Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to part 9 of “What I Tell My Patients,” as this afternoon, we focus on the management of myelofibrosis. We have a great faculty today and as with all of these programs, we have 2 nurse practitioners and 2 medical oncologists. We’re really going to focus on taking care of patients. Not just myelofibrosis, but a little bit about just taking care of patients in general.

As we’ve been doing all week, we will be talking about new agents, new strategies. Please consult package information — prescribing information for more details.

For the clinicians in the room, all the slides we’re going to show today are on your iPad, as well as there’s a survey for you to take, and you can use the iPad to ask questions or ask about patients. We’ve gotten some great questions this week. The same functions in the chat room for the people on Zoom. Hi to everybody out there. Lots of people here this afternoon. I’m really thrilled to be able to talk about this here today.

Also, we’re going to talk about a patient of Sara’s that she’s been taking care of for more than 10 years. And the patient’s wife is a writer, and actually wrote, I think she’s writing a book, but we have some content from that she’s written about her experience with this patient, you’re going to hear about this patient. If you see that little red circle in the iPad, if you click on that, you can read, there are several pages there if you want to kind of look through that as we talk about this man as we kind of go along. Interesting there.

So we have a 1-minute premeeting and postmeeting survey for you to take. If you take that, you’ll get a lot more out of this experience right now.

We are recording this program, all of these programs. We’ll let you know in a couple weeks when it’s all posted and edited together for your colleagues who weren’t able to make it here to Washington.

This is the 9^th meeting. Tonight, we’ll be doing gastroesophageal cancer and colon cancer. It should be a great program tonight. This has been a fantastic experience.

We’ve tried to do something a little bit different this year. And prior to this meeting over the last few weeks, I met with these 8 nurse practitioners, oncology nurse practitioners who have participated in previous programs. We’ve been coming here to ONS for 16 years. We weren’t able to kind of work it out with them, they weren’t available or we weren’t covering their tumor. So we talked to them, and we call them the agnostic nurses because we weren’t talking to them about their tumor type. We’ve been talking about tumor-agnostic trials. But we were talking about some themes that go across oncology. We’re going to show you a couple of these sound bites. We actually edited these together. We’ve been doing a lot of short-form video, 60 to 90 seconds, also using it both in meetings like we’re doing here as well as distributing it on social media. You’ve heard about TikTok, this is TikTOnc. So if you’re interested, check it out. ResearchToPractice.com/ONS2024Clips. We’d like to know what you think we could do with some of this content. We have 85 clips posted there for your interest, an hour and a half of content. We’re going to show you a couple of these during the program here today.

So we are going to talk about myelofibrosis and so-called “myeloproliferative neoplasms,” a pretty interesting part of medical oncology. We’ll kind of just start out chatting a little bit about taking care of patients and considerations of financial issues, which is, again, a theme that goes across of oncology. Then, we’ll talk about the biology of this disease, and then some of the various therapeutic strategies including a number that have come about fairly recently.

First, we want to take a breath before we sort of jump into myelofibrosis and talk about an issue that really goes across oncology. Ms Broadway-Duren is actually at MD Anderson. She focuses on CLL, but the issues that she brings up are relevant to everybody here. Here are her thoughts.

MS BROADWAY-DUREN: One of the greatest financial situations would be copays for these drugs. Those on clinical trials, those drugs are provided by the pharmaceutical company but some of the drugs if it’s a combination therapy and they’ve already been FDA approved, the patient is responsible for those drugs. So copay is a big stressor for our patients. So we reach out. We have a specialty pharmacist who is excellent. They have a whole group of persons within that department that’s all they do is to try to find foundations and grant money and so forth to try to help cover copays for patients. There are times patients come down here and they may have spent their last just to get here and there are times we’ve had to literally go in our pockets and buy lunch for patients. So whatever it takes. Some people have to stay down here for 3 or 4 weeks so we try to provide housing or resources to help them with housing during that time.

DR LOVE: So Ilene, one of the themes over the years here at ONS has been the whole patient, not just the medical aspect. In terms of financings, too, it’s not just paying for copays. It’s all the other expenses the patient has. What are some of the things you’re thinking about when you meet with patients for the first time?

MS GALINSKY: So it’s changed over my career. We didn’t have all these oral agents. It was IV, you got admitted to the hospital. It was what it was. And then, due to medical changes, obviously, we have all these oral agents. When I meet with patients, right away, when we are discussing potential therapies, I preface it with this is what we’re thinking about, but we need to run it through. Because what people don’t realize, they’re like oh, my insurance will cover it. It is the copay part that I think medical personnel and even industry, pharmaceutical companies forget that it’s the copay. Also, if someone is, I work at the Dana-Farber, so if we have a clinical trial. But that’s for the cost of the drug. You have to think about where the patient lives. Do they have the family support? Can they come to the visits? And if not, what support does your facility have to help these patients? They’re devastated with their diagnosis. And if their physician says I’m going to give you this drug, and then they write the script and the copay is $15,000, people are willing to mortgage their house. And you don’t want that to be done because nothing is 100%. So I think it’s always important to be honest and open with your patients, and actually talk to your patient about what supports and what they have.

DR LOVE: So Sara, yesterday, Katie Moore, who is at University of Oklahoma, was talking about her situation, more rural, a lot of patients with food insecurities, aren’t able to access food. They presented a patient yesterday that didn’t have electricity in their home. Again, any thoughts on how you think through trying to figure out what’s going on with the patient?

DR TINSLEY-VANCE: I think really talking to them and telling them up front this is one of those expensive medications. We send them typically to our specialty pharmacy and stay in communication with them. It all comes down to politics too. What can we do on the political level to make an influence, to make these medications more affordable and available to all patients who need them?

DR LOVE: So we’re going to move on now and talk about myelofibrosis, what it is and how it’s managed. It’s such an interesting, not necessarily very common, but very important disease, particularly in terms of what we’ve learned about it, and maybe implications for other diseases. And this whole situation completely changed around 2011. I’m sure you’ve all heard about ruxolitinib. When the 2 big trials came out, they looked at ruxolitinib in this situation. We’re going to talk about that and what happened. One of the most dramatic stories really in the history of oncology. But I have to let Andrew share the fact I was asking him what he was doing when these trials came out and everything changed. And he said he was in med school. And you had to give a talk on myelofibrosis, Andrew?

DR KUYKENDALL: Yeah. So in residency, I think we were assigned to do a senior talk, and it was kind of arbitrary what you get responsible for. So I was assigned to do a talk on myeloproliferative neoplasms, which was a bit frustrating because I wasn’t 100% sure what they were.

DR LOVE: So you were still an internal medicine resident?

DR KUYKENDALL: Yeah, internal medicine resident. So, of course, after getting the assignment, I was like oh, yeah, absolutely. Definitely, I’ll take that. The first thing I had to do was Google myeloproliferative neoplasms. But little did I know that would kind of translate into a career.

DR LOVE: Right. And Abe, the thing that struck me, again, it was kind of off my radar because it’s so unusual, but the stories we were starting to hear, I’d never heard these stories in oncology before. What are some of the, we’re going to get into sort of the biology, but just sort of clinically, what did these patients look like when they were presenting and that went into these ruxolitinib trials? And what did you all observe? You were just coming into oncology at that point, right?

DR YACOUB: Correct. Yeah, absolutely. We actually, even in training, in fellowship, we didn’t train much on MPNs and myelofibrosis. There wasn’t much. There’s the disease and that was the end of the talk. But 2011 was a pivotal year. We had active agents that radically changed the way we practice myelofibrosis. A, there was increased awareness. Now, we actually are looking for MPNs and myelofibrosis. And B, we actually have tools to help those patients. So those patients had suffered, you know, the disease manifestation for so long, and we had very few tools to help them. But after 2011, the field is very different where we actually have tools to help. Those patients are living a lot longer. We still have patients from the original COMFORT study still on therapy and enjoying life, and that is remarkable.

DR LOVE: Ilene, can you provide a little bit more of a picture of kind of, you know, it’s such a unique situation. Sometimes, these people come in with these enormous spleens, they may be losing weight because they have compression on their stomach. And then what you were starting to see as we started to use these JAK inhibitors.

MS GALINSKY: We, just thinking about back then, I actually just saw her recently, we had a patient that came from Florida and was told to be on hospice. Her spleen was massive, like you would have thought she was 9 months pregnant. She couldn’t eat. They wanted to put in a feeding tube. She was an absolute mess. And we put her on ruxolitinib, and she’s actually still on it to this day.

DR LOVE: Wow.

MS GALINSKY: She obviously came off hospice, she went back to work, she now has a flat stomach, she’s eating, her quality of life. And as you said, previously, you had basically 2 treatment options. You had hydroxyurea and interferon, and maybe a splenectomy. But people’s quality of life is so affected by this disease. And starting with ruxolitinib and now we’ll talk about other therapies, it’s literally transformed people and gave them a new listing on life. It's been great.

DR LOVE: I was mentioning yesterday, at the beginning of the pandemic we were doing all these virtual things. One year, I interviewed like 25 nurses for the ONS because we were doing all-virtual. And I asked every single one of them the same question and every single one of them gave the same answer, which is how often do people come up to you and say, isn’t oncology depressing? And we’ll talk about the fact that, yeah, there are a lot of people who don’t do well and you see a lot of people going through trauma. But I’m just kind of curious what it was like to see that process evolve for you.

MS GALINSKY: Yeah. It was amazing. Not everyone, obviously, has such a response. My cousin was on ruxolitinib. He had PV, transformed to myelofibrosis.

DR LOVE: Polycythemia vera.

MS GALINSKY: Yeah. And he passed away from probably progression of disease. And he was out in a community setting where people weren’t familiar with the disease and ruxolitinib. So obviously, these drugs can work, but they need to be followed cautiously.

DR LOVE: And when these studies started to come out, there was a lot of confusion because people thought, we’re going to talk about what actually the biology is of what’s going on here, but in the beginning, people thought that only people with JAK mutations would respond to JAK inhibitors, so a lot of people didn’t get treated until they started to get the message. So, Andrew, let’s just talk a little bit now, we kind of heard the clinical story, more about what’s going on and what this disease actually is. So can you talk a little bit about what MPN is and what myelofibrosis is?

The Biology of Myelofibrosis (MF)

DR KUYKENDALL: Yeah. I think you can look at MPN through 2 different lenses. So in one setting, you can look at it through what it is. It’s a cancer, it’s a chronic leukemia. And oftentimes, patients may come to us without knowing that that’s the case, and so that can be overwhelming and kind of a hurdle to get over discussing that. But at the same time, it’s an inflammatory disease. And so I think what really helped us understand the biology of this disease is when we discovered in 2005 the presence of these JAK2 mutations.

DR LOVE: And these are in the tumor cells themselves?

DR KUYKENDALL: Correct, correct. In the — so these are mutations that occur in hematopoietic stem cells. And we knew that, you know, we learned about CML, chronic myeloid leukemia, that had BCR-ABL translocations. We had developed good drugs for that.

DR LOVE: But again, CML had mutation in the leukemic cells that could be attacked.

DR KUYKENDALL: Correct, correct. So they had these abnormalities, these genetic translocations in the leukemic cells. But we had these other diseases that looked very similar to CML as far as what the blood counts looked like and how patients were presenting that did not have those. And ultimately, we found in 2005 that probably 60% of these patients have a mutation in their blood cells in a gene called JAK2. And JAK2 is a protein that’s really implicated and involved in blood cell production. It’s involved in red blood cell production, involved in platelet production, involved in kind of myeloid white cells like neutrophil and monocyte, those types of productions. So what happens when you get this mutation is you get constitutive activation of the blood cell process. And so instead of just making blood cells when you need to, you’re kind of making them all the time. The gas pedal is put down. And so patients are coming in with very high platelets or very high red blood cells or very high white blood cells or maybe all three of those.

And when we talk about these non-CML myeloproliferative neoplasms, the classic ones we talk about are ET, which stands for essential thrombocythemia. That’s where we predominantly are seeing too many platelets. You talked about polycythemia vera or PV that was referenced earlier. That’s going to be — it’s defined by too many red blood cells but really, you’re making too many red blood cells and platelets and white blood cells. And then down the road, you have primary myelofibrosis when that’s what the initial diagnosis is, or you can have secondary, so myelofibrosis that occurs after a prior diagnosis of PV or ET. And that’s where things start to get a little more challenging in the sense that you have some counts that are high, some counts that are low, more symptoms. And when you look in the bone marrow, you see this characteristic scar tissue or fibrosis that makes it very difficult to make normal blood cells. Oftentimes, those patients start to make blood cells in other organs such as the spleen. So then, you start to have splenomegaly and the implications and clinical scenarios that come along with that.

DR LOVE: So listening to you reminds me of an oncologist who, we were talking about the audio programs that people like to listen to, and we had an oncologist contact us and said I drive to work every day listening to programs on the drive home and I listen in double speed. And I was like that guy’s got a smart brain to be able to do that. And I’m trying to listen to you. You’re cracking along there for me a little bit there. So, Abe, let’s take it a little bit farther in terms of sort of I guess it’s really fundamentally different that these inflammatory pathways are activated. And that’s what’s causing, in the long-run, why the spleen is big, why they have these symptoms, fatigue, et cetera. How is it that these JAK inhibitors, and ruxolitinib was the first but now we have others, that the patients clinically get better? What happened that Ilene just described?

DR YACOUB: Okay. Thank you very much, Neil. And I would like to reiterate that these are cancers and we underestimate the fact that these are more complicated than a disease that is only addicted to 1 pathway. So JAK-STAT pathway has been identified as the leading driver for these cancers. It’s probably not the only one. And probably, there’s a lot of branching, it’s not a linear pathway. But we’ve learned that all MPNs, particularly myelofibrosis, are addicted to this pathway. And if we can suppress that pathway, we can affect this cancer in many different ways. We can affect the symptoms, we can affect the spleen. And actually, if you do that well enough, you can actually prolong survival, so patients actually live longer if you tackle this pathway effectively. We’ve also learned that this is not only driven by the JAK2 mutation. We’ve also identified later on, there are other driver mutations on the surface of the cell. But the intracellular pathway ends up being the same. And if you suppress that pathway, you’re tackling all these disease manifestations similarly regardless of which is the driver mutation that led to that pathway. So successful therapy will result in reducing the spleen size and every symptom that is attached to that. It could actually improve the blood counts in a more favorable way and it improves the patient’s quality of life substantially, enough to actually improve their longevity with therapy.

DR LOVE: So we’ve been talking about the fact that it’s natural for people to present patients who do really well, and we’re not trying to say everybody responds for 10 years to ruxolitinib. Abe, what is a more typical length of time a patient could stay on ruxolitinib feeling good before they start to require another therapy?

DR YACOUB: So ruxolitinib is one of the more rewarding medications in which you actually take the medicine today, and tonight, you actually start feeling the benefit of it. So it’s not the same narrative with the other JAK inhibitors. So again, that is really the rewarding thing about treating patients with myelofibrosis, is how much better they feel with successful therapy. Unfortunately, again, these are cancers that are progressive. Every patient eventually, unfortunately, will progress. And even if they’re having a homerun benefit with their first-line therapy, eventually they will lose their therapy. The average is about 3 years for a standard patient. But, of course, individual patients will have different journeys with this cancer. It might be slightly different with other JAK inhibitors in terms of dynamics of how fast they respond. But we’re glad we have more than 1 option. So for patients who progress on one line, it is very common that patients get a second-line JAK inhibitor and maybe even a third-line JAK inhibitor. So patients have multiple, we have multiple points where we can touch their lives with therapy that can improve it.

DR LOVE: So we want to talk a little bit more granularly about what happens to these patients and how they’re actually managed. And actually, Sara put together some really great slides that I wanted to use and let the whole panel kind of use that as a baseline to talk about this. Certainly, quality of life being a key issue. You don’t hear stories like this, I think, anywhere else in oncology. The story you just described, you see people feel better, their tumors shrink down. But this scenario is such a life-changing scenario. So Sara, maybe you can just start out a little bit about how you think about quality of life in these patients.

DR TINSLEY-VANCE: That’s a perfect question for me. I’m a quality-of-life researcher.

DR LOVE: I’m a quality-of-life person.

DR TINSLEY-VANCE: He asked me an easy question. Quality of life is very individualized. And so with the myeloproliferative neoplasms, they have these groups where they came up with their most common and distressing symptoms and then they came up with a tool that actually measure the symptoms that were given them the most problems. And so we have a tool specifically designed for myeloproliferative neoplasms. You can see this Total Symptom Assessment Scale — or Score. And they also cluster the type of symptoms. If you take this instrument and you give it to patients, a lot of the clinical trials, this is a key part of the clinical trial, is they evaluate their symptoms either daily or, most of them, it’s daily. Some of them, they do it for 16 weeks or more. They have little instruments.

DR LOVE: Just through the phone?

DR TINSLEY-VANCE: Yeah, it’s pretty cool.

DR LOVE: Awesome.

DR TINSLEY-VANCE: It’s a little bit overloading to analyze that type of data, but you really get a granular picture on a daily basis of what their symptoms are like and get a personal picture of that patient.

DR LOVE: Ilene, can you talk a little bit about some of the things that you talk about in the first couple visits in patients with newly diagnosed myelofibrosis?

MS GALINSKY: So I think it’s important, just like Sara said, it’s a very individualized process, obviously, for all of our patients. There’s the diagnostic part about explaining to them what the disease is. Going through what the risk of why we want to treat the disease is extremely important so they understand the goals of what we’re trying to achieve. Knowing what their own goals are, what their symptoms are, how they perceive their symptoms. We may, when they describe them to us as a provider, you may be like, that’s not so bad. But if they’re expressing that that’s important to them or they feel so bad they can’t go to work even though we kind of don’t understand that, that’s okay and you have to take that into consideration. I think once you go through the risk factors and their quality-of-life, you try and think about what is the best treatment option for them. Again, I always look for clinical trials. I think in any of our diseases nowadays, if they’re young enough, talk about, at some point, is there a role for allotransplant to eradicate the disease on a permanent? And just always on every visit, it’s an ongoing, it’s always fluid, open discussion. And as we go through, I also explain what I’m going to be doing for them, why I’m monitoring their counts, why I’m having them come in so often, why they should know once they start a medicine to document any medicine that they take over the counter to reach out to us, tell us how they’re feeling, what their side effects are. Some of these will go into the other drugs. They have specific increased risk of certain side effects, so give them that prophylactic medicine upfront and explain to them what to look for.

DR LOVE: Abe, Ilene referred to transplant. This is allotransplant. Maybe you can explain what that is compared to autologous transplant. Who are the patients that you think about that in? And how do you sequence it?

DR YACOUB: Thank you. So as we all realize, patients with myelofibrosis have different presentations and also different disease biologies and different severity of their disease. And almost you kind of have to individualize your approach to each patient based on how you perceive their risk. We’re lucky that we have a few tools, calculators that can factor in patient’s factors, age and blood numbers and their DNA results and mutations and other individual valuables in that patient to create a risk assessment. And based on that risk, we can provide a calculated or educated guess of the patient’s journey and survival of myelofibrosis. And that divides patients into patients who are higher-risk who are at risk of losing many years of their life because of myelofibrosis versus patients who are doing slightly less — more favorably are likely going to benefit with just medical management.

So for the patients with the higher risk, we try to focus at advancing therapies that can be curative. So myelofibrosis, as Andrew mentioned, is a cancer of the bone marrow in which eventually, the bone marrow will fail either into not making blood elements or turning into acute leukemia. And patient’s journey with it will, unfortunately, always will end with poor outcomes. So in those patients with the higher-risk in which you can provide a curative therapy by replacing the bone marrow through the bone marrow transplantation with a healthy graft, healthy bone marrow, those patients who go through that successfully can get their lives back. They can have a curative outcome in which they can enjoy the rest of their lives without having to endure myelofibrosis. So for those patients, this will be a very life-changing therapy.

DR LOVE: So now it’s about the time I’ve got to get your input on something I just learned about recently that was super interesting. So last year, we had one of the top people in the field also here, Dr Ruben Mesa. And we just did a webinar with him a few weeks ago and I was looking at his papers that he published. And I saw this poster that they did at the American Society of Hematology meeting. And this is the same meeting where we’re going to talk about some new drugs where they, you know, one of the things they do is when they give new drugs, they look at the symptom score and they see if the symptoms improve. And it’s not that easy to do that because ruxolitinib is already very good. There were a couple of papers, we’ll talk about, at ASH where they tried to add on to ruxolitinib. The spleen shrunk a little bit, but the symptoms really didn’t get that much better. They’re not sure where it’s heading. But I saw that he had studied, in a small, randomized study, another intervention that I was fascinated. This one actually worked. Ever hear of the Mediterranean diet? That’s what it is. Okay. And pretty simple, right? It’s vegetables, not very much fat, very, very little meat. And they had an objective change in these scores.

DR TINSLEY-VANCE: That’s exciting.

DR LOVE: Andrew, any thoughts?

DR KUYKENDALL: Yeah, I think it’s fascinating. So Angela, Ruben and Angela Fleischman, so Angela Fleischman is a researcher, physician scientist at UC Irvine, and she’s, kind of like her whole focus on researching myeloproliferative neoplasms is this focus on inflammation, which I think we know is kind of this broad word but it’s really, really relevant to patients with MPNs. From her work, we know that actually, if you just look at the kind of cellular level, cells that have JAK2 mutations will, in the presence of inflammation, outcompete normal hematopoietic stem cells. And so the question we’ve had, getting back to the core of things, these JAK2 mutation happen quite randomly, what makes them turn into disease in some patients and not in others?

And really, what it comes down to is probably inflammation to some extent. We don’t exactly know what that means, but we know that probably inflammatory stimuli, endogenous versus exogenous stimuli, allow for progression of this disease over time. And when we think about ruxolitinib and JAK inhibitors, these are conceptually, these are anti-inflammatory medications. They’re blocking the JAK-STAT inflammatory pathway. So that’s how we’re able to get control of symptoms and splenomegaly and things like that. But I think Angela’s thought is, can we act earlier in the disease process? Can we do something that’s not a medication? Is there a way that we can create less inflammation? And one of the ways to intervene on that is diet, right? And so Ruben’s group has also looked at yoga and meditation, and that’s other ways of being anti-inflammatory. But this is kind of coming down to a randomized trial where Angela, they randomized patients to either be on kind of a normal diet versus this Mediterranean diet. And one, I think, is this feasible in an MPN patient population? Because they were doing this as kind of a remote clinical trial.

DR LOVE: Yeah, right. It was online counseling. Right.

DR KUYKENDALL: Right. So people were not having to come into the clinic, which is one of our challenges with clinical trials. So this was done online and it showed that it is feasible to run a clinical trial like that. And in the patients who were on the Mediterranean diet, we saw kind of more improvement in symptoms in those patients, suggesting this may be a way to intervene upon symptoms. I think as researchers, we’re also wondering, okay well does that do anything to the underlying disease too? Because if we do this early enough, is this a way we can actually get at the core of disease and move beyond just symptom control? And I think that’s to be determined. But right now, it’s certainly positive results from these early trials.

DR LOVE: It’s interesting how in oncology, the different tumor disciplines are pretty siloed by each other. We were doing a think tank last week, I think it was, with 4 breast cancer researchers. And we said, have you ever heard of this Mediterranean diet and what happened with myelofibrosis? Nothing. But they said we’re doing a study on diet and exercise in patients with breast cancer to try to improve, to reduce the recurrence rate. So it may be a completely different strategy than anti-inflammatory, but they have a huge cooperative national study, again, same thing you described, randomizing between dietary intervention with exercise or not. And they think it’s going to be positive. And the old saying is if that was a drug, we would give it. But who is going to pay for all this and how are we going to get it done? I think we’re going to have to — and not that complicated to explain, for example, what a Mediterranean diet is, I think. Sara, any thoughts?

DR TINSLEY-VANCE: Yes. I just reviewed a, I’m on a feasibility committee at Moffitt for nonintervention — well some of them are interventional studies. But they have found in mice models that you can overcome some of the resistance in non-small cell lung cancers by using a ketogenic diet. And so there’s a study that they’re hoping to do feasibility testing on where patients are provided with a 7-day prepacked meals to follow a ketogenic diet.

DR LOVE: Wow.

DR TINSLEY-VANCE: So it’ll be very interesting to see what those results are.

DR LOVE: Yeah, but that doesn’t sound as easy as this does. Yeah, it seems — we’ve got to consider whether it’s feasible, how hard or easy it is to bring people up to speed.

Let’s bring in another really important issue that almost every patient, this becomes an issue, which is anemia, both from the disease and the treatment, which makes it even more complicated. Abe, can you kind of provide an overview of sort of how you approach this issue with patients?

DR YACOUB: Of course, yes. So anemia is a hallmark of myelofibrosis. It’s almost 100% of patients with myelofibrosis will have a hemoglobin that is below the normal limit. And then if you keep cutting down on the threshold how you define anemia, the severe anemia is less common, but it also does present. Some patients present with severe anemia in about 10 to 15% of patients diagnosed with myelofibrosis today, and they are already transfusion dependent. So this is a significant disease burden just because of the sheer prevalence of it in those patients. So we’ve learned a long time that this is something you’ve got to tackle. As you treat the patient, treat the cancer, you’ve also got to always have a strategy for the anemia.

And anemia is always multifactorial. It’s really rarely that you would expect that one factor you modify will change the disease, so we always try to apply multiple things at the same time. So among the common things, you look for iron deficiency, you look for nutritional deficiencies, you look for anything you can reverse. We’ve also had genetic anemia drugs that we’ve used in patients with myelofibrosis, so try to use ESA agonists, try to use testosterone agonists or androgen agonists in these patients. Try to use immune modulatory drugs to try — we’ve really tried a lot of tools over the years to try to see how can we make a dent in the anemia. Not necessarily completely reverse it, at least bring the patients to a level where they’re not tethered to the cancer center, they’re not transfusion dependent. That is better quality of life.

So now that wave of interventions has really increased our armamentarium. We have a few options that we refer to now. And many of our patients receive all of them during their journey with myelofibrosis. And then we have the JAK inhibitors. And the first 2 JAK inhibitors approved, ruxolitinib and fedratinib, are drugs that are very effective but they also induce anemia. So that added an extra layer of complexity. So now, we also have to factor that in as we provide therapy that treats the cancer. More recently, we have 2 other JAK inhibitors that seem to achieve very effective disease control, but also have favorable benefit of anemia, they actually bring the anemia up. So now, this has become an extra layer of decisions. So we have patients with myelofibrosis who need disease control, but we have JAK inhibitors that could improve the hemoglobin, JAK inhibitors that can lower the hemoglobin. So this is becoming a lot more of an individualized choice as we get to that part with anemia therapy on which JAK inhibitors to use even in these patients.

DR LOVE: So in a second, we’re going to hear about this Air Force pilot which you have a long description on, on your iPad. But just a quick question, Andrew, from the chatroom. Adalee wants to know whether or not these diet approaches maybe are affecting the microbiome, and could that be part of what’s going on? Can you kind of explain what the microbiome is and the kind of research? Is that being looked at also?

DR KUYKENDALL: Yeah. So the microbiome is obviously a hot topic now in all different fields of oncology. Just the different kinds of bacterias we have in our gut and how that plays a role in inflammation and kind of basal inflammation rate. I’ve already referenced that inflammation, we think, is interesting.

From my recollection to this point, the studies we’ve done in microbiome in MPN have not been exceptionally revealing to this date. There are some different bacteria that tend to be present. But whether or not that’s been tied to kind of clinical presentation or outcomes, we haven’t seen yet. How the Mediterranean diet plays in, certainly that’s a possibility of how this impacts inflammation. It may be more of avoidance of some things with the Mediterranean diet that may allow for this decreased inflammatory state, but it could be related to microbiome. I don’t know if we know yet.

DR LOVE: I don’t know that much about it, but it kind of looks like it’s low fat, so I’d assume somehow fat is part of the problem and maybe we don’t exactly know why.

All right, let’s get back to real patients. And what a saga this story is. We’re going to talk about this a couple other times during this meeting. But let’s just start out with the beginning with your Air Force pilot.

DR TINSLEY-VANCE: Yeah. So I had a patient that unfortunately passed away last year, but we had about 12 years together. And he was diagnosed with myelofibrosis from polycythemia vera in the 80s. When he was flying for the Air Force, he developed a high hemoglobin. And at the time, they thought it was because he was flying jets. But it wasn’t. He had polycythemia vera. And over the course of many years, so from the 80s until right around the time ruxolitinib was FDA approved, he was getting phlebotomies and then he developed myelofibrosis. And the reason we knew that is because he went from having too high counts to he became anemic and his spleen started growing and he was having a lot of symptoms, especially fatigue. And that was the perfect drug for him at that time. He got started on ruxolitinib. His spleen shrunk down very nicely. He had decreased fatigue and he started living a better life. But over time, it stopped working.

DR LOVE: This is a story going on all over the world after the ASCO meeting, I forget when it was, 2011, when these 2 trials were presented. The next week, you started to see this stuff. Well maybe not the next week, but very, very, very, very soon after that. So again, one of the themes that we have is that no 2 patients are the same. One of the things we ask people is, why was it different to take care of this patient than another patient with the same exact oncology situation, the same myelofibrosis story, but a different person? Not only as it relates to the person, but to the caregiver because one of the things of interest that we found out is Sara’s husband was also an Air Force person. And she kind of was aware of sort of what the military culture is.

DR TINSLEY-VANCE: Oh, yeah. He came in with the, I’m in charge and we’re going to work on this together because I’m really in charge. And so we hit it off right away because I could recognize, okay, you’re from the military. You have that military bearing. He was respectful, but he just got down to the nuts and bolts. You knew exactly what he needed from you. And it made it a lot less — you didn’t waste a lot of time. And at the end of every meeting, he would say, so we did this, this and this. I’m like yeah. And so we knew what the plan was for the next time. And as he got more and more sick, I adjusted my schedule to accommodate him. I had so much respect for him. So he came at 6:00 to have his labs drawn and I saw him at 7:30 because he needed transfusions earlier in the day so he could get in and get out and help other people learn how to fly. Not up in the air, but he was teaching like drones and different skills for flying.

DR LOVE: Right.

DR TINSLEY-VANCE: So I knew that was important to him.

DR LOVE: I was watching Ilene. She’s just shaking her head about first thing, because I know she’s thinking of patients like that. Tell them about the spouse though, Sara.

DR TINSLEY-VANCE: Oh, yeah. Honey is his wife. I only met Honey once. She came to his first appointment. She cried the whole time. He was so embarrassed. So he’s like, Honey is not coming back. And so that just tells you he didn’t, he really wanted this to be take care of the disease and I’ll relay everything to Honey because I don’t want to bother her. Even when he got very sick, close to death. That was the only time I heard from Honey again. And now Honey and I have a really good relationship. I kept in touch with her. But it really impacted me after he was gone. Too bad I didn’t know ahead of time of how much the disease impacts the whole family, not just the person in front of you, even if you don’t see them.

DR LOVE: Later on in the program, I want to talk a little bit more about end-of-life care and what this patient went through and the spouse’s description in that thing on your iPad and in the chatroom really getting to a level of granularity of what people experience, both caregivers and the challenges of getting hospice out to your house. She described an episode where her husband was on the floor for 2 hours.

DR TINSLEY-VANCE: Yes.

DR LOVE: She couldn’t find anybody to help her. The real-life issues that come up. Ilene, any thoughts?

MS GALINSKY: Yeah. I think what’s important for an oncology nurse, and I think we all have this in us and that’s why we went into this profession, is our patients, and I know this sounds corny, but our patients are not our patients, they actually become part of, I look at them as part of my family. And so I spend a lot of time obviously taking care of them and their disease, but I try to also know what’s going on in their lives and what’s important. And we do do those things that Sara said. I’m going to work with the infusion room saying my patient needs to come in at this time, needs to get this done. Or say they say to me, I know I need transfusions but I want to go to my cousin’s wedding. Well so their cousin’s wedding is, say, in Pennsylvania. So we’ve all done this. I call up my colleagues in Pennsylvania and say my patient is going out there. He may need transfusions. Can I give him your name and work it out? And I just think none of us can lose sight of these people and their families. Nothing different between them and I except bad luck.

DR LOVE: We’re going to talk a little bit more about some of these deeper issues at the end here. But Sara pointed out this really incredible resource, this 112-page patient ed thing on myelofibrosis online. You can print it out. And there’s one there for MDS, because it was from the MDS foundation, so for people who like print patient ed. This is incredible to me. I thought it was really great. But also, I’m wondering about media again, you know, should we try to get these things across using video, et cetera? Anyhow. Any thoughts? Any other thoughts, Sara?

DR TINSLEY-VANCE: Well, they have little snippets. If you have a patient, or yourself, who has a short attention span, they’ll break it into little segments.

DR LOVE: But reading?

DR TINSLEY-VANCE: And you can find it on YouTube. No, like, pictorials.

DR LOVE: Oh, video. Great, great, great.

DR TINSLEY-VANCE: And, like, how fibrosis develops. So if you don’t have a lot of time and you just want to YouTube Building Blocks of Hope MPN. And if you contact them, they can also ship you resources to give to patients. Myelofibrosis is a rare disorder, so you probably don’t want a box of 25 depending on where you work.

DR LOVE: And you and Andrew actually were part of the team that put this together.

DR TINSLEY-VANCE: Yes.

DR LOVE: Andrew, what was it like for you to help put this together?

DR KUYKENDALL: I think that anytime anyone is interested in putting something together that’s going to be a resource for patients, I think I’m always on board. In reality, we have a unique patient population that has a massive appetite for information about their disease and understanding the disease. And so most of the referrals we get right now are self-referrals from seeing some sort of media or some sort of group that’s put together something on MPNs where they learn about it on a Facebook group or YouTube or whatever and then they refer themselves in to be seen based on that. So we have a huge appetite for this. So anyone who is interested in putting something like this together, I’m always on board.

DR LOVE: I’m just kind of curious also, Ilene, harkening back to the beginning here. I think Abe was talking about patients who walk into the clinic and don’t realize they have cancer. What’s your experience with that? And how do you explain it to them, Ilene?

MS GALINSKY: So being that I work, my title, we used to always joke about this, being at the Dana-Farber Cancer Institute. I was always amazed that people that had MDS or MPNs never thought about it as being a cancer. And so when we say well you have this cancer and you’re explaining, they’re like I don’t have cancer, I have MDS or I have MPN. And then so you start from the basics about the bone marrow factory and what is going on. And part of it is, I think, the connotation of saying cancer is also a very difficult thing for patients to digest. But once you get over that and show them what it is and that you’re going to work together and develop a plan, you can usually move on.

Role of Available and Investigational JAK inhibitors for the Management of MF

DR LOVE: All right. We’re now going to Module 2. And also, we’re going to pick up the gear here in terms of some of the data. We want to start to get into these drugs in particular and how we utilize them, starting out with the first one, which is ruxolitinib. And let’s go back to some cases. And, Andrew, you have a 78-year-old woman. What happened with her?

DR KUYKENDALL: Yeah. So a 78-year-old. I think I initially started treating her back in 2017, ‘18. And she came in kind of a classic, if there is such a thing, a classic myelofibrosis patient who presented with mild anemia, mild to moderate anemia, maybe hemoglobin in the 9 to 10 range. But really, the main issue for her was massive splenomegaly that was causing her to lose weight. The spleen was growing, pushing on her stomach. Early satiety, feeling full early, not eating full meals, also having kind of drenching night sweats on a multiple-night basis.

DR LOVE: Could you see her spleen? Could you see it?

DR KUYKENDALL: Well, I mean, it was under her skin.

DR LOVE: All right, we’re even now. Keep going.

DR KUYKENDALL: Yeah. So she did —

DR LOVE: Actually, I noticed you’re kind of slowing down a little. Anyhow.

DR KUYKENDALL: So very easily palpable. So you could definitely feel her spleen. It was palpable almost to where her belly button was. And so she was someone that, you know, when we talk about night sweats, these aren’t kind of I sweat a little bit at night or I wake up damp. It’s I’m changing my pajamas 2 and 3 times a night because it’s just soaking through.

DR LOVE: Wow.

DR KUYKENDALL: So these aren’t something that you get good sleep with. And so we’d put her on ruxolitinib, and she had this rapid massive response. So the spleen shrunk down, night sweats virtually went away. She basically was like, came in saying you gave me my life back and all this. But then she did become more anemic. And so her hemoglobin, which initially would have been kind of in the 8’s to 9’s, went down below 7. So she started requiring transfusions. Those became more frequent. She still retained that good response that she had, but then started to get more and more blood transfusions. And even over the past year, she’s still on ruxolitinib right now. She requires blood transfusions once a month. She comes in regularly once a month, gets her blood transfusions. But she’s also had a side effect that we started to realize with ruxolitinib that’s becoming something that we’re being more aware of, which is increased risk of nonmelanoma skin cancers. And so we think this has to do with the immune suppression role of ruxolitinib. It’s a JAK1/JAK2 inhibitor, and so it does cause some degree of T-cell dysfunction and immune suppression that allows more of these skin cancers to pop up. It typically happens in people that have already been dealing with skin cancers. But obviously, it can happen in someone without a history of skin cancers as well.

DR LOVE: So this is basal cell and squamous, nonmelanoma?

DR KUYKENDALL: Typically, yeah. Basal and squamous. Rarely Merkel or something like that.

DR LOVE: Where did she get it?

DR KUYKENDALL: She had them all over her arms, face.

DR LOVE: A bunch of them?

DR KUYKENDALL: Yeah. So she got them more and more frequently.

DR LOVE: Wow.

DR KUYKENDALL: And I think the last time I saw her was probably 2 or 3 months ago. And she’s like yeah, I think since the last time we talked 6 months ago, I’ve had 2 or 3 Mohs surgeries. And I keep coming back and saying we really can consider other options. We’ll talk about other options in a little bit. But she’s like —

DR LOVE: Yeah, because she could take another JAK inhibitor, right?

DR KUYKENDALL: Right. We have other JAK inhibitors now that don’t cause as much anemia. Maybe it would offset some of these transfusions. We don’t know how much they’re associated with nonmelanoma skin cancers, so I can’t say that’s a good reason to switch yet. But every time I mention bringing her off that to something else, she’s like yeah, over my cold dead body you’re going to take me off that. So just the symptomatic benefit she had was amazing.

DR LOVE: I can imagine going through this experience of feeling so horrible with all these night sweats and having that all go away. And to have somebody go, oh, well why don’t we try something else. I guess you never know whether it’s really going to benefit as much. Maybe as long as she’s feeling good, it’s her decision. Let’s talk a little bit though now, Abe, though about we now have a number of JAK inhibitors. This often happens with these small molecules, tyrosine kinase inhibitors. They don’t exactly hit the exact same thing. We talked about that yesterday. We did an entire program just on EGFR mutations in lung cancer and how each one is somewhat different and how different drugs affect them differently. Here are the 4 drugs that we have right now. Not just to go through all these numbers and stuff, but more like can you paint a picture of sort of how we use them and when we use them?

DR YACOUB: Thank you very much. Because when we had ruxolitinib, we were very happy with that advancement. But again, we’ve always realized it’s not universally that everybody will respond and the response is not going to be indefinitely, so it’s finite and patients eventually will progress. We’ve always needed options. Now, we have 4 different options and we’re still not content. I think we’re still looking for more options and more combinations. But ruxolitinib being the stereotypical JAK inhibitor, it inhibits JAK1/JAK2, and it does a fantastic job with spleen reduction. It’s probably the best symptom medicine we have for controlling of myelofibrosis symptoms. So that being the stereotypical agent, also by inhibiting both JAK1 and JAK2, it does cause anemia and thrombocytopenia, which has always been the hassle of delivering ruxolitinib.

And then a lot of the newer drugs are actually a lot more unique. And it’s really none of them are a me-too drug in which they’re just doing the same pattern of suppression of all these enzymes at the same rate. They’re really all unique. And you kind of have to think of them as completely different classes of drugs rather than identical inhibitors of JAK-STAT pathway. So some of the 2 that stand out is pacritinib and momelotinib. So pacritinib, for example, is almost none, does not touch the JAK1. If you see that number with the JAK1, the 1,280, that means you really need a really high concentration of pacritinib to slow down JAK1 pathway. So it’s almost uniquely JAK2 inhibitor, which spares a lot of the side effects. The anemia, we talked about, the thrombocytopenia, the immune suppression and the skin cancers. It actually does have significantly a lot less incidence of such cancers.

DR LOVE: And you notice too that number, which I don’t understand other than you said the higher it is, the worse it is — or the better it is, but ruxolitinib is low, 3.4.

DR YACOUB: Correct

DR LOVE: That’s a very big difference.

DR YACOUB: Yeah. So a little bit of ruxolitinib goes a long way with that. But again —

DR LOVE: But you don’t necessarily want that hit.

DR YACOUB: Yeah, we want that. Yes.

DR LOVE: Oh, you want JAK1?

DR YACOUB: Yeah. So JAK1 has, again, it depends on what you’re trying to deliver. So that’s why these drugs are different and they do different things for different patients. And different patients need different things. So a patient who comes in with really big spleen, a lot of symptoms, you really want to hit that JAK1 and JAK2 real hard, and that is an advantage. On the other hand, for patients who are really anemic or patients who are having a lot of infections and secondary cancers and skin cancers, you want to spare the JAK1, so that becomes a different decision making. That’s why ruxolitinib also works in GVHD, which is because it has JAK1.

DR LOVE: Graft-versus-host disease.

DR YACOUB: Yeah, graft-versus-host disease. So that is another advantage. So being different is a good thing here, being unique.

DR LOVE: Yeah, this stuff is barely understandable from my point of view, but I hear things. And when I start hearing things over and over again, I realize they’re important. One of the things I’ve been hearing, Andrew, about is ACVR1. I’m not sure exactly what it is, but I know it’s related to anemia. Can you explain how you look at — these drugs actually used to be considered “dirty” because they hit so many different things.

DR KUYKENDALL: Yeah.

DR LOVE: But the point is, if you get the right combination for the right patient, you can help them. So what about these other things like AVCR, Andrew?

DR KUYKENDALL: Yeah, we don’t know. So in general, these targets, they’re going to tell us something about why the drug is effective, why it’s ineffective, or what the toxicity profile is going to be. And so as Abe mentioned, the one thing that all of these drugs have in common is they’re very potent JAK2 inhibitors.

DR LOVE: Right.

DR KUYKENDALL: So they all shrink spleen, they all help symptoms from that standpoint.

DR LOVE: All low numbers there.

DR KUYKENDALL: Where they differ is whether or not they hit JAK1 and some of these other targets that we think may have some implications, but maybe not. To Abe’s point about JAK1, we’ve tested JAK1 inhibitors that are specific JAK1 inhibitors before, and they tend to help with symptoms, they don’t help that much with spleen. But we also think that JAK1 has a role in immune surveillance and immune function. So it might be that inhibiting JAK1 makes someone have more immune suppression. So you may get some symptom benefit from that, but it may be offset by the fact that you have some more infections or more non-melanoma skin cancers. These other targets, ACVR1 is probably the one that we’re most interested in. It’s probably the one that’s been most linked to clinical outcomes. It’s acting on this hepcidin activin receptor pathway.

DR LOVE: Hepcidin.

DR KUYKENDALL: Yeah. So hepcidin, master regulator of iron homeostasis and is associated with anemia of chronic disease. All in all, this is a way that we think we can target anemia. So if we’re able to inhibit ACVR1, we can actually have low hepcidin levels which make us utilize iron more effectively to make red blood cells. And so it turns out that momelotinib for a long time was developed as this JAK1/JAK2 inhibitor that was also an ACVR1 inhibitor which may mean that while it may cause anemia through its inhibition of JAK2, which makes blood cells, maybe it’ll offset that by inhibiting ACVR1. And we’ve seen through the development of momelotinib that it tends to be associated with better blood counts. So it doesn’t cause as much transfusion dependency, it tends to have stable red blood cell counts. And then more recently, we found out that pacritinib, which had been developed as something that we could use in patients that have very low platelets, also inhibits ACVR1. So now, we’re going back to see whether or not pacritinib has a favorable impact on hemoglobin as well, and it seems like it does.

DR LOVE: So yeah, really fascinating biology here to keep in mind that has such important patient implications. We’ll talk a little more about pacritinib and momelotinib, particularly in terms of patients with cytopenias. But I’m just kind of curious, Abe, if you start a patient — let’s say a patient doesn’t have anemia when they start, they don’t have thrombocytopenia, then you put them on ruxolitinib, either they get anemic or thrombocytopenic or both. Do you switch to these newer agents or you keep the JAK inhibitor going and transfuse and et cetera, lower the dose?

DR YACOUB: Yeah. So not necessarily. We accept that every therapy we have has goals to achieve and there’s also side effects. There is not going to be any cancer therapeutic that we’re going to use that will not have side effects. And as oncologists, and we work with a team of wonderful nurses who help us manage those side effects. So that’s really part of having a team approach to every patient.

So as you mentioned, ruxolitinib is, and this photo is from the original COMFORT patient series, it is a life-changing therapy for patients who benefit from it. The spleen, the symptoms and the survival advantage, actually almost doubling the life expectancy with successful therapy. Yes, with the anemia being a collateral. But we also know that anemia from therapy is not necessarily as adverse. Patients who have anemia with ruxolitinib therapy do equally well as patients who don’t have anemia, and still better than patients who don’t get therapy. So we’ve learned that we deliver ruxolitinib effectively and support the patient for the anemia as the paradigm for how we treat with ruxolitinib.

DR LOVE: This is what I mean by seeing the spleen because I’ve heard lots of stories about this. But Andrew, what about this issue of, you know, we do see greater survival, but the question is why. If they’re gaining weight and better performance status, you would imagine that could have an effect. But is this actually affecting the progression of the disease or really just the symptomatic treatment?

DR KUYKENDALL: Yeah. I think there are shades of gray. I don’t think the answer is super black and white. I think in general, we’re not seeing complete responses in terms of if we look in the bone marrow, we’re not seeing the disease go away. We’re not seeing the mutations go away that are driving this disease. So in that way, I don’t think it’s truly disease modifying at the core of the disease. But clearly, you can look at this and it’s disease modifying for that patient, right? It’s completely modified their life. And you could understand that that patient is probably going to live longer on the right than they are on the left.

If you think about the survival benefit, it was shown in the COMFORT trials, it really, significantly in COMFORT-I, also in COMFORT-II, definitely pooled together, we saw a really robust survival improvement as well. But it’s a survival improvement for patients that went on this trial. So that’s one of the things that we have to kind of specify, is that every myelofibrosis patient is different. If you get someone who comes in with myelofibrosis who does not have splenomegaly, is just dealing with anemia and thrombocytopenia, low platelets, that may not be a person that you want to put on ruxolitinib for that survival benefit. The patients that went on these trials had massive spleens, they were higher-risk patients. If you look at the size of the spleens on this trial, the median size of the spleen was around 2,400 cc, which is like a rugby ball. It’s bigger than a football. I was trying to look it up. It’s not as big as a basketball, but somewhere in the middle there. These were massive spleens. If you look at the trials we’re doing now, they’re somewhat smaller. So I think that for the right patient, it definitely is disease modifying and definitely has a survival benefit.

DR LOVE: So Ilene, in a second, I’d like you to talk a little bit about some of the things you bring up to patients who are about to begin ruxolitinib in these type of clinical situations. But just you were mentioning this study looking at survival. It’s interesting. When you look at survival, on the right, you see corrected for crossover. And what that means is maybe they didn’t get ruxolitinib right away but once they got worse, they got ruxolitinib, and then, you know, it was maybe only 6 months later. So you would not expect necessarily to see a survival benefit. But then on the left, you see the patients who didn’t have access to ruxolitinib. Maybe they were living in a country where they couldn’t get it, et cetera. And now, we’ve been talking about this all week, the hazard rate. So you look down there at the bottom, 0.7. So that’s a 30% reduction in the chance of having progression, symptoms, et cetera. So at any point in time along this follow-up, a patient who got ruxolitinib would be 30% less likely, correct me if I’m wrong, to have progression. Ilene, what do you tell patients to expect who are starting ruxolitinib?

MS GALINSKY: So I first, once I go through their copay, I start them on it. And probably the first thing I tell them is never stop taking it. They can have a rebound cytokine that can be life-threatening. So I always reiterate that to them. Monitor their blood counts. I tell them at least initially, I’m going to monitor their blood counts at least for the first month, probably weekly, and then I spread out. Depending where they are, starting with their anemia and their platelet count, I may adjust their visit schedule and the need for transfusions, and discuss their symptoms so we can monitor if they’re having improvement in not only their spleen size, but their fatigue, their shortness of breath, their night sweats, their itchy skin after they take a shower. All those type of symptoms that they could have, we discuss them so we can monitor them and see how they’re doing.

I think it’s also important on the anemia part, everyone’s hemoglobin or if you use hematocrit, everyone has a different level of where they feel their fatigue limit is. And I’m lucky enough that I work in a place where if someone is really fatigued, even though their hematocrit is above 24, I can give them a transfusion. And I think along what we’ve been saying about talking to the patient, if they feel better with a little higher hematocrit, I feel part of their care is that’s what we should deliver. So I think that open communication and willingness to work with your patient is really important.

DR LOVE: Do you use luspatercept in these patients with anemia?

MS GALINSKY: We have started. Most of them, they have to have the mutation for the insurance coverage for the luspatercept.

DR LOVE: Right.

MS GALINSKY: Another topic, but that too has its own side effects. Not really a homerun. It causes fatigue. So you have to think about what you’re trying, are you treating a number, treating the patient, and what is the right balance? Because you’re trading off something for something else.

DR LOVE: Right. Can you just explain a little bit what luspatercept is? Really, it came out in MDS first.

MS GALINSKY: Correct. So luspatercept is another approved agent to help with anemia. It was originally for people that had a specific SF3 mutation.

DR LOVE: Biomarkers, biomarkers, all over. Everything is biomarkers.

MS GALINSKY: But now, what people are finding that it can improve anemia, even in people that don’t have the mutation. The key is it’s an IV drug, it’s given every 3 weeks, has cost to your facility. It’s a very costly drug. So in our place, if you’re going to prescribe someone luspatercept, you have to run it through their insurance. So it’s not like you could just start it on the day that you decide. We have seen improvements in the drug in helping anemia. And I’ve had patients who had frequent transfusion requirements. I’ve had it go down very low. But as I said, the biggest is the fatigue. And so it’s a wait out game.

DR LOVE: So Andrew, can you talk a little bit about fedratinib, that’s another JAK inhibitor, in terms of how it’s different? Also, a little bit about the thiamine story.

DR KUYKENDALL: Yeah. So fedratinib actually was developed kind of at the same time that ruxolitinib was being developed. So even though it got approved around 8 years later, it was kind of developed at the same time. It’s also a JAK1/JAK2. It has a little bit more selectivity to JAK2 than JAK1, but still hits JAK1. It also hits FLT3, which will come back up as far as the toxicity profile goes. It may hit BRD4, which we won’t talk too much about. It may have some implications when we talk about BET inhibitors.

But fedratinib was studied in these, really got approved based on this Phase III trial called the JAKARTA study where patients were randomized to 2 different doses of fedratinib or placebo. And really, the results were very similar to what we saw with ruxolitinib. These waterfall plots we call them, each of these is an individual patient. And if the bar goes down from baseline, that means their spleen is getting smaller. So virtually, everyone had shrinkage of their spleen. If it meets that dotted line, that’s a 35% reduction in spleen volume. That’s what we consider to be a spleen response. So actually, the spleen responses may, if you kind of do what we’re not supposed to do and compare across trials, may have actually looked a bit stronger for fedratinib than they looked for ruxolitinib. The one nuance, of a few, the one nuance was fedratinib — so JAKARTA enrolled down to 50,000 platelets. COMFORT enrolled 100,000 and greater, and still saw responses in patients that had this moderate thrombocytopenia.

For a few reasons, we don’t use a lot of fedratinib, and one is because it got approved 8 years later. Two, it’s because it causes the same degree of anemia and thrombocytopenia or comparable rates of anemia and thrombocytopenia that we see with ruxolitinib, and so it doesn’t offer a benefit there. Three is that it has more GI side effects. And so really high rates of nausea, vomiting, diarrhea on the JAKARTA study. They didn’t really prophylax that well in that study and there wasn’t a lot of guidance on how to give the medication. So in the kind of Phase IIIB studies that have been done, we’ve been able to mitigate that with taking it with a high-fat meal, giving prophylactic antiemetics and then educating patients about having antidiarrheal support. And we’ve actually cut those numbers in half with the Phase IIIB studies.

DR LOVE: No high-fat meal though.

DR KUYKENDALL: Yeah, well, not if you want your disease progressing, right?

DR LOVE: Just saying.

DR YACOUB: Be sure of that.

DR KUYKENDALL: One of the, the black box warning about the thiamine story really came up. And this is what really halted development of this agent, was in 7 patients, I think, out of 600 that were on fedratinib in some way, shape or form, so not all of them had myelofibrosis. There were some polycythemia vera trials, there were some head and neck cancer trials. But 7 patients had encephalopathy, which, and a provisional diagnosis of Werneke’s encephalopathy, which is associated with thiamine deficiency, we often see in alcoholics, patients not eating that well. And basically, the clinical hold came out on a Friday, the company shut down the studies and development of the drug on a Monday. So basically, the drug was kind of shelved for a few years. People went back and actually bought the drug, started a new company, analyzed the data, their company got bought. And ultimately, this led to an approval 8 years down the road. Because it was a very effective drug. And they actually reanalyzed these cases of Werneke’s. And really, there’s like 1 or 2 that truly met criteria for Werneke’s. In some of the patients, they had brain metastases. In others, they were refusing feeding tubes and they knew their thiamine was low. But still, it’s something that we keep an eye on. And now when we use it, we have to check thiamine levels prior to administration, make sure their thiamine levels are good. We put everyone on a multivitamin who is taking it just because it has thiamine in it, and kind of avoid these concerns.

DR LOVE: So Abe, you have this 52-year-old lady, kind of a classic fedratinib situation in a patient who didn’t do that well on ruxolitinib. But first, Sara, anything that you say to patients who are about to begin fedratinib? What are some of the things you bring up?

DR TINSLEY-VANCE: We do talk about monitoring their blood counts, what we’re trying to achieve when we start them on the medicine, do they have any concerns, those type of things. But the thiamine issue has been a problem for a couple of my patients who, when they started, they were normal. And then when I checked them later, they were low. So based on that, I keep a close eye on that thiamine level.

DR LOVE: Interesting.

DR TINSLEY-VANCE: And talk through that.

DR LOVE: So Abe, what happened with your 52-year-old lady?

DR YACOUB: Yeah. So this woman presented with a very classical primary myelofibrosis picture, very symptomatic patient, a large spleen. But she’s young, she’s 52. And during the process, we learned that she has a sister who is a full match. And these are the patients where you really strive to do things right and get them in a timely way to a curative therapy with a bone marrow transplantation. So she received first-line therapy with ruxolitinib just on-label just like one would, you know, a pretty standard approach. She just had an uncommon side effect, which is dizziness. That is reported and just we could not manage it. And even with interruption, dose reduction, we just thought there was no way to deliver any ruxolitinib to this woman. And so at the time, fedratinib was just recently approved but we actually had the clinical trial, the FREEDOM clinical trial, which was presented earlier. So to kind of manage cost of care, we actually enrolled on that Phase IIIB study and had free access to the drug.

DR LOVE: Awesome.

DR YACOUB: Which really hit multiple birds with 1 rock. So she got therapy, she responded excellently to that. As everybody mentioned, proactive management for nausea and diarrhea and vomiting. On the FREEDOM study, actually, the rates of that decreases with time. So by cycle 3 and 4, this is really minimal, nausea and diarrhea that happens. And I give everybody thiamine on — in addition to testing thiamine, we just give thiamine. We just did not want to have anybody get Werneke’s. And there hasn’t been any cases after marketing, fortunately, because of this awareness. And then within 6 months, she was all in all, kind of, stars are met, and then we proceeded with a curative transplant, and she’s doing great.

DR LOVE: Awesome. What a great story. We want to talk a little bit more about these other JAK inhibitors. But Sara, just to come back to part 2 of your Air Force pilot. I guess over the next 10 or 11 years, he actually was in a number of clinical trials. We’ve had a number of patients presented this week who went from trial, to trial, to trial. They go in a trial, the drug responds, and a new drug comes out, they go on that trial. What were some of the agents he got? And how did he respond to the idea of going into these trials?

DR TINSLEY-VANCE: Well, he wanted to get a transplant initially, but he didn’t have a donor. So he had on his signature line of all of his emails, be the match. Make sure you register so that someone will have that benefit. Because he was 68 when I started seeing him. But since he couldn’t go to transplant, he got ruxolitinib first. And then almost every clinical trial that we had available, we screened him and he went on them. Some of them he had a response to that would last like a year or 2. The one that I remember that he had the best response to most recently was the momelotinib clinical trial. And he went from needing transfusions regularly to not needing very many transfusions at all. So I didn’t have to go to clinic at 7:30 and he didn’t have to come in at 6:30 or 6:00 am. But it really gave him time back. It gave him more time. He was on the imetelstat clinical trial, which is now, I think, just got FDA approved for treating patients with myelodysplastic syndrome who have anemia. But they were testing it for anemic patients with myelofibrosis. But I don’t think they had the dose worked out because he was screened for that trial again when it came back around. And he was also on the navitoclax trial. So many of the drugs that have been approved for other things, he was on those. And it really extended his life by many years. Most patients who have high-risk myelofibrosis don’t live very long at all, and he lived 12 years after he was diagnosed with myelofibrosis.

DR LOVE: Let’s talk about these newer JAK inhibitors that are really opening up opportunities to people with really the most common issue that comes up, which is cytopenias. So, Andrew, what is pacritinib? How did it sort of come to being, so to speak? And how is it different than the other JAK inhibitors?

DR KUYKENDALL: Yeah. So pacritinib really, another complicated development process as well where it was actually owned by a very small kind of government owned company that actually went kind of bankrupt, and so we had to go and pry the data out of that government agency. And I say we, I don’t mean we. Someone else did. But really, what it’s known for is being a JAK2 inhibitor selective to JAK2, doesn’t hit JAK1, that can be really used in patients with very low platelets. In the COMFORT trials, patients with platelets less than 100,000 were not enrolled. The label for ruxolitinib does allow use down to 50,000, but you have to use low doses that are not that effective. Fedratinib enrolled down to 50,000. But below 50, we don’t have anything.

And so pacritinib had a couple different studies but really, the main one is the PERSIST-2 study, which enrolled thrombocytopenic patients, patients with less than 100,000 platelets. They could have been treated with a prior JAK inhibitor, but they didn’t have to be. It was about 50/50. And it randomized them to do 2 different doses of pacritinib versus best available therapy, which about 50% of that was low dose ruxolitinib or a JAK inhibitor. And what it showed is it improved quality of life in that patient population, spleen reduction was better, symptom scores were better. And even though it actually went through some more iterations of development with this kind of dose finding study, which confirmed the right dose, and it still has an ongoing Phase III study, it received accelerated approval for patients with markedly low platelets. So this is what we can use in patients who have platelets less than 50,000.

And recently, I think the story that’s been gaining some traction is that we found that it’s an ACVR1 inhibitor as well. And so now, it may be something that we could utilize not just for in low platelets, but maybe for patients with anemia. It is also a FLT3 inhibitor. And so just like fedratinib, that tends to come with more GI toxicity, so we have to think and counsel patients on the potential for GI tox. And the only other side effect I’d mention is a bit higher rates of bleeding, so about 14% versus 7% had Grade 3 or higher bleeding events. It’s a high-risk population already when you’re talking about very low platelet counts. But something to keep an eye out. And then there’s actually recommendations in the label for stopping it prior to major surgeries and things like that.

DR LOVE: Yeah, it’s really interesting. As you were saying, I think it was the last ASH meeting that we started to see more data on anemia. And it’s not like black and white with these drugs in general. Andrew, you had a 74-year-old man who got pacritinib. What happened with him?

DR KUYKENDALL: So I think this is kind of the classic pacritinib patient, which is someone who had massive splenomegaly. He was a snow bird. He spent 6 months of the year in New York, 6 months of the year in Florida. I share him with one of my colleagues. We talk about him as he’s transitioning each year about what we’re going to do, what’s our plan. He wanted to go on a clinical trial, but it’s hard to do that when you’re in 2 different places. And so I didn’t have a clinical trial for him at the time and so I said — sorry, initially, he gets treated with ruxolitinib, but he can’t really tolerate it too well because his platelets drop to 30 every time he goes on it, even at low doses. Otherwise his platelets are between 100 and 150. And so my colleague at Cornell was getting him ready for a clinical trial, but it was the winter. And so that wasn’t going to work for him. So he left and came to Tampa. And I said, well while we’re getting that geared up, let’s try pacritinib. It’s used for these patients with lower platelets. We put him on pacritinib. He actually had very minimal GI toxicity from it, didn’t have too much nausea or diarrhea. He had a very good spleen response and platelets jumped up to about 100, and have been stable there for a couple years.

DR LOVE: So let’s talk a little bit about momelotinib. And we’ll come back to both of these. But I think, Abe, you have a 68-year-old woman who started out on ruxolitinib and then went to momelotinib. What happened?

DR YACOUB: Yeah. So in this, we expect anemia to be associated with ruxolitinib. But if there is anemia, there is anemia. So this woman who started with, you know, had a straightforward post-ET myelofibrosis and had a preserved hemoglobin, 9.5. Again, all our patients are anemic so this is something we have learned to treat. So she received standard ruxolitinib as a first-line therapy except for within a couple weeks, her hemoglobin is down to 5. So she goes into the hospital, we look for bleeding, we scan her, there’s just no bleeding. We stopped ruxolitinib, she recovers. She tries this again with half the dose, same thing happens. So we realize just we cannot deliver ruxolitinib at any effective dose in this woman, and there’s not enough transfusion to keep her out of the hospital.

So that’s when serendipitously, momelotinib got approved. And she was a candidate for it. Also, at the same token, she had a transplant cooking, so we also wanted to get as much objective response. So that was the goal of care, was to get objective response of her spleen and her symptoms and improve her constitutional symptoms to get her fit for a transplant. And a lot fewer transfusions would be also more favorable for a transplant. She received momelotinib, the full dose, which is 200 mg once a day. It is a medication with very little to no hematologic side effects, so really no need for a lot of pre-therapy, pre-medications, no risk of nutritional issues. And she had the expected response. And then after she felt so good, she started negotiating when to go for the transplant, so pushing it back a little bit. So we kind of put our foot down at no longer than 12 months you’ve got to get your transplant. And we kind of, she got to delay it as much as she could, but she still got her transplant in that window. And she is going great.

DR LOVE: So Andrew, can you take a shot at talking about this graphic? I like these kind of graphics that are a little bit more straightforward in terms of how it actually works.

DR KUYKENDALL: Yeah. So this is kind of talking about the potential for anemia benefits with hepcidin. So Abe had mentioned earlier anemia in myelofibrosis is very multifactorial. And obviously, we have disease-related anemia and treatment-related anemia. But one of the things that we know about it is that this is an inflammatory disease, so you get what we call anemia of chronic inflammation. And so with that, we often see high hepcidin levels. When hepcidin levels are high, it restricts iron from being used by the bone marrow, and so you can’t make red blood cells from that sense. And so one of the ways to kind of potentially leverage our understanding of hepcidin is to downregulate hepcidin and basically give an ACVR1 inhibitor, which prevents hepcidin production, allows for iron utilization and would ultimately lead to better production of red blood cells.

Stephen Oh from Wash U actually did a Phase II translational study looking at momelotinib and measuring hepcidin levels during the course of treatment. And it really kind of showed that the patients who had the reductions in hepcidin levels were the ones that had the best anemia responses. So that’s what implicates this is probably the working mechanism.

DR LOVE: Abe, do you want to talk about some of the trials that were done as this agent moved towards its approval just in September?

DR YACOUB: Correct. So the study that actually led to the FDA approval is this MOMENTUM clinical trial, which really was designed after all this knowledge we’ve had about efficacy, about symptom improvement and about the anemia benefits. So that study was designed enriched for patients with myelofibrosis and anemia. And a key secondary endpoint was anemia benefit. And the control was an anemia drug that we use as the standard of care, which is danazol. So that study was successful. So the primary endpoint, although it’s not the anemia or symptoms and the secondary endpoint was the spleen, they all were superiorly met by active therapy with momelotinib versus danazol. But really, the take-away point from that is the anemia benefit that was when you compare momelotinib to an actual anemia drug, it won. It was more successful at achieving that. And when we cross over patients from the control arm to the momelotinib, they also improved. So obviously, it’s a true anemia benefit that is unique to momelotinib, and you’re checking multiple other boxes. You’re improving the symptoms. You’re reducing the spleen. And actually, with, again, hemoglobin.

So that was the study that actually led to the FDA approval, but that was submitted with the data that is from the original Phase III studies, SIMPLIFY-1 and SIMPLIFY-2. So SIMPLIFY-1 was a very ambitious, one of the largest studies at that time that compared a JAK inhibitor to a JAK inhibitor. For the very first time ever, well actually, probably the last time too, that we compared 2 active drugs in first-line setting. But this study, when momelotinib was compared to ruxolitinib head-to-head in treatment naive patients, it was not inferior to ruxolitinib for spleen reduction. In other words, it probably is equivalent in spleen reduction to ruxolitinib, which is a very important endpoint in myelofibrosis therapy. It was slightly inferior to ruxolitinib with symptoms. So ruxolitinib came out the winner in that study because both are equal in spleen, but ruxolitinib is a very good symptom reduction agent. So that study was not, did not meet the primary endpoints and that’s why we didn’t have momelotinib 6 years ago. So we — but the data from that study in addition to the data from most recent MOMENTUM study were added together into the approval package. And now, we have momelotinib that is approved in treatment naïve patients and in previously treated patients.

There was another study called SIMPLIFY-2, which was dedicated to patients who had prior rux and failed it. And this also resulted in significant evidence of activity in second-line setting. So we really have data in first-line, data in second-line, and data against anemia drugs showing momelotinib to be a very effective agent for the right patients. And now, it’s becoming a preferred first-line therapy in patients with anemia and a preferred second-line therapy in many patients after rux.

Promising Agents and Strategies for Patients with MF

DR LOVE: So to conclude, I mentioned we’ve been coming here for 16 years. And one of the people we worked with almost every year except this year was Amy Goodrich, a nurse from Johns Hopkins who is one of the great teachers that we’ve encountered over the years. So we had to, of course, talk to her and get her thoughts. She’s already, we’ve shown several videos of her including talking about participation in clinical trials. But she also had some comments about the issue that we kind of, Ilene was particularly alluding to, which is when you have a patient who is in a situation where they’re kind of running out of options. And all patients really, the issue of self-advocacy and finding out really what’s important to the patient and trying to do your best to see that that comes through. When I brought this subject up to Amy, she mentioned a patient she had taken care of. We were talking about bispecifics the other day in lymphoma. This was a patient who was about to go on a bispecific trial. She was feeling pretty good, she got her first dose, but the trial required that the patient stay in the hospital for observation because there’s a possibility they could get delayed cytokine release syndrome. Here's what happened.

MS GOODRICH: I think about the first person that we gave epcoritamab to as standard of care. And she was a young woman. She was in her 30s. She had 3 young children. She got her first full dose of epcoritamab and she wanted to go to LEGOLAND with her son. Her youngest child was going to be going to kindergarten, and she wanted to go to LEGOLAND. And she got admitted for her observation and her plan was to leave when she got discharged. And the physician I work with told her she couldn’t go. And then I was the one who said, why are we saying this to her? I said, I’ve already given her a list of the ERs that she should go to with her information card. She’s probably not going to be here for this kid to start kindergarten. And she wasn’t. And she went to LEGOLAND and she was so happy. So it’s just advocating for patients. And really, I knew this was important to her. And after she died, it was maybe 2 or 3 weeks, the physician I work with, we were just sort of huddling in the hallway. And he said, I just really want to thank you for making me see that she should go on this trip with her family. That that would have been a really horrible thing to let her not go. So it’s really understanding what’s important to our patients.

DR LOVE: So Sara, any thoughts? And maybe you might have had some thoughts about the last days of your Air Force pilot in that regard.

DR TINSLEY-VANCE: Yes. Really, I’ve been part of this improving goal-concordant care. And it’s so important that we explore the patient’s goals and wishes. We talk about it, but there’s really a specific way that you can pursue that, like how you explore that, and looking at the whole big picture. I remember I was at a SOHO meeting when my Air Force pilot got admitted to the hospital. And his wife said, I think Jim is done. He wants to go to hospice. What do you think? And we were emailing. And I said, make sure Jim knows that if he goes to hospice, he can no longer get blood transfusions, which was keeping him alive basically. And she says Jim is ready to go. So we had talked about what was important to him. He had his affairs in order. And he went to hospice. I think nurses are good at advocating for patients. But if you don’t have a lot of time, if you can take a communication skills training course, it’s really very beneficial and many of them are free.

DR LOVE: Ilene, any thoughts? Sara referred to goals of therapy. And those goals change depending on your situation. You alluded, I think, that sometimes patients have goals that really are just a few months in the future. And it also ties into you hear the connection that Sara has with her patient. I’m sure there are people out there kind of new to oncology who are saying, how do you do that and keep yourself together?

MS GALINSKY: Well, I think when we say goals of care, we have to think about what we mean. So there’s the medical part like oh, I want to give this treatment because this is the best chance for the person to do well as of now. I think we have to think for goals of care is, what’s important to the patient? What’s going on in their life as well? It’s not just making their CBC better. And I think that’s a constant reminder. I think sometimes, our physicians and us as prescribers, if someone says they’re done, we’re like oh, we didn’t do a good enough job giving them that silver bullet. So we feel like we failed our patients because we want our patients to be well. But we have to step back and be like we’ve done everything that we can. And if they’re ready or they want to do something, that’s what’s important to them. And then our big role is to grant what they want done.

DR LOVE: Andrew, I don’t know if you checked the ASCO papers or just the schedule, it was just published, the big meeting every year in June. And they pick 4 papers that are like the big papers of the year. One of them is on virtual palliative care, which in lung cancer had been shown to improve survival. And then they were comparing that to online palliative care. Of course, we don’t know what the results are. But just the fact that that was picked as 1 of the 4 papers. Any thoughts about the palliative care scenario, Andrew?

DR KUYKENDALL: Yeah. I think I would say in hematologic malignancies, palliative care is really challenging. Because as Sara alluded to, sometimes hospice specifically doesn’t allow you to get transfusions, and that’s really a main part of our treatment for these patients. And so you often are having to choose between kind of continuing someone who has a pretty decent quality of life who is getting transfusions and then hospice, which obviously is focusing more on symptoms. But, I think, I come back to this is why we get to know our patients. This is one of the great things about myelofibrosis. I often have fellows that rotate through my clinic, and they’ll have been with an acute leukemia physician, they’ll have been with a high-grade lymphoma physician, they’ll come in and do my clinic and they’ll be like you don’t talk about anything. You just chat with the patient the whole time. I’m like well that’s a good thing. But also, that’s when you learn what’s important to patients, is through those conversations. So when things aren’t good the next time, you know what’s important. You’re not saying what do you want to do. And you can really kind of advocate for your patient because you’ve had those conversations.

DR LOVE: So I can’t thank you all enough. I think you taught us more than just about myelofibrosis today. Thank you for coming. Come on back tonight, 6:15, GI cancers.