Personalizing Treatment of Myelofibrosis-Associated Anemia

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic. Today, I'm happy to be joined by Dr. Akriti Jain, a Staff Physician in the Leukemia and Myeloid Disorders Program, and a Hematologist and Medical oncologist here at Cleveland Clinic. She's here today to discuss personalizing treatment of myelofibrosis-associated anemia. So, welcome.

Akriti Jain, MD: Thank you for having me. Dr. Shepard. It's my first time here and I'm really excited to talk more.

Dale Shepard, MD, PhD: Well, first maybe of many. Let's see, we can come up with in the future.

Akriti Jain, MD: Yes.

Dale Shepard, MD, PhD: So, start off, why don't you tell us a little bit about what you do here?

Akriti Jain, MD: Yeah, so I joined the Leukemia and Myeloid Disorders Department almost two years ago. I came from Florida, I trained at Moffitt Cancer Center and I came here to do myeloid disorders. So, as clinical practice, I see myelodysplastic syndromes, myeloproliferative neoplasms, as well as acute and chronic leukemias. I have a personal interest in treating chronic myeloid leukemias and I'm passionate about that. And then in the research focus, I focus on myeloproliferative neoplasms, which includes Philadelphia negative MPNs like ET, PV, and myelofibrosis, as well as the Philadelphia positive MPN, which is CML, which I have personal interest in.

Dale Shepard, MD, PhD: Excellent. So, we're going to talk about myelofibrosis-associated anemia. When we think about myelofibrosis, how common is it?

Akriti Jain, MD: So, myelofibrosis by itself as a cancer diagnosis is relatively rare. If you talk about anemia in myelofibrosis, that is very common. So, at diagnosis, there are almost 40% of patients that present with anemia accompanied within myelofibrosis and then during their course of their disease, all of them. So, a hundred percent of the patients develop anemia, and that can be from a multitude of reasons. It could be from the pathophysiology of the disease itself. So, myelofibrosis is marked by elevated pro-inflammatory cytokines, ineffective erythropoiesis, and some amount of dyserythropoiesis or abnormal blood cell production, which leads to anemia, which is from the disease itself. And then sometimes, we give treatment that causes anemia. So, because of one reason or the other, all of the patients, a hundred percent of the patients develop anemia during their course of disease.

Dale Shepard, MD, PhD: So, when we think about myelofibrosis, everyone would eventually get anemia, but there's a lot of people with anemia and it's fairly common, well, unfortunately common and people don't actually work it up too often, but when they do, what would an anemia work up? What should it look like to make sure someone doesn't miss a diagnosis of myelofibrosis?

Akriti Jain, MD: That is a great question. I'm glad you bring that up. Anemia is common. It's one of the most common reasons for referral to a hematologist. So, a lot of times, when I see a patient in clinic, they've already had a bone marrow biopsy and that bone marrow biopsy either shows fibrosis, which is the hallmark of myelofibrosis or one of the three markers of myelofibrosis, the molecular markers that are JAK2, CALR, or MPL. There is an entity like triple negative myelofibrosis, but you still have a molecular marker, whether it's another mutation that you see on the next generation sequencing. I think even if you have a bone marrow biopsy that is showing you the stigmata of myelofibrosis to be able to make that WHO criteria diagnosis, it is important to go back to the basics and make sure there's nothing else confounding the anemia.

So, talking about workup, I always make sure we have basic nutritional workup like iron panel, B12, folate, and other nutritional workup that might not be done in the community like vitamin B1 level, B6 level, copper and zinc level. I think it's easy to miss those parts of the diagnosis and sometimes, anemia is multifactorial. It's not all just the bone marrow, but it's also nutritional deficiencies.

Dale Shepard, MD, PhD: When we think about myelofibrosis, the anemia's associated with, why is it important to recognize it early and jump on that treatment?

Akriti Jain, MD: I think that's a good question. Whether we jump on treatment or not is individualized. A lot of times, we're able to tolerate hemoglobin up to a eight or nine. I think some people get symptomatic even at a nine, and other people do not get symptomatic until they're less than an eight or even sevens. Your body gets accustomed to the low hemoglobin levels because it's not a sudden process. It's a slow gradual process that gets us to that hemoglobin level. It's important to work it up and see the patient that presents to you in clinic. So, it's not just that hemoglobin value, but what is the patient complaining of? Are they mainly complaining of low hemoglobin symptoms like shortness of breath and chest pain and inability to be able to do the things that they used to before, like climb a flight of stairs or they have some of the stigmata of MPN symptoms which are fatigue, night sweats, weight loss?

We have a very nice MPN symptom assessment form or symptom assessment score. So, I make it a point to do that with each and every MPN patient when I see them in clinic. And it has 10 questions including loss of appetite or early satiety, abdominal pain, inactivity problems concentrating. So, going over that helps you decide whether this patient is mainly symptomatic from the anemia standpoint or are they also symptomatic from their MPN diagnosis, as well.

Dale Shepard, MD, PhD: When we think about individualizing therapy, what are the bigger factors that play into making a decision on treatment? Is it things like anemia and the effects of the anemia, the symptom scores? Is there one thing that takes precedent over others in terms of your concern about starting a patient on treatment?

Akriti Jain, MD: I think the number one consideration always is what is the risk score of the disease by itself. And that risk helps us decide, is this disease going to progress into something aggressive like blast phase MPN or acute leukemia in the near future? And we have good risk scoring systems. The newest one is MIPSS V2.0 or MIPSS version two, or it's called the Molecular International Prognostic Scoring System. And going through that scoring system tells you if someone's high risk for progression, then the number one consideration would be irrespective of how they're feeling, they need to see a transplant physician because everything I do, I'm not going to be able to cure their disease. The transplant physician will be able to cure their disease. I think that's number one is when you see a patient in clinic, see what their risk score is.

I think number two along with the symptoms and the MPN symptom assessment score or symptom assessment burden is do they have an enlarged spleen or not? And that goes into the symptom burden, as well. If they have an enlarged spleen, they're going to talk about early satiety and abdominal pain and discomfort because if they have an enlarged spleen and a high MPN symptom assessment score, then you would treat their anemia differently compared to if isolated anemia is the only presenting symptom in someone with myelofibrosis.

Dale Shepard, MD, PhD: And so, maybe expand on that a little bit. How do you separate those two and what do you do in each case?

Akriti Jain, MD: Yeah, that's a great question. So, I think we're getting richer in terms of the treatment options we have for our patients. A few years ago, we only had Ruxolitinib, the first JAK inhibitor that came to market and everyone with myelofibrosis would get put on Ruxolitinib. And Ruxolitinib by itself can cause a lot of anemia, especially in the first few months. By three months, the anemia levels out, but some patients will still be anemic. You would see the benefits from Ruxolitinib, which is reduction in the spleen size and reduction in the symptom burden, but some patients might feel worse because their hemoglobin level is lower. But now, we have other options. So, again, we've become richer, we have more tools in our toolbox. So, if someone has isolated anemia, the first thing, along with the nutritional workup that we talked about, I would get erythropoietin level.

So, erythropoietin is a hormone produced by our liver and kidneys that tells our bone marrow to make more blood. That's how I explain it to patients in a simple way. And if your erythropoietin level is less than 125, we can supplement EPO erythropoietin using erythropoiesis stimulating agents that would help make them more red blood cells, tell their bone marrow to make more red blood cells. And if their EPO level is over 125, then giving them ESAs from the outside are more ESAs less likely to work. Then we look at other options. We have erythroid maturation agents like Luspatercept, which we have a lot of experience using in MDS, but now, we also have experience using in MPNs that can also help the isolated anemia in myelofibrosis. And then there are old tools like Danazol, which can help immunomodulatory agents like lenalidomide and thalidomide can be used for isolated anemia, as well.

However, if someone has MPN symptoms and an enlarged spleen along with anemia, I would probably choose a JAK inhibitor. We have four frontline JAK inhibitors that are approved for myelofibrosis. Again, we have lots of tools which is good, so there's Ruxolitinib, Pacritinib, Momelotinib, and Fedratinib. A lot of times, for frontline, we start patients on Ruxolitinib and if they develop anemia, then we think about switching treatment. Momelotinib and Pacritinib both have anemia benefit because of their mechanism of action. They inhibit ACVR1 along with JAK inhibition, which is central or pivotal to pathophysiology of myelofibrosis. So, from all these options, looking at the patient in front of you in clinic and asking those questions and choosing is what requires that nuance in treating myelofibrosis.

Dale Shepard, MD, PhD: And the last couple of drugs you mentioned, is it that the drug itself doesn't cause as much anemia or is it it's more effective to prevent the myelofibrosis from having red cell production?

Akriti Jain, MD: So, the drug itself can cause anemia. So, anemia comes from inhibiting that JAK that all these drugs do. Ruxolitinib is like a non-selective inhibitor of JAK1 and JAK2 and that's how it works. However, Pacritinib and Momelotinib have an additional mechanism of action, where they block ACVR1 or active in ligand receptor, which removes that anemia of inflammation. It brings hepcidin down and it makes more iron available for erythropoiesis, and that's a way of using that pathway to help with anemia.

Dale Shepard, MD, PhD: And I guess just in terms of a treatment, how you choose treatments there, four drugs all approved front line. The last couple have these dual mechanisms less likely to cause anemia. Why did the Ruxolitinib as a first choice?

Akriti Jain, MD: So, if someone has anemia, I'll probably think about using Pacritinib or Momelotinib. Pacritinib right now is only approved for patients that have myelofibrosis and platelets less than 50. And Momelotinib is approved for patients with myelofibrosis and anemia. So, Pacritinib, because of its FDA label, we can only choose it for patients that have platelets less than 50. Momelotinib and Ruxolitinib are both options. I think it would depend on the degree of anemia. If someone has almost near normal hemoglobin and MPN symptoms, they'll probably go with Ruxolitinib. However, if someone has MPN symptoms with moderate to severe anemia, Momelotinib would be a choice, so that it helps their symptoms, as well as anemia.

Dale Shepard, MD, PhD: Ruxolitinib's been around for a while. Now, there's a lot of drugs to choose. Where do most people get treated? Are community providers using these drugs? It seems like with the nuance involved that seeing specialized centers, seeing someone like yourself would make sense. Are most people seen in centers or most people or are some people being seen in community, as well?

Akriti Jain, MD: I think it's a mix of both. It depends on the comfort of the community physician of how much Ruxolitinib they've used. I've seen both types of referrals. I've seen a lot of patients. So, myelofibrosis can be primary or secondary. So, secondary myelofibrosis is when it arises out of pre-existing ET or essential thrombocytosis and PV. So, I've seen referrals where patients have had ET and PV for a long time and then they develop secondary myelofibrosis and the community physician says, "I need a little bit of help here." And that's when they send the patient to us. I've seen patients been treated with Ruxolitinib in the community and then when that leads to anemia or patients respond and they lose their response, that's when we get the patients. So, I think it's a mix of both because like you said, Ruxolitinib has been around for a while. Some community physicians are comfortable using it. Momelotinib was only approved September of last year, so it's only been around a year and Pacritinib a few years before that. So, some community physicians do not have experience using those two and that's why we see referrals after Ruxolitinib use.

Dale Shepard, MD, PhD: What are some of the new drugs that seem to be exciting?

Akriti Jain, MD: Yeah. So, we actually have, at Cleveland Clinic, two frontline trials open. One of them is using a combination of Ruxolitinib and Navtemadlin. We are very excited about that trial because as a field, we're moving towards combination therapies. We make patients live better and longer with one treatment and say, how can we improve the treatment? But I think a sense is that not everyone probably needs combination therapy. So, this Ruxolitinib and Navtemadlin trial is exciting because we start patients on Ruxolitinib, which is standard of care, and then we monitor them for 12 to 24 weeks. And if they get the response that we want, which is spleen volume reduction, reduction in symptom burden, then that's good. We are getting the response we need. But if they don't, what we call suboptimal responders or non-responders, when you add the second agent. So, we're excited about that trial design because it helps us to know that at the get-go, not everyone needs combination treatment and Navtemadlin is a p53 modulator, so that's a trial we're excited about.

Another trial that was recently published in one of the nature medicine journals was a combination of Ruxolitinib and Pelabresib, which is a BET inhibitor. And the combination in JAK inhibitor naive patients showed much better responses in terms of spleen volume and symptom burden. So, I think as a field, we're moving towards combination treatments, adding whether it's a BET inhibitor or a p53 modulator, MDM2 inhibitor to a JAK inhibitor and everyone uses a backbone of Ruxolitinib because that's what's been around and in the future, they'll probably extend to other JAK inhibitors. So, it's choosing the patient that needs combination treatment that'll get important in the future.

Dale Shepard, MD, PhD: So, back to that individualization that we talked about a couple of months ago, when you think of these combinations, are there particular combinations that would be best suited for particular kinds of patients?

Akriti Jain, MD: That's a great question, Dr. Shepard. I think that's what we need to learn as a field in the future and we would need more data to support and see how we choose our patients better. And that's why using a trial design where we start with standard of care like a JAK inhibitor and then add a second agent in the future if needed. And then going back, we can see which patients, is there a specific subtype of patients, whether it's co-mutations or it's the amount of bone marrow fibrosis or their numbers or their risk score and decide which patients would benefit. I don't think we have the answer as a field for that yet.

Dale Shepard, MD, PhD: It's good to see the stepwise combinations because too often, in the solid tumor world, it's straight to a combination and we may be grossly over treating a lot of people.

Akriti Jain, MD: And then we cure patients and then we start moving backwards. How do we take drugs out of the combination?

Dale Shepard, MD, PhD: Yeah. Right, right. Are there any other particular combinations that you find promising or new pathways that you think are going to change how we treat these patients?

Akriti Jain, MD: Yeah, I think our big aim here is how to cure some of our patients, how to eradicate the disease inside the bone marrow. One thing that we are really excited about is how do we decrease the fibrosis in the bone marrow? Because a lot of the drugs, even JAK inhibitors that we have, we see repeat bone marrows and we don't really see the fibrosis going down. And that tells us that these drugs by themselves are not necessarily disease modifying. And so, that's what we're excited to learn more about. There are two BCL-X inhibitors that are in trials that can potentially improve the fibrosis in the bone marrow. I think the other big thing is monotonal antibodies. So, there are monotonal antibodies against CALR, which is one of the second most common mutations implicated in myelofibrosis and monotonal antibodies have a relatively safer toxicity profile compared to bispecific or CAR-T or stem cell transplants. So, we found that with Rituximab when it came out. So, those are things we need to work more upon and improve the treatment armamentarium for our patients.

Dale Shepard, MD, PhD: So, it looks like some really promising therapies coming up, promising approaches, getting the right patients, the right treatments, but I guess you have to have that diagnosis first. So, jumping back to where we started, a lot of different people might be listening in. What would your recommendation be to make sure that people don't miss a diagnosis?

Akriti Jain, MD: So, that's a great question and we always want to make sure once we rule out all nutritional causes of anemia, that we get a bone marrow biopsy. Even though it's a relatively invasive procedure, we've gotten better at doing them. And I've seen a lot of patients being diagnosed with ET or PV just based on a high platelet count or a high hemoglobin count without a bone marrow biopsy. Specifically in PV, if you have a hemoglobin over 18 or 18.5 for a few times over months and a JAK2 mutation, you can potentially not do a bone marrow biopsy. But in all other diagnoses, before making a diagnosis of an MPN, I recommend getting a bone marrow biopsy because you could mean that the patient has pre-fibrotic myelofibrosis. And that's a nuanced diagnosis that requires a hematopathologist that's trained in reading bone marrows with MPNs to make that diagnosis.

So, the WHO criteria for myelofibrosis requires at least reticulin fibrosis grade of two, one to two or more, on a scale from zero to three. It requires a molecular marker. So, whether it's JAK2, CALR, MPL, or another molecular marker that is seen on NGS. And then it requires you to have excluded other diagnoses like CML, PV, and ET through their WHO criteria. And the other part of it is sometimes, the LDH is elevated, so I recommend checking that, checking a uric acid level, checking their spleen. So, a lot of times, we need to examine the patient and examine their spleen size. It's hard to examine in some patients. You could get an ultrasound and all of those markers or criteria help you get to the diagnosis.

Dale Shepard, MD, PhD: That's fantastic. So, important information. Looks like a lot of encouraging things in the future. Now, we'll have to have you back for another topic.

Akriti Jain, MD: Sounds good.

Dale Shepard, MD, PhD: All right. Thanks for being with us.

Akriti Jain, MD: Thank you, Dr. Shepard. I'm glad to be here and looking forward to talking to you more in the future.

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