So, as a clinician, how do you define shared decision-making?  

Dr. Naveen Pemmaraju:

Very important. So, shared decision-making to me means a partnership. It means a journey that the patient and the providing team are about to embark on. It’s a very different approach than a one-way, I tell you, you do this. Instead, I see it as a bi-directional exchange of ideas.  

Each visit, each EPIC in-basket or EMR communication, each touch with the healthcare system, the pharmacist, the PA, nurse, whoever is dealing with the patient, I think that’s the key.  

So, a bi-directional exchange of ideas, what’s important to you as the patient? What’s important to the caregiver? What are the worries? What are the barriers? Designing a treatment system around that, a treatment paradigm and approach. Discussing risks, benefits, side effects, toxicities, alternatives, and then a constant dynamic reevaluation throughout. That’s what I pictured. It has to be a journey and a partnership.  

Katherine Banwell:

Well, part of making care decisions is setting goals and I think you’ve just alluded to that. What are treatment goals for myelofibrosis, and how are they determined?  

Dr. Naveen Pemmaraju:

That’s a great question. Myelofibrosis treatment goals are changing in real-time. I would say as of this recording, 2024, the main three things that I want patients to think about and the caregivers.  

Number one is a stem-cell transplant eligible or not? It used to be based on age and comorbidities, but there are other factors. So, are we going to stem cell transplants or not? That determines a lot of the journey. Two is a clinical trial or not. So, are we doing the standard of care therapy, often one pill at a time, or clinical trial, either an IV drug, a pill, or combinations? Then three is that dynamic assessment that we talked about, which is what are the goals of care? Often our patients with myelofibrosis have decreased quality of life, enlarged organs, fatigue, cachexia, and malnutrition.  

These are the central components. A lot of times they’re due to the myelofibrosis itself. So, the treatments may improve that. A lot of times it’s the other comorbidities, other health issues. So, working with the PCP, the primary care provider, and the local team. In my case, many of my patients are referrals, as you know, the local MD team. I think these are the three components, transplant eligibility or not, clinical trial versus standard of care. 

Then once we’ve made a treatment decision, minding toxicities and quality of life.  

Katherine Banwell:

Right, okay. So, you’ve touched upon the factors that are considered when choosing therapy for myelofibrosis. Let’s talk about test results. What sort of tests should be done following a myelofibrosis diagnosis?   

Dr. Naveen Pemmaraju:

Well, I think this is something that’s an active area of evolution. I think the good news is I can give you a few standard items. I think most, if not all, of our patients, will require a bone marrow biopsy to be done at baseline and possibly even later on to assess the status of the therapy. Now, in some cases, that may not be available or accessible due to patient preference or comorbidities.  

However, a bone marrow biopsy is a way to look inside and see how the bone marrow tissues are doing. Outside of that, for the blood tests, the two most critical sets are what we call a CBC and a CMP. So, CBC complete blood count. This is where you get your hemoglobin, platelets, and white blood cell count, very important to know at baseline and dynamically.  

Then the complete metabolic profile is very important, Katherine because we need to know how the potassium, kidney function, and liver function are doing. Then finally, I would also say you’ll see your provider add in other blood tests over time, depending on the particular case. Thyroid testing if it’s needed in the case of fatigue, just to name one example. So, I think these are the main categories.  

I think what’s also interesting over time is that this is an issue with us as well in the MPN clinic. You end up seeing your MPN provider and team so much that it’s easy to forget and lose sight of the primary care items too. So, this is a good time to remind folks to stay in touch with their MPN team, the provider, and their caregiver, whether it’s colonoscopies, mammogram, or prostate. I remember over the COVID pandemic time, especially, a lot of that was either sacrificed, forgotten, or on purpose put aside. So, let’s remind people in 2024 to remember to have that partnership as well.  

Katherine Banwell:

How does molecular testing affect treatment options and prognosis? 

Dr. Naveen Pemmaraju:

Right, yeah, I haven’t mentioned that yet because that’s something that we’re trying to layer into. I do find that to be the standard of care now in the treatment of myelofibrosis. What you’re asking about is very important. So, outside of the normal labs in bone marrow morphology, seeing what it looks like under the microscope, we’re starting to add three or four items. One is called cytogenetics, that’s chromosomes. You’re born with 46, so 23 from mother, 23 from father, for example, 46 total.   

Even though most people are not born with an MPN per se, those chromosomes can change and become abnormal over time. So, we want to know that, and that can help us tell low versus high versus intermediate risk. Two is the molecular test you ask about. Most people have heard of JAK2, that’s the most common out of myelofibrosis, maybe 50 percent to 60 percent of cases, JAK2V617F. However, did you know there’s also CALR, which is the second most common molecular mutation, and then MPL. 

Those three are the big three driver mutations. They make up roughly about 90 percent of our cases, 10% being so-called triple-negative. So, you’re negative for all three. When you do deeper sequencing, which is available now clinically, and we check that here, you will find almost always, some other mutation, ASXL1, EZH2, SRSF2, etc. It becomes an alphabet soup very quickly. However, I think basically you should know that there’s JAK2, CALR-MPL, the big three driver mutations, and additional molecular mutations.  

So, therefore we and others believe you should check these as standard. Finally, there’s also flow cytometry. Just want to give a shout-out to that. Most people haven’t heard of that. When you send your bone marrow for testing, in addition to the pathologist looking under the microscope with the human eyes, there’s also a test that does side scatter of light called flow cytometry. That helps to look at a deeper level, maybe the thousandth, maybe even down to the millionth level, what these cancer cells do.  

Katherine Banwell:

What sorts of questions should patients be asking about test results?  

Dr. Naveen Pemmaraju:

I think the number one and number two questions that I advocate for patients or on programs like this, I think the one question that may help a lot is this question of when you hear all the data and ask the question, “Hey, is there any other questions I should be asking that I’m missing?” It’s an interesting question, right? It’s almost a meta, right, kind of a situation. However, when you ask that, every time I’ve been asked in the clinic, it makes me pause and say, “Now that you mentioned it, X, Y, and Z.”  

So, I think it’s a good one to ask either your physician or whoever healthcare provider is in the room, again, nurse, or PA. It’s an interesting one, right? It kind of makes someone maybe even put themselves in your shoes. So, I like it as a device to make people pause in a busy clinic. Yeah, the second question that I think is a good one is to say, “While things are going well right now, I wanted to ask you, doc, what are some things that could happen in the next six months, one year, or two years, adverse events or abnormal things, and is there something I can do to plan for it?” 

Again, it may be somewhat of a theoretical question. The doctor may say, “Okay, right now things are going well,” but it kind of makes people think about contingency plans, and alternative things. Well, now that you mention it, there is this one side effect of this drug. I don’t know, I think those are two kinds of go-to questions that I want people to be equipped with.   

Katherine Banwell:

Yeah, that’s great advice. I’d like to add that if you, the viewer, are interested in learning more about myelofibrosis testing and treatment, PEN has a number of resources available to you. You can find these at powerfulpatients.org/MPN or by scanning the QR code on your screen.  

So, once all testing is complete and the patient has an accurate diagnosis, they’ll work with their doctor then on a treatment approach. You’ve touched on this a little bit, but  

What are the types of treatment available for people with myelofibrosis?  

Dr. Naveen Pemmaraju:

Yeah, thanks, Katherine. We’ll keep it general and standard of care. As you mentioned at the top, I’ll reiterate, that none of these are intended to be specific instructions for specific folks. However, in general, for the category of patients with myelofibrosis, in general, there’s not many treatments, unfortunately. As of 2024, we have only four standard JAK inhibitors. So, that’s this pathway we’re talking about, JAK-STAT. Interestingly, you don’t have to be JAK2V617F mutated. These are for the whole pathway.  

So, all patients with myelofibrosis, are intermediate to high risk. The first one, Katherine, is ruxolitinib (Jakafi), which has been around for more than a decade, and first in class JAK inhibitor. The second drug is fedratinib (Inrebic). The third is pacritinib (Vonjo), approved only in 2020 for those patients with less than platelets of 50. Then the myelofibrosis drug, momelotinib (Ojjaara), just approved not even a year ago, in September of 2023 for myelofibrosis with anemia. So, those four are considered as called JAK inhibitors.   

They are really the only targeted therapy class of drugs specifically approved in the MF space. Outside of that, there’s older and other drugs that me and others have used, if you will, so-called off-label or historical use, hydroxyurea  (Hydrea), interferon products such as pegylated interferon. Hypomethylators such as azacitidine (Vidaza) and decitabine (Dacogen), particularly in more advanced cases. Some of those drugs are borrowed from MDS and AML and have been around for decades.  

Then of course, finally, clinical trials. We really recommend folks, if they have the ability and feasibility, clinical trials, even in the first diagnosis setting. So, untreated, first therapy. These clinical trials, Katherine, are based on three factors. One is JAK inhibitor plus another agent. So, that’s kind of like a combination trial. Two is add-on agents. So, you’re already on the JAK inhibitor for a while, maybe it’s starting to not work. Then you add in a third agent.  

Then three is a completely novel agent beyond the JAK-STAT pathway. Then maybe we can even add a fourth one now as this is evolving in real-time, which is anemia-targeting drugs. Many of our patients have either transfusion-dependent or bad anemia. Some of the drugs that are being developed are specifically aimed at them.  

Katherine Banwell:

There are a couple of new and emerging treatments as well, right? What are those?  

Dr. Naveen Pemmaraju:

Yeah, so right. So, I’m proud to report to the viewers that just now in real time, just in the last year, really we have had several major developments. Now these are not yet FDA-approved agents. They’re experimental investigational agents, but they’ve reached what’s called Phase II or Phase III testing which are the later stages of testing. I’d like to highlight four or five of those.  

These are mostly in the combination space. So, this is a JAK inhibitor plus the new agent. One is called navitoclax. That’s a BCLXL inhibitor, not yet FDA-approved for any indication. However, this has been shown to have activity in the Phase I and II trials, either as a single agent or in combination.  

Now that’s reached Phase III testing. The second one is the pelabresib agent, which is a bromodomain or BET inhibitor. A third, if you can believe it, it’s selinexor (Xpovio), which is an XPO1 inhibitor. Also, a fourth really now entering into Phase III trials is the MDM2 inhibitor navtemadlin. You have these four drugs, which are either completing or starting Phase III, which is the most advanced testing.  

That means they’re randomized trials, usually international trials, many hundreds of patients. It’s an amazing effort that’s unprecedented. By the way, these are being tested in the frontline setting before patients have ever had a JAK inhibitor in combination with. Beyond that, Katherine, there’s many, many trials with novel agents by themselves. So, imetelstat (Rytelo) comes to mind, which is a telomerase inhibitor, for example, which is also in Phase III testing in the relapse setting. So, you’ve already had a JAK inhibitor, it didn’t work out for you. Interestingly in that trial, the overall survival is the primary endpoint rather than spleen and symptoms, which marks the first time we’ve ever seen that. 

It also marks the understanding that these chronic diseases, chronic myelofibrosis can then turn into a more advanced acute in the relapse setting. So, that’s just a sample of some of the ones that are now entering the late stages of trials, many more in Phase I and II. In a good way, there’s a new trial opening once a week.  

Katherine Banwell:

That’s exciting news. So, the symptoms of myelofibrosis as well as the side effects of certain medications can vary greatly among patients. 

Dr. Naveen Pemmaraju:

Yeah. 

Katherine Banwell:

Why is it critical for patients to share any issues they may be having with their care team?  

Dr. Naveen Pemmaraju:

Yeah, exactly what you said. So, those two concepts are tied. Since the disease is so rare and it’s so heterogeneous, not just patient to patient, but within the same patient over the journey of years, that is the reason. So, because of that, that’s why one has to communicate every single thing to the healthcare team. It’s interesting. Something that the patient may not believe is serious, the caregiver sometimes knows, right, team?  

So, sometimes the person who’s your loved one or caregiver, “Oh, you know, that’s not-quite-right.” Sometimes the patient knows obviously, and then sometimes the healthcare team may say, “You know, that’s not-quite-right.” I think the not-quite-right thing is the key because that is what supersedes or at least precedes lab testing, X-rays, imaging, and bone marrows, it has to be some provocation. So, what I try to tell people is you know your body best. So, you want to be in touch with yourself, with your body, and anything that isn’t right, don’t be the final judge on that.  

Push it up the chain, let your caregiver know, let your doctors know, let your team know, and let them help you decide. Sometimes it may be nothing, that’s fine. Sometimes it may be something. Sometimes it may be something outside of your MPN. That’s another key theme, I think, I mentioned here a couple of times. Anemia is a good example. So, lowering of the hemoglobin. It’s exactly what you just asked me. So, in addition to looking to see if it’s the disease progression itself, okay, fine.  

However, could it also be drug toxicities, as you mentioned? So, the JAK inhibitor may be causing the anemia or whatever. Then the third bucket is, could it be anemia of regular life stuff, iron deficiency anemia. Could it be a colon cancer or a polyp that’s hiding there? Could it be vitamin B12 deficiency, hemolysis, immune, or something destroying the red blood cells, etc., etc.? So, you make an awesome point, which is all of that can be alleviated or the ball can be started rolling, if you will, by mentioning it. So, the key is no shame, no silence, and mention everything.  

Katherine Banwell:

No silly questions.  

Dr. Naveen Pemmaraju:

No silly questions, that’s right.  

Katherine Banwell:

Right. I’d like to get to a few audience questions that we received prior to the program.  

Dr. Naveen Pemmaraju:

Sure. 

Katherine Banwell:

Cliff wrote in with this question. “Can you explain the dynamic international prognostic scoring system or DIPSS?” Thank goodness there’s an acronym for that.  

Dr. Naveen Pemmaraju:

Yeah, no, it’s a great question, scoring systems, right?  

Katherine Banwell:

Yeah, and Cliff wants to know how he can ask his doctor about it.  

Katherine Banwell:

Right, so the easiest way to talk about it, the good news is everything we’ve been talking about is incorporated in the scoring system. So, said in another way, we’ve been talking about it subjectively, the scoring systems try to make the subject objective. So, quick history, these started in 2009 with the IPSS, International Prognostic Scoring System. The concept there were a thousand patients in Europe and basically trying to observe the natural history of the progression of myelofibrosis. This was just before, just as the JAK inhibitor era was starting. What we found is that the four groups nicely separate.  

So, the lowest of the low-risk group potentially can be measured in decades for overall survival. Intermediate one, intermediate two, and high risk, again, all separated by overall survival and AML leukemia transformation risk. Now, that’s evolved over time as the questioner is asking for more sophisticated scoring systems. So, that’s all you need to know. So, DIPSS Plus just means Dynamic International Prognostic Scoring System.  

Then there’s DIPSS plus, and can you believe it? There’s even the MIPSS now, the Molecular International Prognostic Scoring System. All right. So, at least there’s a rhyme and reason there. I think each iteration is telling you that we are dynamically understanding more about the disease. Two, the IPSS, the original one, was meant to be only at diagnosis, and the DIPSS by definition, dynamic scoring, is any time during the course of the disease, that’s interesting. Then three, they’re incorporating new factors each time.  

So, from the time of the IPSS to the DIPSS and now the MIPSS, you’re incorporating all these factors that we couldn’t before. Cytogenetics, molecular findings, anemia, transfusion, burn, thrombocytopenia, etc. So, that’s basically it. You can ask your doctor. I mean, basically, in the course of what we do in the non-clinical trial standard of care, even if somebody doesn’t hand stop and calculate these risk scores, we’re talking about the same thing, right? The subjective or the objective matchup.  

However, of interest to the patients, there are calculators that are available, you know, obviously rather than doing it in isolation in your house. Yes, it is better, I agree to do it with your doctor, with your provider team, and see what it means for you. The goal of these is twofold. In clinical trials to help stratify patients so you can understand who’s high risk versus lower. However, in the standard of care, sure it may help with transplant decisions, referrals for clinical trials, etc.  

Katherine Banwell:

Okay. All right, this next question comes from Joel. “I understand that mutational testing should be done at diagnosis. Is there a point where there would be a need to repeat this test?”  

Dr. Naveen Pemmaraju:

Oh, that’s an awesome question. So, we were mentioning that earlier. I do believe and I advocate that all patients should have molecular testing, particularly now as it’s more available widely before it wasn’t. Again, we level set what we’re talking about. In myelofibrosis, three common driver mutations, JAK2, CALR, MPL makes up about 90 percent. 

Then in addition to that, there’s the triple-negative, and you usually find an additional mutation. Then on top of these big three, it’s common to have co-mutations, ASXL1, etc. What we found in this MIPSS score that we just mentioned ties into that. We found now that for the first time, we can incorporate these molecular findings to prognosticate for the patients. That’s why it’s important to check them. So, to this question by Joel, yes, if you have access and availability, not only checking it at baseline but later on at a provoking event.  

So, at the time of relapse, progression, going onto a clinical trial, just to name three of several. I think it’s a good idea to recheck the molecular status. The problem and barriers are what you would expect, cost, expense, access, availability, justification, etc., etc. So, it’s not a mandatory part of the field, especially in the standard of care, non-research aspect. However, if we can get to the point where we can do that, it would be nice and helpful because these mutations change, they’re dynamic.  

You can have negative for mutation  at baseline, positive, and even vice versa, depending on therapies. Are you goimg to go for a transplant? Are you going to go to a clinical trial? Are you changing therapy? It would be nice to know.  

Katherine Banwell:

Right. All right, here’s one more from Diana. “Can diet play a role in either manifesting the disease and or helping with healing? Also, how important is exercise to the healing?”  

Dr. Naveen Pemmaraju:

I give a lot of credit to this area, to my colleagues, Ruben Mesa, Dr. Angela Fleischman, and Dr. Robyn Scherber. A lot of data that’s come out of these groups, which has shown two major findings in our MPN patients of potential clinical significance. One is as the questioner is asking about diet. It is true that we’re, several studies are pointing towards the anti-inflammatory Mediterranean diet as a potential benefit to our patients with MPN. Lots of different ideas there when they measure cytokines. 

These abnormal protein signatures that are in MPN patients can cause fatigue and some of the bad quality of life can be dramatically improved in some cases by following a strict Mediterranean diet over weeks and months. So, that’s something important. People should check it out. Obviously, diets have to be addressed with each patient and each provider because sometimes a diet may work for someone and not for you because of comorbidities, vitamin deficiencies, electrolytes, etc.  

Then the second aspect, if I may include in this question, is also the concept of yoga/meditation. Dr. Ruben Mesa and others have shown, the same thing, that you can have a potential downregulation of some of these abnormal cytokines. However, the caveat is it must be done right with a guided trainer in a real program over a certain period of time. What I think both of these non-pharmacological interventions tell us is that there are things beyond medicines and pills that may really help our patients in some aspect of the disease.  

Well, if that aspect is fatigue, night sweats, headaches, I think that’s a really important thing. So, let’s say together on this program that these data sets are evolving, they’re interesting, they’re intriguing. For some people, it may be an easy incorporation. Frankly, some people may already be doing these things, but as you ask nicely, let’s include in the discussion non-pharmacologic as we heavily investigate the pharmacologic as well. We’re all open to that. Let’s see the data, and the data is evolving.  

Katherine Banwell:

Yeah, absolutely. Well, those were all great questions from our viewers. We ask that you continue to send them to question@powerfulpatients.org, and we will work to get them answered on future programs. I’d like to turn back to self-advocacy for a moment, Dr. Pemmaraju. Managing the worry associated with a diagnosis or concerns about the future, and we did touch upon that earlier, it can lead to anxiety and fear. Why is it important for patients to share any worries they may be having with their care team?  

Dr. Naveen Pemmaraju:

Well, I love this question. It really wraps up everything we’re talking about here. I believe that part of the journey for the patient does include mental and psychological safety. So, it’s very difficult to make major life decisions when one is not feeling mentally, or psychologically safe. So, that’s what you’re hitting on here. Anxiety, fear, and worry, of course, are a natural and important part of the patient journey with any cancer, much less a rare cancer and blood cancer on top of that. However, sometimes in some patients, it can become so paralyzing, so overtaking, and overwhelming that it may prevent the ability of the patient to receive information, process it, and then make a decision back. Yes, we want people to have caregivers, and power of attorney, all those things are essential, but we also want people to have their own agency in aegis.   

So, I would approach this from three aspects. I really love this question because I don’t think we were addressing it head-on 10 or 15 years ago. One aspect is the disease itself. These MPNs, systemic mastocytosis, eosinophilia, myelofibrosis, PV, ET, all of these MPNs can secrete these cytokines and granules that can mess up the patient’s mindset, even just profound fatigue leading to a slowing down of the neurological process. So, I think underlying control of the disease is something that can affect this. Number two is the side effects from some of these medicines. Interferon is a great example, a wonderful class of drugs that’s been around for decades, treated for solid and liquid tumors, but it has a known side effect of causing brain fog. Some of these issues can even cause depression and anxiety in some people. So, education, mitigation, following these things with dose reduction, that’s an important part.  

A third aspect, Katherine, is actually looking with a counselor and a therapist on the spectrum of this. So, normal, adjustment disorder, depression, for example. What we’ve had as a breakthrough at our center has been the supportive palliative care team. They’ve been phenomenal. So, this is a group of doctors who’s kind of one-third internist, one-third oncologist, and one-third psychiatry support.   

So, rather than the usual consults that we used to do either to psychiatry or to social work case managers, there is this burgeoning field of supportive care medicine which has revolutionized the care, I think, particularly for solid tumor patients and now hopefully for our blood cancer patients. So, I’m able to refer patients for a variety of reasons. There’s a fatigue clinic for overwhelming fatigue. There is obviously depression, and anxiety support, either with medications, talk therapy, or both. Smoking secession for folks who are still smoking and maybe either withdrawing or quitting is causing stress.   

So, it’s a really cool science and if your center has that, that’s something to inquire about. Then lastly, as we mentioned, a nice running theme today, Katherine, is looking for other medical stuff outside of the MPN. I mentioned thyroid earlier. Remember, you have a thyroid abnormality that can cause fatigue, depression, and anxiety, right? So, what’s your TSH thyroid function, and vitamin deficiencies?  

Screening for your other well-person screening exams, looking for solid tumors, looking for other conditions that may be mimicking the MPN, or mimicking one of your other aspects. So, again, it comes down to partnership with the primary care team and looking at that. So, I think those are some of the aspects that I want to mention, but it’s such an important part of the journey. I really have to mention that as well.  

Katherine Banwell:

Financial concerns may weigh heavy on patients and families. While everyone’s situation is different, do you have advice for where patients can turn for financial support?  

Dr. Naveen Pemmaraju:

I think this is going to be the next great revolution. Just like I mentioned, the psychiatry, mood, and quality of life realm, I think this will be the next one of the next decade. I think largely it has been not even overlooked, just misunderstood. I’m an academic. I’ve been an academic my whole life, so I’ve never practiced in a private practice. So, some of these issues are quite difficult and foreign for many of us academic doctors.  

In the community setting, there’s a whole set of pressures. Then of course, as you mentioned, there is a whole theme of the pharmaceutical companies helping. In the case of the JAK inhibitors, many of them have patient assistance programs, which have been vital to our patients. So, I think that financial toxicity, that’s what you’re asking about, right, is going to be the next era, the next realm, has been severely underlooked at, really misunderstood.  

You know, I think at the academic centers, you know, obviously we have access to financial counselors, business office, those folks are invaluable. I see them as an essential part of our team, particularly on patients who are trying to get on clinical trials, etc. I think in the community aspect where many of our patients are treated, I think there’s going to be a challenge. So, we have to work with insurance companies, pharmaceuticals, local clinics.  

For patients who don’t have healthcare insurance, try to get them insurance, county systems, cache safety net systems. However, I think you hit on it. I think this will be a new vital sign. It’ll be a new toxicity. It’ll be a new aspect when we consider new drug approvals, and financial toxicity. 

Katherine Banwell:

As we close the program, Dr. Pemmaraju, what would you like to leave the audience with? Why are you hopeful about the future of myelofibrosis care and treatment?  

Dr. Naveen Pemmaraju:

You know, I am hopeful. I am very hopeful. I think the two biggest things that I’m excited about for our patients and their caregivers are one, the burgeoning clinical trial portfolio that we have all over the world.  

Very excited to see the interconnections from Asia, Europe, North and South America. We’re trying to make inroads into Africa and Australia as well. So, a true worldwide  effort for MPNs, particularly myelofibrosis and clinical trials. So, stay tuned for that. I think that’s an exciting aspect.  So, not just the existence of them, but the interconnectivity,  communication, improvement, and availability. I think the second aspect that I’m super excited about is the democratization of information.  

Honestly, 10 years ago, it was kind of difficult to find out information about these diseases, not 100 years ago, just 10 years ago. I really attribute social media and the interconnectivity of folks on these platforms to getting information out there. I would put this type of a platform as well in that same conversation, which is newsflash, nobody’s reading books anymore. Okay, there I said it. 

However, people do have time for a quick two or three-minute blurb while they’re in the coffee line. So, if they can watch a snippet of an interview like this. They can get an email blast about a community town hall. They can get a paragraph on the new drug that just came out. People can take in information in small amounts so I think we have to meet folks, Katherine, where they are.  

We cannot expect people to go to the library and open up a dusty book. I mean, that was in my generation 30 years ago. So, people are on their phones, let’s meet them on their phones. They’re online let’s meet them there. If you’re going to have an in-person town hall, make it high-yield, make it worth somebody’s time and energy and effort frankly, to leave their house to come. Finally, let’s make things affordable from an educational standpoint, if not free, to get the information to the people who need it the most. I’m hopeful about that. I think social media and online platforms have helped us with that.  

Katherine Banwell:

Yeah. Well, that’s great advice, Dr. Pemmaraju. I want to thank you for joining us today. It’s been a pleasure speaking with you.  

Dr. Naveen Pemmaraju:

Thank you so much, Katherine, to the team. I love doing these with you, and thanks for doing this good work.   

Katherine Banwell:

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

Which Emerging Myelofibrosis Therapies Are Showing Promise?

Which Emerging Myelofibrosis Therapies Are Showing Promise? from Patient Empowerment Network on Vimeo.

What are the latest advances in myelofibrosis therapy? Expert Dr. Gabriela Hobbs discusses various inhibitor therapies, including BET inhibitors, that are currently being studied in clinical trials for patients with myelofibrosis.

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.

Download Resource Guide

See More from Evolve Myelofibrosis

Related Resources:

Evolving Myelofibrosis Treatment Options: What You Should Know

What Are the Currently Approved Myelofibrosis Therapies?

What Are the Currently Approved Myelofibrosis Therapies?

Myelofibrosis Clinical Trial Participation | How Does It Move Research Forward

Myelofibrosis Clinical Trial Participation | How Does It Move Research Forward?

Transcript:

Katherine:

Can you share with the audience how the field of myelofibrosis has changed over the course of your career? 

Dr. Hobbs:

Yeah, so it really has been a very exciting journey. So, when I was in medical school, I think that we basically had just discovered the JAK2 mutation.  

So, in the course of my own training and then my professional career, we’ve gone from myeloproliferative diseases being conditions where we really didn’t necessarily have a reason why people would get these conditions. Now not only do we know about the JAK2 mutation, but we know about many other mutations that patients can have. Then in 2011, the first JAK inhibitor was approved, ruxolitinib (Jakafi), and since then, three additional JAK inhibitors have now been approved, including pacritinib (Vonjo), fedratinib (Inrebic), and most recently, momelotinib (Ojjaara).  

So, the field has definitely advanced concretely in that regard. But we also just have much more information about how to diagnose these conditions and also how to treat them. Outside of the JAK inhibitors, we’re better at recognizing when patients need to go to get a bone marrow transplant. For example, and our outcomes with bone marrow transplantation have improved significantly. We also have many other treatment approaches that wouldn’t have existed before, and we also recognize that patients with MPNs live with a lot of symptoms. So, I think that we’re better at just the doctoring part of taking care of patients with MPN. So, definitely, the field has just really, really changed significantly in the last two decades.  

Katherine:

What are new and emerging therapies that are showing promise?  

Dr. Hobbs:

Yeah, so the list is long and it’s getting longer. So, in addition to the fact that we now have four JAK inhibitors approved, which is worth just remembering that, because not that long ago we only had one, and one of them was just approved less than six months ago.   

There are many new agents that are being studied in combination with the JAK inhibitors. This past year at the American Society of Hematology meeting, which is the annual meeting where we go to share our research and learn from our colleagues, there were two Phase III studies that were presented at the same time.  

I can’t remember, or I don’t think, but that has really ever happened before for myelofibrosis. One of them was with an agent called pelabresib, which is a type of molecule called a BET Inhibitor. And the other one was with an agent called navitoclax, which is an agent called a BCLXL-BCL2 inhibitor, which is a molecule that helps cells to undergo apoptosis or programmed cell death.   

So, these molecules were both combined with ruxolitinib. And we saw the results of the Phase III studies for each of these agents, and they were really quite exciting. The punchline for both of these studies is that they demonstrated that when you give two drugs as opposed to just one, the amount of patients that have a significant reduction in their spleen is doubled than when you give ruxolitinib in it by itself. So, for some of our patients that is a really meaningful number. You know, if you’re a patient that suffers from a big spleen, knowing that there’s a possibility of having two drugs that you can take to really shrink that spleen in a significant way, I think is very, very promising. On the symptom front, taking two medicines versus one medicine really didn’t seem to make a huge difference. I think we can analyze this in two different ways.  

We can see the negative or the positive side of this. So, on the negative side, well, it’s too bad that, you know, added medication didn’t help patients feel better. But on the upside, it’s also good that taking two medicines didn’t make people feel worse. Sometimes you can think of, you know, if you’re taking more medication, maybe you will feel worse. So, the jury is kind of still add on the significance of those results.

But regardless, without getting into too much detail about these studies, I think it’s really exciting for myelofibrosis patients to know that there are two agents that are in Phase III testing. That means that the next step is really consideration of FDA approval. So, when medications go through clinical trials, they go through earlier phase studies, Phase I, Phase II, and then finally they get to Phase III. A lot of work and effort has gone into these two compounds to try to get them to FDA approval. So, we’ll wait and see if in the next year or so we have new agents for the treatment of MF. 

In addition to these two, which of course are the most advanced, there really are a variety of other agents that are being tested. Those, for the most part, are still in Phase II testing. And similarly to the ones I mentioned before, most of the compounds, the way that they go into trials is first they start out showing that they’re safe by themselves, and then they get added to a JAK inhibitor.

So, far, because ruxolitinib has been the one that we’ve had around for the longest, most of these studies are being tested in combination with ruxolitinib. But we start to hear rumblings from clinical trials that perhaps some of the newer trials will consider using other JAK inhibitors as combination partners, which is a natural evolution. So, to name a few other agents, we have drugs like selinexor (Xpovio), and navtemadlin we have a PIM kinase inhibitor, a lysyl oxidase inhibitor, an LSD1 inhibitor, the list is long of all these different agents.  

Preliminarily, at least from the data we’ve seen from all of these compounds, I think there’s a lot of room for excitement. We see that combining these drugs together, the new agent plus the ruxolitinib, leads to a significant reduction in the spleen. And in some of these agents, we’re starting to see other endpoints. So, in addition to just looking at can we make patients feel better and can we shrink their spleens?

We’re starting to look at other things such as when we add these medications, do we see a reduction in the scarring or the fibrosis in the bone marrow? Do we see a decrease in the cells that have the mutation? Do we see the patients live longer? All of those things are endpoints in our studies that we really haven’t tested before. So, I think the field really will produce a lot of exciting data in the next couple of years.  

Katherine:

You mentioned clinical trials, and we will talk about those in a few moments, but are there innovations in technology that are accelerating myelofibrosis research?  

Dr. Hobbs:

So, the most obvious way to answer that question is simply that it’s much easier to diagnose myelofibrosis now, thanks to the ability to do genetic testing now much more easily than before. So, I think that previously, you know, getting JAK2 testing or testing for the other mutations was not as simple or would take a long time for the results to come back.  

Now, you know, I see even in the smallest of practices, ordering not just the JAK2 gene, but ordering what many of us do, which is like a panel of genes, where you test for a lot of the genes at the same time, has become almost commonplace. So, that’s really a meaningful advance in that it’s a technology that’s available and it’s no longer as prohibitively expensive as it was before.  

That doesn’t mean that some patients don’t end up getting charged in ways that doesn’t make any sense anymore, but that’s a conversation for another time. But I think just having the ability to make those diagnoses because of how easy it is now to test for these mutations is really very meaningful. Outside of that, I mean, I would say that along with the improvement in the knowledge of what mutations patients have with myelofibrosis, we definitely have deeper ways of analyzing what genes are being expressed and in what cells they’re being expressed to really understand, you know, when do patients first get those mutations and how do those mutations change over time.

So, we’re really diving deep into the actual biology of the bone marrow and there’s some studies that have demonstrated that patients may even have the JAK-2 mutation in utero, which is really, really fascinating. So, definitely a lot more understanding of the actual biology of how these diseases happen.   

Evolving Myelofibrosis Treatment Options: What You Should Know

Evolving Myelofibrosis Treatment Options: What You Should Know from Patient Empowerment Network on Vimeo.

Myelofibrosis treatment and care is evolving quickly so it’s essential to understand your options and work with your healthcare team when making treatment decisions. In this webinar, Dr. Gaby Hobbs discusses the latest updates in research and clinical trials, the role of new and emerging myelofibrosis therapies, and shares advice for accessing quality 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.

Download Resource Guide

See More from Evolve Myelofibrosis

Related Resources:

Is Stem Cell Transplant the Only Curative Option for Myelofibrosis?

Is Stem Cell Transplant the Only Curative Option for Myelofibrosis? 

Myelofibrosis Therapies in Clinical Trials | BET Inhibitors

Myelofibrosis Therapies in Clinical Trials | BET Inhibitors 

Choosing a Myelofibrosis Treatment Plan | Key Questions to Ask

Choosing a Myelofibrosis Treatment Plan | Key Questions to Ask 

Transcript:

Katherine:

Hello and welcome. I’m your host, Katherine Banwell. As patients collaborate on treatment decisions with their healthcare team, it’s important that they understand all of their options and how these options may be impacted by research developments. That’s why the Patient Empowerment Network created the Evolve Series, to arm you with the latest information and to help you feel empowered and confident during conversations about your care.  

In today’s program, we’re going to hear from an expert in the field about the evolving treatment landscape for myelofibrosis and discuss how you can play an active role in your care.  

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 us is Dr. Gaby Hobbs. Dr. Hobbs, welcome. Would you please introduce yourself? 

Dr. Hobbs:

Hi, how are you? Thank you so much for inviting me today. My name is Gaby Hobbs. I’m the clinical director of the leukemia service at Mass General Hospital in Boston and the director of the MPN program at MGH as well. I conduct clinical trials as well as see patients with myeloproliferative neoplasms.  

Katherine:

Thank you so much for taking the time to join us today. We really appreciate it.  

Dr. Hobbs:

My pleasure.  

Katherine:

Before we get into our discussion, can you share with the audience how the field of myelofibrosis has changed over the course of your career? 

Dr. Hobbs:

Yeah, so it really has been a very exciting journey. So, when I was in medical school, I think that we basically had just discovered the JAK2 mutation.  

So, in the course of my own training and then my professional career, we’ve gone from myeloproliferative diseases being conditions where we really didn’t necessarily have a reason why people would get these conditions. Now not only do we know about the JAK2 mutation, but we know about many other mutations that patients can have. Then in 2011, the first JAK inhibitor was approved, ruxolitinib (Jakafi), and since then, three additional JAK inhibitors have now been approved, including pacritinib (Vonjo), fedratinib (Inrebic), and most recently, momelotinib (Ojjaara).  

So, the field has definitely advanced concretely in that regard. But we also just have much more information about how to diagnose these conditions and also how to treat them. Outside of the JAK inhibitors, we’re better at recognizing when patients need to go to get a bone marrow transplant. For example, and our outcomes with bone marrow transplantation have improved significantly. We also have many other treatment approaches that wouldn’t have existed before, and we also recognize that patients with MPNs live with a lot of symptoms. So, I think that we’re better at just the doctoring part of taking care of patients with MPN. So, definitely, the field has just really, really changed significantly in the last two decades. 

Katherine:

That sounds like it’s been a rapid change, really. There may be some confusion, Dr. Hobbs, among people wondering what is the difference between primary and secondary myelofibrosis? Could you describe the differences?  

Dr. Hobbs:

Sure. Great question. So, that term, primary and secondary, is actually used in medicine very frequently for the description of many conditions that are not that different. So, primary means a patient has myelofibrosis and did not have any myeloproliferative neoplasm, or MPN, before their diagnosis.  

So, they went to the doctor and the first diagnosis they received was a diagnosis of myelofibrosis. Now sometimes we suspect that a patient may have had another MPN previously, such as essential thrombocythemia or polycythemia vera, but they just weren’t diagnosed.   

What I mean by that is, you know, let’s say you meet a patient and you look through their chart and you see that five years ago or 10 years ago, they had really, really high platelets or very high red blood cell numbers. So, there you could say, well, you know, you were never diagnosed with ET or PV, but maybe you had that. So, you probably have secondary myelofibrosis, but the diagnosis, you know, that you come with to the doctor is myelofibrosis. So, secondary myelofibrosis means that you had an underlying condition before, meaning you were first diagnosed with one condition like PV, polycythemia vera, or ET, and then those conditions turned into myelofibrosis.  

And then we call that secondary myelofibrosis, meaning it is secondary to the primary condition, meaning ET or PV. One area of confusion that I’d like to be able to clarify also related to this is if a person has secondary myelofibrosis, they don’t have two myeloproliferative neoplasms or two conditions. It is one and the same. They just live on a spectrum and over time, they can turn into, one into the other. So, it’s not that you now have two diagnoses, it’s still the same condition, it’s just morphed a little.  

Katherine:

Okay, thank you for that explanation. I’d like to talk about the importance of a patient’s healthcare team. What are the benefits to seeking care with a myelofibrosis specialist, even if it’s just for a second opinion or a consultation? 

Dr. Hobbs:

Great question. I think that one thing that COVID has given us is the ability to have webinars like this, but also that you can seek second opinions more easily with the advent of telehealth.  

So, whereas before I think that getting that second opinion would have been maybe more challenging, perhaps now it’s easier. But to answer your question, these conditions are rare. Myelofibrosis in particular is even more rare than the others.  

The landscape, as I kind of alluded to in our initial question, has changed significantly in the last two decades. So, getting a second opinion, whether that’s, like you said, just for an initial consultation, and then you never see that person again. Or you end up having kind of two doctors, one that treats you for your day-to-day needs and an expert or specialist that sees you occasionally as things may change, which can be very beneficial for a variety of reasons. I think that the first one is to just hear hopefully the same information that your initial doctor gave you, but maybe from a different perspective. I think that’s always helpful when dealing with a new diagnosis.  

Second is, you know, a specialist may have access to clinical trials. Although that may not be the right thing for you when you first meet them, it may be something you would want to consider or may be appropriate for you later down in your treatment. So, being connected to somebody that has access to research is something that, you know, it opens a door.   

Katherine:

We’ve established that research in the field is moving quickly. What are new and emerging therapies that are showing promise?  

Dr. Hobbs:

Yeah, so the list is long and it’s getting longer. So, in addition to the fact that we now have four JAK inhibitors approved, which is worth just remembering that, because not that long ago we only had one, and one of them was just approved less than six months ago.  There are many new agents that are being studied in combination with the JAK inhibitors. This past year at the American Society of Hematology meeting, which is the annual meeting where we go to share our research and learn from our colleagues, there were two Phase III studies that were presented at the same time.  

I can’t remember, or I don’t think, but that has really ever happened before for myelofibrosis. One of them was with an agent called pelabresib, which is a type of molecule called a BET Inhibitor. And the other one was with an agent called navitoclax, which is an agent called a BCLXL-BCL2 inhibitor, which is a molecule that helps cells to undergo apoptosis or programmed cell death.  

So, these molecules were both combined with ruxolitinib. And we saw the results of the Phase III studies for each of these agents, and they were really quite exciting. The punchline for both of these studies is that they demonstrated that when you give two drugs as opposed to just one, the amount of patients that have a significant reduction in their spleen is doubled than when you give ruxolitinib in it by itself. So, for some of our patients that is a really meaningful number. You know, if you’re a patient that suffers from a big spleen, knowing that there’s a possibility of having two drugs that you can take to really shrink that spleen in a significant way, I think is very, very promising. On the symptom front, taking two medicines versus one medicine really didn’t seem to make a huge difference. I think we can analyze this in two different ways.  

We can see the negative or the positive side of this. So, on the negative side, well, it’s too bad that, you know, added medication didn’t help patients feel better. But on the upside, it’s also good that taking two medicines didn’t make people feel worse. Sometimes you can think of, you know, if you’re taking more medication, maybe you will feel worse. So, the jury is kind of still add on the significance of those results. But regardless, without getting into too much detail about these studies, I think it’s really exciting for myelofibrosis patients to know that there are two agents that are in Phase III testing.

That means that the next step is really consideration of FDA approval. So, when medications go through clinical trials, they go through earlier phase studies, Phase I, Phase II, and then finally they get to Phase III. A lot of work and effort has gone into these two compounds to try to get them to FDA approval. So, we’ll wait and see if in the next year or so we have new agents for the treatment of MF.  

In addition to these two, which of course are the most advanced, there really are a variety of other agents that are being tested. Those, for the most part, are still in Phase II testing. And similarly to the ones I mentioned before, most of the compounds, the way that they go into trials is first they start out showing that they’re safe by themselves, and then they get added to a JAK inhibitor.

So, far, because ruxolitinib has been the one that we’ve had around for the longest, most of these studies are being tested in combination with ruxolitinib. But we start to hear rumblings from clinical trials that perhaps some of the newer trials will consider using other JAK inhibitors as combination partners, which is a natural evolution. So, to name a few other agents, we have drugs like selinexor (Xpovio), and navtemadlin we have a PIM kinase inhibitor, a lysyl oxidase inhibitor, an LSD1 inhibitor, the list is long of all these different agents.  

Preliminarily, at least from the data we’ve seen from all of these compounds, I think there’s a lot of room for excitement. We see that combining these drugs together, the new agent plus the ruxolitinib, leads to a significant reduction in the spleen. And in some of these agents, we’re starting to see other endpoints. So, in addition to just looking at can we make patients feel better and can we shrink their spleens?

We’re starting to look at other things such as when we add these medications, do we see a reduction in the scarring or the fibrosis in the bone marrow? Do we see a decrease in the cells that have the mutation? Do we see the patients live longer? All of those things are endpoints in our studies that we really haven’t tested before. So, I think the field really will produce a lot of exciting data in the next couple of years.  

Katherine:

You mentioned clinical trials, and we will talk about those in a few moments, but are there innovations in technology that are accelerating myelofibrosis research?   

Dr. Hobbs:

So, the most obvious way to answer that question is simply that it’s much easier to diagnose myelofibrosis now, thanks to the ability to do genetic testing now much more easily than before. So, I think that previously, you know, getting JAK2 testing or testing for the other mutations was not as simple or would take a long time for the results to come back.  

Now, you know, I see even in the smallest of practices, ordering not just the JAK2 gene, but ordering what many of us do, which is like a panel of genes, where you test for a lot of the genes at the same time, has become almost commonplace. So, that’s really a meaningful advance in that it’s a technology that’s available and it’s no longer as prohibitively expensive as it was before.  

That doesn’t mean that some patients don’t end up getting charged in ways that doesn’t make any sense anymore, but that’s a conversation for another time. But I think just having the ability to make those diagnoses because of how easy it is now to test for these mutations is really very meaningful.

Outside of that, I mean, I would say that along with the improvement in the knowledge of what mutations patients have with myelofibrosis, we definitely have deeper ways of analyzing what genes are being expressed and in what cells they’re being expressed to really understand, you know, when do patients first get those mutations and how do those mutations change over time. So, we’re really diving deep into the actual biology of the bone marrow and there’s some studies that have demonstrated that patients may even have the JAK-2 mutation in utero, which is really, really fascinating. So, definitely a lot more understanding of the actual biology of how these diseases happen.  

Katherine:

Dr. Hobbs, a key part of research moving forward is the clinical trial process. Can you talk about the benefits of patient participation? 

Dr. Hobbs:

Yeah, so I think to answer that question, I should preface that by saying that I conduct clinical trials, and so certainly my answer is going to have that as a bias, so it’s important to know that. And I tell my patients that as well when I’m talking to them about clinical trials. Now, why do I think clinical trials are beneficial? Well, there’s really no way to advance the field without the sacrifice that patients do by allowing us to conduct clinical trials. Without clinical trials, we cannot get drugs approved. Without new drugs, we certainly can’t help our patients anymore with newer therapies. That being said, a clinical trial is something that is not just an experiment. Many times patients will be like, well, I don’t want to be a guinea pig. And I completely respect that.  

So, I think it’s really important to recognize too, that we take conducting clinical trials very, very seriously. The machinery that needs to exist in each hospital to conduct trials includes a ton of people. So, we have a lot of regulatory bodies, both within the hospital and outside of the hospital, to ensure that clinical trials are conducted in an ethical and in a safe way. So, one of the benefits, which you may not consider when you’re contemplating participating in a trial, is that your care team actually becomes much larger. You’re much more closely scrutinized actually, when you’re a member of a trial.

So, whereas before you would have just primarily seen me and my nurse practitioner, when you participate in a clinical trial, all of a sudden you have all these research nurses that are calling you, checking in with you, making sure you’re feeling well, et cetera. So, that’s actually a nice perk to participating in trials. So, an important thing to know with clinical trials is that they may not benefit everybody. 

And that not every clinical trial may be right for you and that there may be times when trials are appropriate and times where trials may not be appropriate. So, it’s not a decision that you make that’s black and white and that’s a decision that you make forever. I think it’s something that you can continue to discuss with your care team as you go through having this disease.  

Katherine:

Let’s move on to treatment. Would you provide an overview of the currently approved therapies for myelofibrosis?  

Dr. Hobbs:

Sure, absolutely. So, I’ve alluded to this a little bit. So, in 2011, we had the first JAK inhibitor approved called ruxolitinib, the brand name is Jakafi. After that, we had the approval of Inrebic or fedratinib and then pacritinib or VONJO, and then most recently momelotinib or Ojjaara. So, we have four different JAK inhibitors that are now approved for myelofibrosis.  

So, who needs to get a JAK inhibitor and how do we choose between the JAK inhibitors? So, the traditional indications for JAK inhibitors are, does a patient have bothersome symptoms from having a big spleen? Does a person have symptoms from their disease? Symptoms can include things like night sweats, itching, unintentional weight loss, brain fog, and fatigue. Fatigue can be challenging because of course many things can cause fatigue. But those are some of the symptoms that can occur with having this disease. So, if a patient has both splenomegaly symptoms or one or the other, they’re eligible for a JAK inhibitor.  

So, just having myelofibrosis doesn’t mean that you need to have a JAK inhibitor right away. Probably the most commonly used JAK inhibitor, and this will be the case probably for a long time, is ruxolitinib.  

The reason for that is that it’s been around for a long time, and it’s a very well-tolerated medication. Patients that have platelets that are very low, meaning platelets that are less than 50, should be considered for pacritinib first, as that’s the indication for that agent. Patients that don’t do that well on ruxolitinib initially, let’s say that the dose gets increased and the spleen and the symptoms are still present, but still have good blood counts, are good candidates for then receiving fedratinib. Fedratinib can also be given upfront. It rarely is given upfront, simply because ruxolitinib has been around for longer and it’s a better-tolerated medication. So, therefore most providers feel more comfortable giving that upfront. I have had some patients that are concerned about the weight gain that is a side effect of ruxolitinib. For those patients, I’ve occasionally considered giving fedratinib first before ruxolitinib. And then lastly, we have momelotinib. It’s approved primarily for patients with myelofibrosis and anemia.  

Now momelotinib is still a JAK inhibitor, so it can still improve symptoms, and it still improves spleen size. So, I struggle with that recommendation of just using it for anemia in patients that don’t have splenomegaly or symptoms.  

But the FDA label was pretty broad, and it’s important to recognize that. So, how is momelotinib being used? It can be used in the upfront setting for patients that have spleen and symptoms, and also anemia, meaning low red blood cell levels. Or,  it can be used for patients that have been treated with a JAK inhibitor first and then develop anemia. So, momelotinib is given to continue to improve the spleen and symptoms, but also help the anemia. So, that’s kind of like an overview of the four JAK inhibitors. Now we have a group of patients that maybe doesn’t have a lot of spleen symptoms or symptoms in general but has issues with having low hemoglobin. So, for those patients, we’ve used a variety of different medications, including medications that are called erythropoietin, which is a hormone that helps to boost the red blood cell levels.  

A medicine that’s similar to testosterone that can also help boost the red blood cell levels called danazol (Danocrine). And then there’s a medication called luspatercept-aamt (Reblozyl) that has been approved for a related condition called myelodysplastic syndrome. And in some clinics, it can be used even though it’s not approved either by itself or in combination with ruxolitinib. And then lastly, patients that have what is called high-risk myelofibrosis, meaning they have some mutations that may indicate that a patient has a higher risk of having complications of their disease, or they have very low blood counts, are usually considered high-risk. Those patients should be recommended and referred to transplantation as soon as they’re identified as having high-risk disease.  

Katherine:

When you say transplantation, you’re referring to stem cell transplant. 

Dr. Hobbs:

Yes, and I’m glad you said it that way actually. So, stem cell transplantation or bone marrow transplantation, same thing, interchangeable, same procedure. You got it.  

Katherine:

Yeah. So, where do clinical trials fit into a treatment plan? 

Dr. Hobbs:

So, it really depends on what is available at the site where you’re seeking care. Clinical trials come in a variety of different flavors. So, there may be a clinical trial for patients that are newly diagnosed, that are about to start a JAK inhibitor, for example.  

So, if you’re a patient that’s considering a JAK inhibitor to treat your spleen symptoms or your systemic symptoms, and there happens to be a clinical trial for adding on another medication, like the first JAK inhibitor you receive, well, that’s a great place to consider a clinical trial.  

There may also be clinical trials in later lines. Let’s say you were treated only with a JAK inhibitor first, but the study that’s available at your center is adding another medication to the JAK inhibitor if the JAK inhibitor by itself didn’t quite do the trick. 

There’s also other studies, for example, at the time of transplantation, for example, using the JAK inhibitors during transplant. So, really the clinical trials can be relevant at any time during treatment. In addition to clinical trials, testing new medications, there’s also other ways to participate in research throughout your time as a patient with your care team, which may include things like, for example, consenting to participate in a tissue bank.  

You donate a sample of your blood or bone marrow that is then later on used for research. Or we may have studies investigating the symptoms a patient has throughout their disease or their experience living with their disease. So, there’s many different ways of participating in research and clinical trials, even if those don’t necessarily include trying a new medication.  

Katherine:

What questions should patients be asking if they’re interested in learning more about clinical trials?  

Dr. Hobbs:

Yeah, great question. So, the first is understanding, you know, what is the medication that you will be receiving? Are you going to be receiving a placebo? Is that an option? This means a sugar pill. That’s a common question that I get. How do you get assigned to different groups? So, in one trial, there may be a group that gets one dose, another group that gets another dose, et cetera. So, it’d be important to know how are you going to get assigned and what are the options potentially for you before you sign up. After that, it’s important to know what phase the study is in.

So, is this a first-in-human study where your doctor may not be able to tell you a whole lot about what’s expected in terms of side effects or safety or toxicity? Or is this a Phase III study where maybe the trial has been open for many years and there’s been many patients that have been enrolled in it already? Or maybe this is a drug that’s already been approved for another condition and we’re borrowing it for myelofibrosis, for example, and then your care team can tell you lots of information about the safety and toxicities, etc.  

So, having a sense of where the drug is in its development, I think can be very helpful. Then there are some practical things that we sometimes do not spend enough time talking about.  

So, I’m glad to have the space to talk about that here. Participating in a clinical trial takes time. And it’ll take more time as a patient to participate in a clinical trial than to receive regular care. You may have to go to the hospital where you’re being treated more frequently. If you’re somebody that receives virtual care where some of your visits are telehealth and some of them are in person, you need to be aware that you may have more visits that are in person because the clinical trial procedure requires that certain labs or tests be done in the facility, not anywhere else. Clinical trials by definition, unfortunately, sometimes have to be very inflexible in order to ensure that we collect data in a uniform way.  

So, just being aware that it may take more time to participate is important. And along those lines, asking if the clinical trial will reimburse you for some of that time. So, for example, if you need to park in the expensive hospital parking more frequently, some trials will actually reimburse you for that. Or they may offer a hotel reimbursement if you need to travel from far away and spend a night there. So, don’t be afraid to ask those things because many times that’s built into the clinical trial.

So, that’s an important thing just practically to know. So, asking for a study calendar so you get a sense of how frequently you’ll need to be going to the doctor is really important. Also, then realizing that potentially you may have to go to see the doctor or the care team more frequently initially, but then after the first couple of months, if everything is going well, you’ll likely have the flexibility to go less often. So, all those questions are important to have in mind.  

Katherine:

That’s great information, thanks, Dr. Hobbs. When considering therapy, how do you approach a treatment plan for someone diagnosed with myelofibrosis?  

Dr. Hobbs:

Great question. So, when approaching how I care for a patient with myelofibrosis, I take several things into account. The first thing is, who is this patient? What other medical conditions do they have? How impacted are they by their myelofibrosis? Then what I like to do is to plug in the numbers of the patient, their blood work, their mutations, etcetera, into one of the many risk calculators that we have to determine what the risk of their myelofibrosis is. 

If a patient is considered high-risk, I will generally consider transplantation or discuss a referral to a bone marrow transplantation in one of our first visits, if not the first visit. After that, I need to determine whether or not the patient has symptoms from their disease, and if so, if they should receive a JAK inhibitor. Then I’ll look through their blood work, what their symptoms are to decide which JAK inhibitor to use first.  

If really the spleen and symptoms aren’t the primary issue, if it’s more related to low blood counts, then we can think about treatments directed at improving the hemoglobin, for example. There may be a group of patients that don’t actually require any treatment when I first meet them. So, just providing them with education, what to expect. Then discussing more of the psychological impact of living with a condition and approaches to handle that, maybe more the focus of my care.

And in general, for most of my patients, we also talk about the rest of the care. So, not just what the blood work is and what medicine I’m going to start them on, but also other things that they can do to take care of themselves, including making sure that they are actively monitored by their primary care doctor or by other specialists if that’s still appropriate. You know, one of the things we don’t discuss that frequently in myelofibrosis, we discuss that more often in essential thrombocythemia or polycythemia vera is a risk of blood clots.  

But the truth is that myelofibrosis patients can also have risks of blood clots. So, therefore, making sure that patients with MF that may have issues like hypertension, diabetes, high cholesterol, etc., get those well-managed is also really important to prevent them from having blood clots. So, lifestyle management is also an important part of the care of a patient with myelofibrosis. 

Katherine:

That’s all great advice. A note to our viewers, PEN has also created downloadable office visit planners to help you organize your thoughts and communicate effectively with your healthcare team. You can find those in the MPN Toolkit at powerfulpatients.org or by scanning the QR code on your screen.  

Well, it’s been a lot of great information, Dr. Hobbs, and I’d like to close with your thoughts on the future of myelofibrosis care. Where are we headed and what would you like to leave our audience with?   

Dr. Hobbs:

Well, the first thing I wanted to say is just kind of piggyback with what you said about the visit planner. I love that. I think that many times patients come to a visit and they’re like, oh, I had this question that I wanted to ask you and now I can’t remember what it was. And especially if you’re seeing a doctor every six months or something like that, making sure that you come to that visit prepared with lots of questions is an excellent way to make the most use out of your visit with your provider. So, I definitely encourage you to do that. In terms of what to leave patients with, so going back to what we were discussing initially, the list of new agents that are being investigated for myelofibrosis is long and longer by the day. So, as a myelofibrosis doctor, I really feel very optimistic that in  the next year and hopefully in the next couple of years, we’re going to have a variety of new treatment options that are going to really help our patients to live not just longer with their myelofibrosis, but truly to live much better with their myelofibrosis.  

So,  continue to get informed by watching webinars such as this one and reading reliable sources of information on different patient advocacy organizations because there’s really a lot of changes that are happening. So, I definitely think it’s a time to feel hopeful about the future of  myelofibrosis.  

Katherine:

Well, thank you so much for taking time to join us today, Dr. Hobbs, we really appreciate it.  

Dr. Hobbs:

Sure, it’s always a pleasure.  

Katherine:

And thank you to all of our collaborators. 

To learn more about myelofibrosis and to access tools to help you become a proactive patient, visit powerfulpatiens.org. I’m Katherine Banwell. Thanks for joining us.   

Expert Perspective | Disease Modification in Polycythemia Vera

Expert Perspective | Disease Modification in Polycythemia Vera from Patient Empowerment Network on Vimeo.

Is it possible to change the course of disease in polycythemia vera patients? MPN specialist and researcher Dr. Lucia Masarova shares an overview of the research in disease modification, discussing her work as the coauthor in an article entitled Moving Towards Disease Modification in Polycythemia Vera, recently published in the journal Blood.

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

 

Related Programs:

Are There Predictors That an MPN May Be Progressing

Are There Predictors That an MPN May Be Progressing?

Myeloproliferative Neoplasm News and Research Updates

Myeloproliferative Neoplasm News and Research Updates

How Molecular Markers Affect MPN Treatment | Advances in Research

How Molecular Markers Affect MPN Treatment | Advances in Research


Transcript:

Katherine Banwell:

Dr. Masarova, you are a coauthor in an article entitled Moving Towards Disease Modification in Polycythemia Vera, which was recently published in the journal Blood. Can you share some of the highlights of the article and what it means for PV patients? 

Dr. Lucia Masarova:

Disease modification in polycythemia vera. I’m so excited finally being talking about this because we’ve been really, really, really so hungry for this term, although we still don’t know what it means.  

So, we group together with lots of experts in the myeloproliferative neoplasm field and try to brainstorm and put together, “What does it actually mean?” And to me, and to all of us, it was to offer our patients the normal or not-normal lifespan without the consequences of the disease that they face. Because we historically divided polycythemia vera into high-risk or low-risk disease based on the age or previous history of thrombosis or clotting complications.  

However, there is a huge area of patients that wouldn’t have either, and still suffer tremendously a bad quality of life, and ultimately also face the disease progression to myelofibrosis, which is the most actual complication of long-term polycythemia vera duration.  

So, the concept of disease modification would be to actually prevent the complications to even occur. To allow our patient to live free of having the fear of living with a thrombosis or clotting complication or ultimately progress into myelofibrosis. We have to learn how to get there. What are the relevant endpoints of tools for us to utilize to really understand? We have learned a lot from seeing what we call molecular remissions, or control of the JAK2 mutation with certain medications, for example, interferons or latest ruxolitinib (Jakafi), the JAK inhibition, where the decrease of the allele burden, which represents the disease, is correlated with better outcome.  

So, that is something that we have to be learning down the road with a longer follow-up. But that basically triggered us to focus on what can we do better? How do we prevent this from even happening rather than only controlling the historically main points of the disease which are presented by the blood counts symptoms and display? And where we are actually failing quite a lot of patients because despite them having a control count, they still don’t have a happy life, and lots of them suffer and complain.  

So, this is something to be learned, and this is opening the disease modification not only for polycythemia vera, but also for all patients with myeloproliferative neoplasms, which have a little bit of a different feeling in the whole myeloid malignancies field. Because it is a very long disease, and it could evolve and change, and only now we starting to understand what does actually happen there. Why some people could live for 30 years, and never face any consequences, and the others would progress very fast? 

So, disease modification would normally allow us to develop and learn more tools and better biomarkers, but also focus on drugs that are really needed to help with these long-term outcomes of our patients.  

Choosing a Myelofibrosis Treatment Plan | Key Questions to Ask

Choosing a Myelofibrosis Treatment Plan | Key Questions to Ask from Patient Empowerment Network on Vimeo.

When considering therapy for myelofibrosis, where do you start? Dr. Lucia Masarova shares advice and key questions to ask your provider when making myelofibrosis treatment decisions.

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.

See More from Evolve Myelofibrosis

Related Resources:

Myelofibrosis Therapies in Clinical Trials | BET Inhibitors

Myelofibrosis Therapies in Clinical Trials | BET Inhibitors

Is Stem Cell Transplant the Only Curative Option for Myelofibrosis?

Is Stem Cell Transplant the Only Curative Option for Myelofibrosis?

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

Myeloproliferative Neoplasm News and Research Updates

Transcript:

Katherine Banwell:

When considering treatment options, what key questions should patients ask about their proposed treatment plan? 

Dr. Lucia Masarova:

What’s the goal of my therapy? That is one of the most important things to know. Patients don’t even know how long they have to be on the medicines. What to do and how does it look when the medicine is still working? What do I need to be looking for in this medicine? And then what are we going to do if it fails? And what does it actually mean when it fails? What is the schedule? How burdensome the treatment is? How often do I have to come?  

How often and what do I have to pay? Because the financial burden we have to really, really face the truth. It is very, very, very significant and somebody living with this disease predicates. It’s something we cannot take lightly, and we really have to combine our efforts and help with that. There are fantastic patient support organizations, but is not well-known, and is still in the rare – in rarer field. So, there’s more effort that we do. 

When do I need more help? Where to be referred to more experts? What is the role of stem cell transplantations, if ever? So, those are really the key things.  

Where do I find reliable resources to learn about my treatment, to learn about the disease? How do I connect with people from the same community? It is a disease with a lower age in a lot of circumstances and really facing this disease in the 30s or 40s or 50s is a really challenging thing. Although we have more and more medications currently, we really do have now to start thinking about their durability, about the safety for long-term, about their assessments for not performing, and where do we place the ultimate cure for stem cell transplants?  

And how do we make it actually happen in more and more eligible patients? Because we have to face the truth. It is still not utilized to where it belongs. Patients are not being referred. 

Patients are not being transplanted. And they may change with novel therapies. But we have to really consider all of our tools to offer the longest life span and to prevent all the disease trouble that comes with living with MPNs.   

Katherine Banwell:

When it comes to clinical trials, where do they fit in in choosing treatment? 

Dr. Lucia Masarova:

For me, it’s number one., and always number one.  

That’s just the academic centers which are dedicated and focused on developing better and novel and up front and just tailored and customized drugs. But I know that the life is out there and it’s a little bit more challenging for everybody to deal with such a rare disease.  

I would definitely say any patient that does not respond to current therapy in terms of uncontrolled symptoms or spleen, or other concerns should be referred and evaluated for participation in clinical trials. It is the only way we could understand what is driving that this is not responding and how could we help the best?   

For patients with myelofibrosis, which is the most aggressive myeloproliferative neoplasm, I would definitely put it in. If they are not doing well on number  one, JAK inhibitor, whatever is being used, they should be highly encouraged to be referred to centers and evaluated for clinical trials. 

We have been developing as others and own strategies to potentiate the benefit and efficacy of the current treatments, as well as agents in what we call salvage or refractory setting.  

However, I cannot emphasize enough to really focus on the first track that providers choose for their patients and utilize it to the best ability to avoid frequent or quick switching. Because in a salvage or  refractory setting we cannot offer the same benefit we could offer upfront. We are pushing the disease, maybe being less responsive, maybe more refractory, if we don’t handle the medication we have currently on the table to the best ability.  

Those are excellent medications, fantastic drugs, but there are shortcomings in each and every one of them. And we could do better to really start thinking about what has happened with the medication, why is it failing the patient, and what else could we do? And that’s only possible in the clinical trial setting, especially in such a rare disease as myeloproliferative neoplasms are.   

Katherine Banwell:

Why is it important for patients to feel like they have a voice in their treatment options? 

Dr. Lucia Masarova:

Because it’s about the patients. I would say, as I always say to my patients, “Nobody’s a better advocate for you than you.” I really, really, really like working with patients. They are educated. They understand where to find resources. They’re not afraid to ask. That challenges all of my team and everybody to really be engaged. They know when to notify me. Not to be quiet when they need something. And really raise their voice when something doesn’t work.  

Patients know their bodies more than anybody can. And no data, no boxes, no books can ever tell me how it actually is. It’s not by chance we have two ears to listen and one mouth to talk.  

So, we have to really listen what the patient has to say and take all the abilities, the resources, the knowledge, the capabilities to really make the best thing for the patients, because it is ultimately and only about that.  

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.

 

Related Programs:

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 MPN Treatment Options _ What’s Available for MF, PV, and ET

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

MPN Essential Testing | How Results Impact Care & Treatment Options

MPN Essential Testing | How Results Impact Care & Treatment Options


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

 

Related Programs:

Expert Advice | Living and Thriving With an MPN

Expert Advice | Living and Thriving With an MPN

Expert Advice | Strategies for Managing MPN-Related Fatigue

Expert Advice | Strategies for Managing MPN-Related Fatigue

Increased MPN Symptoms | What Does It Mean for Patients

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.

 

Related Programs:

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

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

Expert Advice | Strategies for Managing MPN-Related Fatigue

Expert Advice | Strategies for Managing MPN-Related Fatigue

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.   

What Are the Long-Term Effects of JAK Inhibitors?

What Are the Long-Term Effects of JAK Inhibitors? from Patient Empowerment Network on Vimeo.

MPN expert Dr. Gabriela Hobbs discusses what researchers know about the long-term safety of JAK inhibitors and options for patients if the treatment loses effectiveness over time.

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.

See More From MPN Clinical Trials 201

Related Programs:

Advances in Essential Thrombocythemia Research

Advances in Essential Thrombocythemia Research

Advances in Myelofibrosis Research

Advances in Myelofibrosis Research

Should All MPN Patients Undergo Molecular Testing

Should All MPN Patients Undergo Molecular Testing?


Transcript:

Katherine:

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 (Jakafi), 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 (Inrebic) and also pacritinib (Vonjo). 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.