 If the JAK/STAT [Janus kinase and signal transducer and activator of transcription] pathway is a uniform, always-present, intracellular signaling pathway that is hyperactive in all the patients’ myelofibrosis, we need to account for its presence—and we do. We have JAK inhibitors, including pacritinib, that would inhibit that particular pathway to extent possible. With that, it decreases the amount of proliferation and improves the patients’ quality of life. But we know, particularly in patients with a low JAK2 allele burden, for example, where the number of cells in the sample of the patients gives us a clue that this pathway is not the only parameter leading to the disease existence. For example, you have patients with advanced myelofibrosis with the 

 mutation that has only, let’s say a 15% 

 allele burden. That means 15% of the cells in the sample are affected by the mutations and activate the JAK/STAT pathway. What about the other components of the biology of that disease in those particular patients? Here is a possible role of 

 [interleukin-1 receptor-associated kinase 2] receptor on an IRAK1 [interleukin-1 receptor-associated kinase 1] pathway that activates the NF kappa B, a central protein involved in the enhancement production of the cytokines. Cytokines are part of inflammatory disease. Therefore, having a medication like pacritinib, for example, that will do dual things, inhibition of 

 may potentially provide extra benefit to the patients. Particularly patients with a low blood cell count, in which you can deliver pacritinib because it’s not myelosuppressive, and you cannot deliver ruxolitinib and fedratinib in optimal doses.

 The 2 randomized phase 3 trials of PERSIST-1 and PERSIST-2 trials were focusing on looking at pacritinib in patients with myelofibrosis. Although these were randomized, controlled trials of a JAK inhibitor vs placebo, or best available therapy, the 1 thing that sets apart the PERSIST studies is that patients who are thrombocytopenic were included. If we look at the COMFORT [Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment] studies and the JAKARTA studies—the studies that ultimately lead to the approval of ruxolitinib and fedratinib—as well as ongoing studies with other JAK inhibitors, we see there seems to be a hard platelet cutoff at 50,000. Any patient with this kind of myelodepletion or thrombocytopenic myelofibrosis were not included, and that is a sizable population of patients that now don’t have an approved therapy. Thus, the PERSIST trials, the subsequent PAC203 trial, and the ongoing PACIFICA trial are trying to address an area of need.

Looking at PERSIST-1 and PERSIST-2, the key take-home point was that, in patients who had thrombocytopenia, there were improvements in symptom burden and spleen response. If we look across the development of pacritinib, whether we’re talking PERSIST-1, PERSIST-2—although the PAC203 was a single-arm study, we could draw parallels from what we’d expect in that population—we see that a larger proportion of patients had spleen volume reduction and symptom burden improvement than what we would expect with other therapies that are available. There have been a phase 2 study and a pilot study looking at low-dose ruxolitinib patients with low platelet counts, with modest proportions of patients having a decent spleen volume reduction or symptom burden. The amount of patients that have those positive end points are larger when they are treated with pacritinib as compared with ruxolitinib, placebo, or observation, of course. The second major take-home point is that this was done safely. There was an initial concern that there were excess bleeding-related events and cardiac events in patients treated with pacritinib, and that ultimately lead to the FDA [Food and Drug Administration] hold on development of pacritinib. But with additional information, the remainder of the data that was sent in, as well as the results from the PAC203 study, showed 2 things: That this patient population was really sick, and even when you give them pacritinib, they can do well without excess toxicity compared with patients who are just generally sick with myelofibrosis. Those are the key pieces from the PERSIST-1, PERSIST-2, and the PAC203 studies.

 Pacritinib is the JAK2 and IRAK1 inhibitor that has been around for quite some time. I would like to highlight the PERSIST-1 and PERSIST-2 studies. These were randomized studies either in the frontline setting or in patients with low platelets, respectively. In these studies, what we learned that is of particular interest today is its ability to improve the quality of life and improve the spleen size—the 2 out of 3 parameters I mentioned as the major problems in patients with myelofibrosis—in patients with low platelets. Remember the ruxolitinib and fedratinib are approved therapies, but not to be given in patients with platelets below 50, for example, because they may worsen that platelet number and cause anemia. These are adverse effects that are not compatible with optimal care. Even in patients with platelets between 50 and 100, ruxolitinib, for example, is usually delivered in suboptimal doses, and it’s not providing optimal clinical care for those patients. Thus, knowing in subgroup analysis that in these patients with low platelets, particularly in platelets before 50, pacritinib is valuable because, for a significant number of patients, it would control the spleen and the symptoms. Furthermore, there is a signal here that it may also make people transfusion independent. In about the 25% of the patients that are transfusion dependent—now I’m talking about the anemia benefit—it may make them transfusion independent. Thus, particularly in those patients, to summarize, you have a drug that works through 2 mechanisms in parallel that would lead to improvement in the spleen, improvement in quality of life, and also potentially improve the anemia parameters in selected patients.

Videos

Expert hematologist/oncologists review the use of pacritinib for the treatment of myelofibrosis, as seen in the PERSIST-1 and PERSIST-2 trials.

PERSIST-1 and PERSIST-2 Trials in Myelofibrosis

 The JAK/STAT [Janus kinase and signal transducer and activator of transcription] pathway plays a central role in the pathogenesis of myeloproliferative neoplasms [MPNs]. It all started back in 1951, when William Dameshek postulated that there was a connection between PV [polycythemia vera], ET [essential thrombocythemia], and myelofibrosis, since they all had a similar clinical phenotype. It wasn’t until several years later when recurrent mutations in the 

 mutation was discovered by 4 groups independently. After that, we’ve seen a rush of JAK inhibitors, which has no doubt altered the field dramatically and improved the lives of patients. After the discovery of 

, in most patients with MPN, there were additional discoveries identifying the current mutations in a gene called 

, which is the thrombopoietin receptor, as well as a gene called 

 is an endoplasmic reticulum chaperone protein. It helps your cells make new proteins and shuttle along in their maturation process. When all 3 of these genes become mutated, they need a constitutive JAK/STAT activation by different mechanisms, but the result is the same for all 3 mutations at the end. For JAK/STAT pathway, STAT is a transcription factor, and it basically enhances transcription of key genes in the cell, which lead to elevated cytokine levels, abnormal proliferation because, again, this is a cytokine pathway. The thrombopoietin, EPOR [erythropoietin receptor], and G-CSF [granulocyte colony-stimulating factor] pathways all feed through JAK/STAT, as well as alterations in NF [nuclear factor] kappa B, TGF [transforming growth factor]-beta, and some prosurvival signals, all ultimately leading to this proliferation and production of cytokines within the bone marrow space, leading to the clinical phenotype that we see.

After the discovery of recurrent mutations in 

, the JAK inhibitors were developed, and there was a whole cadre of JAK inhibitors being developed from the start. What they do is block the constitutive activation of that pathway. Normally, 2 JAK molecules must dimerize to get the pathway going, but with the mutations, they’re on all the time, and this is trying to block that. Some JAK inhibitors block only wild-type JAK molecules, whether that will be 

, as well. Nonetheless, it’s tamping down that pathway, so instead of having that cytokine signal pathway within the cell firing all the time, it can slow down the proliferation of the cells and their ultimate downstream products it’s producing, once again, loss of TGF-beta, NF kappa B, and these other signals. They aren’t curative, that’s a key piece of all this. This is not CML [chronic myeloid leukemia] where there’s a 

 mutation, we give a BCR-ABL inhibitor, the cells all die off, and we don’t see them anymore. The cells can continue to grow and persist, despite JAK inhibition. JAK inhibitors are not equally effective in all populations. Sometimes we think about JAK inhibitors being difficult to use in patients who are myelosuppressed already, so patients who have low blood counts, in particular anemic patients and thrombocytopenic patients because, again, we’re blocking not only mutant pathways but also wild-type pathways, in general. If a patient already has low blood counts, we are blocking the pathway in which the bone marrow is making more red blood cells and platelets. It’s going to lead to more and worsening myelosuppression. Thus, in those patients, JAK inhibitors may not be a good fit. We know that JAK inhibitors can be slightly immunosuppressive, particularly with respect to latent infections. Someone who has latent TB [tuberculosis], someone who has an untreated hepatitis—it would not be a great idea to use a JAK inhibitor on those patients because we know it can lead to reactivation of viral infections, as well as things like latent TB. In anyone you suspect may have a latent infection, you certainly would want to rule that out before starting a JAK inhibitor.

The JAK/STAT pathway is the major unifying biological abnormality in all patients with MPNs, including all the patients with myelofibrosis. But there are other pathways, particularly myelofibrosis, that may be active through other mutations that are present in about 40% to 50% of patients. It activates the PI3K [phosphoinositide 3-kinase] pathway and RAS pathway, or additional abnormalities, in terms of epigenetic control of the genetic expression in the bone marrow cells. Splicing gene mutations, for example, are present in a number of patients, that may contribute to the bone marrow failure. The pathways that are there, and multiple of them, are responsible to a large degree for the progression of the disease, and for the loss of response and having a medication, for example, the implications are obvious. That will do more than just 1 partway inhibition, it will possibly benefit patients in a different way. Inflammation, for example, is tied to the JAK/STAT pathway and inhibition of the JAK/STAT pathway is known to inhibit the inflammation, but there is also a native immune system tool, like IRAK1 [interleukin-1 receptor-associated kinase 1] pathway. That’s another inflammatory pathway that affects the cells in the bone marrow of myelofibrosis patients through NF kappa B activation and contributes to the inflammatory potential of myelofibrosis as it was recently described.

Aaron Gerds, MD, MS; and Srdan Verstovsek, MD, PhD, share insights on the impact of pathways, including JAK-STAT, on myelofibrosis disease progression and discuss considerations for the use of JAK inhibitors.

Role of JAK-STAT Pathway in Myelofibrosis

 Because the major problems with the myelofibrosis are related to bone marrow failure, low red blood cells, low platelets, then symptomatic splenomegaly and bad quality of life, we would like to look at those signs and symptoms in a relativity objective way. For the blood cell count and bone marrow failure to exemplify, this one is relatively easy, right? We do blood cell count monitoring frequently. We look at the platelets and we adjust the dose of medications where the platelet numbers. We have no medications to improve the platelets, but we need to be cognizant about other numbers because of the effect on the standard practice medications. For anemia, we measure the red blood cell count, but we also look at the transfusion requirement. It’s not only about hemoglobin levels, it’s also about the requirement for transfusions. For example, we would measure the transfusions that happen. The goals of therapy would be getting to transfusion independence. That is not possible for platelets, for example. We don’t have the therapies for that, but we may have some medications to help with the anemia.

For the symptoms and spleen, we would like to have widespread use of the questionnaire—MPN 10 [Myeloproliferative Neoplasm Symptom Assessment Form 10]—which consists of 10 questions that will objectivize the quality to refer the patients, which is endorsed by the NCCN [National Comprehensive Cancer Network] guidelines. That would give us a good sense of what is happening with the patient and where the patient needs the therapy. If the patient is on therapy, is it working? Is the quality of life getting better? Answering those questions will help us guide that aspect of the benefit. For the spleen, we would like to have objective measures by some kind of technique, like an ultrasound, CT [computed tomography], or MRI [magnetic resonance imaging]. Realistically, what happens with the spleen is we measure it by palpation. We basically endorse at least palpation, so we have some measurements in a clinical record of centimeters or inches so that we know what’s happening. There are different aspects of looking at different problems and trying hard to objectivize those problems. Certainly, follow them on and off therapy to see how things develop for good or bad, in a semi-objective way.

When I’m monitoring treatment response in patients with myelofibrosis, particularly on JAK [Janus kinase] inhibitors, there are 3 things that I’m monitoring. One is the blood counts, 2 is the spleen size, and 3 is the symptom burden. These are the 3 things I check at every clinic visit. It’s really a matter of monitoring all 3 because patients can progress in a lot of different ways. Some patients, their counts might be fine, their spleen might not be changed much, but their symptoms get much worse, or the spleen gets larger independently, or the counts change. All those could be an indicator of progression or lack of response to the initial treatment, which could prompt you to switch your therapy. What therapy you choose next is often based on what you’re seeing within each of those 3 domains. Is it mainly a change in the counts? Is it mainly a change in the spleen size or symptom burden? That may say, “OK, we need to either adjust the dose of what we’re doing, or switch to a completely different therapy, or add another therapy on top.”

When a patient with myelofibrosis has been treated for a while, and on a therapy, and we think things are starting to change, again, I’m looking at these 3 domains: the spleen size, the symptom burden, and the blood counts. If it’s clearly a pattern of change visit-to-visit with any of those 3 domains, and we’re starting to see loss of improvement or loss of control, then that would prompt me to switch therapies, or within multiple domains at a single visit. If a spleen is 3- or 4-cm longer and their symptom burden went from a total score of 8 to 14, there’s clearly a lot of badness going on and we’re seeing a lot of progression, then we’ll be thinking about switching to another therapy.

There are few therapies we have readily available in the clinic today, and often, for many of my patients, that’s potentially switching to a clinical trial. Clinical trials are our ability to develop treatments for the future for the broader population, and by offering clinical trials, I can offer more options for my patients, particularly those who had prior treatment that is no longer working for them. Oftentimes we will sit down and say, “This is what’s going on with you. We’ve got these clinical trials. This one is trying to directly address what’s going on with you,” and we may pick that. Or sometimes there are other patients where we do switch to, say, a different JAK inhibitor that is already FDA [Food and Drug Administration] approved, or add on an erythropoiesis-stimulating agent, for example, when they become anemic.

If we have, in our practice, objective ways of measuring the anemia, thrombocytopenia, spleen, and symptoms through looking at CBC [complete blood count] transfusion requirements for anemia, palpation, and measurements with a type of a screen or ultrasound, for example, and the MPN 10 for assessment of the symptoms, then we will be able to objectivize the problem for the patients. While the patient is treated, no other therapy works. Knowing the baseline, knowing the improvements, the degree of improvements and the possible failure as it happens—all of these can be tracked with the proper assessment of how the patient is doing through these tools. Once we’re convinced through objective measurements that the spleen is growing, if the anemia worsens, transfusions worsen, platelets worsen, or symptoms are lost through these measurements, then it’s time to switch. In addition, many times, we have a problem with the toxicity of a given therapy. Let’s say we’re talking about ruxolitinib and fedratinib. They are myelosuppressive. If they are causing excessive anemia or excessive thrombocytopenia, that’s intolerance. Thus, we may not talk about the loss of response in this case; we may talk about intolerance or inability to provide the benefit. That’s another reason to switch.

Hematology/oncology experts review their approach to monitoring treatment response in myelofibrosis (MF) and when they would consider switching therapies.

Monitoring Treatment Response in MF

 Allele burden is a concept in myelofibrosis. In general, MPNs [myeloproliferative neoplasms], where we look at the ratio of mutated reads in, say, a PCR [polymerase chain reaction] test vs nonmutated reads—it’s almost a rough approximation for disease burden. You get out a percentage, so 7% of the transcripts that were looked at were mutated vs wild type, or 80% of the transcripts were mutated vs wild type. That’s a way of quantifying how much mutation you’re seeing. There are clearly some associations with disease course, and low-variant allele frequencies often associate with essential thrombocythemia in MPNs. High-variant allele frequencies of the driver mutation, or the JAK/STAT [Janus kinase/signal transducer and activator of transcription]-activating mutation, will often correlate with, say, PV [polycythemia vera] or myelofibrosis, so there is some difference there. Over time—we particularly see this in patients with PV—the mutant allele burden can increase in patients. In some treatments, we see the mutant allele burden decrease. Again, the prime example is patients with ET [essential thrombocythemia] and PV who get treatment with interferons. Over time, we often see the mutant allele burden decreasing and even patients going into molecular remissions.

In myelofibrosis, allele burden is a little trickier to think about. Sometimes, in these myelodepleted myelofibroses, we often see lower allele burdens of the JAK/STAT-driving mutation, and we see a lot of additional mutations that may be present that are outside of that JAK/STAT-activating mutation. In the proliferative version of myelofibrosis, we sometimes see that’s the dominant mutation with the highest allele burden. I don’t think prognosis is tightly connected to variant allele frequency or allele burden, as best as our knowledge is yet. It’s something we’re still exploring. When we get together at fancy academic meetings, say, the American Society of Hematology Annual Meeting, or the EHA [European Hematology Association] Meeting, we’ll talk about, “Well, is allele burden going up and down?” Not because we think it’s the end-all be-all of measuring disease or treatment efficacy, but it’s something we can measure easily and something we know about, so we’re trying to make that link there. Does a treatment truly affect the disease? Is it disease-modifying? Can we measure that by seeing what the changes are in the allele burden? A lot of us suspect there’s more to the story than just allele burden of the JAK/STAT mutation, or that driver mutation, if you will. It also probably has more to do with the other mutations and other things going on in the bone marrow when we’re looking at responses.

Cytopenias are often present in patients with myelofibrosis. Primary myelofibrosis patients are about two-thirds of the patients. One-third are secondary myelofibrosis from ET or PV patients that transform or progress from essential thrombocythemia. Polycythemia tumor fibrosis is a secondary one. In foraminal fibrosis, cytopenias are particularly present. These are patients that come out of the blue, for example, with the fibrosis in the bone marrow with all these signs and symptoms of bone marrow failure, spleen enlargement, symptomatic splenomegaly, and bad quality of life. In this case, there is a high percentage of the patients present with anemia already. One-third is anemic at diagnosis. Two-thirds are already significantly anemic after living with the disease for 1 year.

Concerning thrombocytopenia, about the same percentages are present in these foraminal fibrosis patients from the beginning. If we cut the number at, let’s say 100,000 or less—which is a significant grade 2, 3, and 4 thrombocytopenia—higher percentage of the patients develop these problems throughout their life with myelofibrosis, starting from about 20% at the beginning to 40% after a couple of years living with the disease. Up to 60% of the patients having low platelets, below 100,000, in a second-line setting. Perhaps cytopenias are present in minority at the beginning, but after 2 or 3 years of living with myelofibrosis, it can become a predominant problem. The problem here is not just that they’re there, but that we cannot counteract them, and they affect what we do with the JAK inhibitors, for example.

How do different cytopenias limit treatment options? They limit treatment options a lot. First, the ruxolitinib, which is used for control of spleen and symptoms, must be given in a limited way with a lower dose, if the platelets are low. Presence of anemia would also affect the delivery of ruxolitinib and will affect the delivery of fedratinib and other approved JAK inhibitors. Because they use the inhibition of JAK/STAT pathway as their primary mode of action, that will decrease the proliferation of malignant cells, but they also lower the production of normal cells. Thrombocytopenia and anemia affect the delivery and management of the patients with currently approved JAK inhibitors, ruxolitinib and fedratinib. Therefore, the presence of cytopenias provide a reason for us to say that suboptimal responses are evident in patients with cytopenias, because of us not being able to deliver the JAK inhibitors in an optimal way. The cytopenias prevent us from giving a patient’s optimal dose of currently approved JAK inhibitors.

Aaron Gerds, MD, MS; and Srdan Verstovsek, MD, PhD, share insights on the importance of allele burden in myelofibrosis (MF) and how cytopenias can limit treatment options for patients with myelofibrosis.

Impact of Cytopenias on MF Treatment

 One of the issues that makes treating myelofibrosis so challenging is the lack of approved therapies. We often get jealous of our colleagues who treat multiple myeloma, and they seem to get a new drug every Tuesday, and they have a lot of tools in their toolbox with which to go to work with every day. Thus, I think that’s one challenge. I think the other challenge is the general age and fragility of these patients. Most patients with myelofibrosis are older. The median age at diagnosis is in the 70s. They often have other medical issues going on, heart disease, lung disease, and other organs that may make treatment more difficult to apply. I think, too, just the general illness itself can make people more frail, so consistently elevated cytokine levels leading to nutrition issues and muscle mass loss. Really, I think it makes these individuals more frail and often more difficult to treat. Luckily, we do have these drugs that are available, like ruxolitinib and fedratinib, where we can use them to restore some of the way that these people feel, restore their muscle mass, their functionality and functional status, which I think is really important for not only having people live better, but even live longer, which has been shown in some larger pooled analyses with JAK inhibitors. I think the other main challenge in treating patients with myelofibrosis is the fact that most patients are cytopenic. Roughly 40% to 50% of patients will be anemic at the time of diagnosis. Upward of another quarter to 30% will be thrombocytopenic. Also, many of the drugs that we have available to treat the myelofibrosis often cause myelosuppression, meaning that their blood cell counts will get lower with treatment. Thus, you’re stuck between a rock and a hard place. You have this myelofibrosis that you want to treat, but the available therapies can drive the counts down even further. And you’re sometimes robbing Peter to pay Paul when using these therapies.

 Myelofibrosis is a challenging disease, as it is, for the patients, causing bone marrow failure, enlargement of the spleen and liver, with symptoms that develop through those enlargements, particularly in the abdominal area. Then, general inflammation causes body wasting, night sweating, and low-grade fevers. Thus, to have therapies that would counteract those signs and symptoms is a challenging one. We have JAK inhibitors ruxolitinib and fedratinib, approved therapies, to control symptoms and the spleen in patients, but with the limitations of not being able to be used in patients with low platelets. They are not effective in patients who have progression to acute leukemia with elevation in blasts. Overall actually, in the chronic phase, they do work on the spleen and symptoms, but there is a limitation on durability. For example, the average durability of ruxolitinib benefit is about 3 years. People fail, the spleen starts to grow, the symptoms start to come back, anemia develops. In fact, anemia is the major reason for failing ruxolitinib, as we very well know. Thus, limitations are, in a selection of patients, those with low platelets: you can’t really give them JAK inhibitors, they lower the red blood cells and platelets as an adverse effect; anemia, for the same reason; progression in the blasts, there’s no effect of the JAK inhibitors on the progression to acute myeloid leukemia. Three major areas. And to top it off, what do you do after, in a second-line setting, after fedratinib or ruxolitinib? That’s unknown at this time.

 Some terms are emerging in the field of myelofibrosis, and one is this thing called myeloproliferative versus myelodeplete, or myelodysplastic-like, or empty, if you will, or spent myelofibrosis. The thought is that the counts are low generally in patients with this myelodeplete myelofibrosis, where in the myeloproliferative myelofibrosis, we see very high counts, thrombocytosis. Patients are less likely to be anemic or maybe even have high white counts, where in this myelodeplete myelofibrosis, we often see lots of thrombocytopenia, and even sometimes, in addition to anemia, low neutrophil counts, or neutropenia, in these folks. What we’re starting to learn is that the mutation profiles within the myelofibrosis cells of someone who’s myelodeplete versus someone who’s myeloproliferative are very different. We’re seeing different mutations and different patterns between these 2 populations, suggesting that while we like to dump things into 1 singular bin, like myelofibrosis, we really know it’s a spectrum of disease. There are a lot of different diseases all within that 1 bin. We’re trying to start to piece some of these things out because we may benefit patients by applying different treatments in different ways going forward. Really, the thought is that this myelodeplete myelofibrosis is a distinct version of myelofibrosis and perhaps may benefit from other treatments.

There’s also this concept of primary versus secondary myelofibrosis, and I want to be clear here that that term is a little bit difficult. Secondary myelofibrosis can also refer to something that is immunologically driven. Thus, a patient with a rheumatologic disorder or a chronic infection can get myelofibrosis or scarring in the bone marrow. But that scarring is not due to a clonal process. There’s no JAK/STAT mutation. It’s just the chronic inflammation within an individual driving the scar tissue in the bone marrow. That’s a completely separate entity. A lot of times, we use the word secondary myelofibrosis to describe what’s probably more precisely called post-ET [essential thrombocythemia] or post-PV [polycythemia vera] myelofibrosis. That is, a patient had ET or PV for some period of time, and then over time, their disease progressed or morphed into myelofibrosis. Thus, I think that distinction is important. But clearly, the outcomes of patients with post-ET and post-PV myelofibrosis are a little bit different than those with primary myelofibrosis. I think the clear indicator is that we now have a model designed specifically to assess prognosis in patients with post-ET and post-PV myelofibrosis. We kind of separate those patients out using a different model, where different clinical factors are added up in order to predict prognosis in those folks. In a lot of our clinical trials, we’re also trying to parse out post-ET and post-PV myelofibrosis from primary myelofibrosis to see if there’s any differential effect on treatments as well in order to better understand how these developing therapies might be best applied to different populations.

Experts in hematology/oncology comment on challenges in treating patients with myelofibrosis.

Challenges in Myelofibrosis Treatment

 In 2019, fedratinib was approved and then incorporated into the national guidelines, these are the NCCN [National Comprehensive Cancer Network] guidelines. It was listed as a drug that can be used in the frontline setting, as is the case with ruxolitinib. It was also listed as the drug that can be used after ruxolitinib, in a second-line setting. Now, the new updates from this year say that you can do it the other way around. If you start with fedratinib, you can use ruxolitinib. If you start with ruxolitinib, you can use fedratinib. There is clarification to say there is no particular order. We have utilized ruxolitinib most of the time as standard practice for the last 10 years as the first choice, then fedratinib second, but you can do it either way around. An additional clarification, which I think is actually the most important part of the update in April 2021, is a listing of luspatercept, which is the anemia drug, as a possibility based on an ongoing phase 2 study, in patients who are on JAK inhibitors and anemic. About a third of the patients had benefit in improving their anemia parameters. That listing of luspatercept as a choice is a major one in the guidelines because we don’t have anemia drugs to use. We utilize prednisone, danazol, and perhaps thalidomide; none of these are very effective. None of these are really approved. Now, luspatercept is a choice. Again, it’s not approved, it’s in a phase 3 randomized study for possible approval as we speak. But it’s a welcome addition of an anemia drug that may help patients in this particular aspect of their problems.

The JAK inhibitors would be standard practice for lower- and higher-risk patients if they are symptomatic. Symptomatic means either symptomatic organomegaly, or general systemic symptoms related to myelofibrosis that I described earlier, like night sweating, low-grade fevers, itching, bone aches and pains, and body wasting. These are general problems that come from inflammation that comes from the disease. Proliferation causes a big spleen, and that can be affected by the JAK inhibitors. For JAK inhibitors for the spleen and symptoms, you would treat the anemia, which is present usually in the high-risk patients, with anemia drugs. Many times, a combination of the 2 together. Then in patients who are progressing to acute leukemia, if the blasts are increasing, you treat with hypomethylating agents. These are limited choices that we have. Out of those, only the JAK inhibitors ruxolitinib and fedratinib are really approved, they’re full-fledged drugs for myelofibrosis. Others are not approved and have a limited ability to help our patients.

 For a patient with primary myelofibrosis, or post-ET [essential thrombocythemia] or post-PV [polycythemia vera] myelofibrosis, really, we think about 2 things. One is disease risk. And the other though and probably more important, is how they’re feeling, or what do they have going on in terms of symptoms and spleen size? The main tool we have in clinic these days, in terms of FDA-approved and regulatory-approved medications, are JAK inhibitors. These JAK inhibitors are really good at shrinking spleens and improving symptom burdens. Thus, if a patient has a significant symptom burden, as measured by the MPN-SAF [Myeloproliferative Neoplasm Symptom Assessment Form], or has significant splenomegaly, or both, I think starting therapy with a JAK inhibitor is really important. There are some other instances where we might think about other treatments. If a patient is anemic to the point where they may need transfusions in the near future, or are already getting transfusions, we will often think about agents that can improve the state of their hemoglobin levels and avoid transfusions going forward. Those drugs often include things like erythropoiesis-stimulating agents, newer drugs like luspatercept, or other oral agents like danazol. There are also some data for a class of medications called IMiDs [immunomodulatory imide drugs], including thalidomide and lenalidomide, in that space to improve anemia in these folks. Thus, that’s kind of almost a special instance outside the general thinking about high-risk disease, or even lower-risk disease with significant spleen sizes and symptom burdens.

For primary myelofibrosis and post-ET and post-PV myelofibrosis, the 2 drugs that have regulatory approval are ruxolitinib and fedratinib. Both are JAK inhibitors. A lot of their action is through inhibition of JAK1 as well as JAK2. The 2 drugs have a little bit different off-target effects. We think about FLT3 inhibition with fedratinib and some other cytokine inhibition with ruxolitinib. But they are of the same class, and we expect similar results with this class of medications, namely the ability to shrink spleens and improve symptom burdens. Outside of that, any therapy use is really off-label at this point. If we’re using an agent to improve anemia, say again, an erythropoiesis-stimulating agent, danazol, an IMiD, or luspatercept, it would be off-label. Thus, certainly, there is a dire need for new medications, new therapies, and new approaches to therapies in this patient population.

Transplantation, to date, is the only thing that has shown curative potential or the ability to put a person in a remission and have that remission maintained for a long time without additional therapies. We really think about transplantation in patients who have higher-risk disease. What it kind of boils down to, and I think the European guidelines put this quite nicely, is if using our prognostic models, or your clinical acumen, if you think a patient’s average survival is less than 5 years, indicating pretty high-risk disease, then you would consider transplantation in someone like that individual. Then you would say, “Well, are they well enough to go through a transplant? What would be the potential complications?” And we start thinking about that. If a person has a predicted survival longer than 5 years, then they may not benefit from transplant at that time, and you might want to delay transplant until something changes. Say they’ve been on a JAK inhibitor, and the JAK inhibitor’s no longer working, or their counts are fine now, and then several years from now, their counts are not fine, say they become thrombocytopenic or anemic, and then maybe you would want to transplant then. But really, we think about that in terms of survival. There was a really nice analysis just published, a collaboration between a number of MPN centers, as well as the CIBMTR, the Center for International Blood and Marrow Transplant Research, which is a large transplant-based database, where they were looking at patients who were treated with transplantation and those who were treated with nontransplant therapies and kind of compared the two based on disease risk. It was clear that the high-risk patients and intermediate-risk patients benefited from transplantation, where the low and low-intermediate patients really did not benefit from transplant. Actually, transplant was somewhat detrimental at that point. Thus, it kind of re-emphasized what we all intuitively know about who should get transplant and who should not, at least those patients with myelofibrosis.

Srdan Verstovsek, MD, PhD, and Aaron Gerds, MD, MS, review key updates to NCCN guidelines for primary myelofibrosis and discuss treatment options for the disease.

Treatment Strategies for Primary Myelofibrosis

 There are a lot of different ways we think about risk for primary myelofibrosis. Most commonly, we think about overall survival. What is the average amount of time someone will live with this diagnosis? The concept is the more aggressive the disease, the more aggressive we should be with it in applying our therapies. Now, we can determine disease risk or average survival in a number of manners. We often use risk stratification systems. Now, unlike solid tumors, where you have an initial tumor, and then it travels to a distant nodal site as a metastasis, or even other organs, and the staging system is based on that, for blood diseases like leukemias, the blood is everywhere, including in myelofibrosis. We can’t necessarily have a stage system based on where the diseases travel, so we use these risk models. The most commonly used risk model is something called the Dynamic International Prognostic Scoring System, or DIPSS. It takes a number of clinical variables that you could easily get at any clinic visit, and you plug them together, and you get a score. And that score is associated with a median survival for that individual. The nice thing about this prognostic scoring system is it is dynamic, that’s what the D stands for, meaning that it can be used at any point along a patient’s disease course. Now, it doesn’t include very deep variables, such as cytogenetics, which we know are strong predictors of disease course and risk of progression. Moreover, it doesn’t include molecular information, such as the mutations that are inside the myelofibrosis cells. These models have been updated to the DIPSS Plus, which includes cytogenetic information, as well as this model called the MIPSS70 [Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients With Primary Myelofibrosis], which includes molecular markers, such as driver mutation status, and additional mutations, such as 

, and these other high-risk mutations. We take all these bits of clinical information together, and we try to think about what is the predicted overall survival for this individual going forward. Is it a very short period of time, say, less than 5 years? That would be on the higher end of risk. Or is it going to be longer than 5 years, which we would say is on the lower end of risk?

When we think about molecular status or mutations that are inside the myelofibrosis cells, first and foremost, it’s incredibly important for diagnosis. We like to identify that JAK/STAT driving mutation, the mutation that is driving that pathway, as part of this disease, whether we’re talking about 

 mutations. There is some prognosis within those. We know that patients with type 1 calreticulin mutations tend to do much better than patients with other types of mutations driving the JAK/STAT pathway in individuals with myelofibrosis. But what’s probably more important are the other mutations that we see inside these myelofibrosis cells. There are certainly some very high-risk mutations, like 

, that predict for a more aggressive disease course over time, more likelihood for progression and those types of things, as well as mutations such as 

, where not only are they higher risk, but we also have now targeted therapies that could be applied in that patient’s treatment at some point in time. Thus, these mutations that we can get in these genomic analyses are incredibly important for diagnosis, prognosis, and now even treatment.

Symptom burden assessment is a big piece of what we do every day in the clinic. It often drives our treatment. A lot of times, you may have a patient with some middle-of-the-road-risk disease, or even low-risk disease, where you may not think you can improve things too much with a JAK inhibitor otherwise, but boy, they’re symptomatic, and starting a JAK inhibitor may make them feel a lot better. That can really drive your treatment. In checking symptom assessment, I think a lot of people just ask the questions, “Well, how are you feeling? Do you have any night sweats? Do you have anything else going on?” But I tend to use the MPN-SAF [Myeloproliferative Neoplasm Symptom Assessment Form]. It’s a validated tool to measure not only the types of symptoms the patient is having, but their intensity, and kind of measuring that clinic to clinic to clinic while they’re on a treatment or even on observation. You can see if they’re getting worse or getting better by simply looking at the numbers that are recorded. This has been validated in a number of studies, as well as used commonly in clinical trials.

Aaron Gerds, MD, MS, provides insight on determining low- vs high-risk primary myelofibrosis, the role of molecular status on treatment, and his approach toward symptom burden assessment.

Risk Stratification and Patient Classification for PMF

 Primary myelofibrosis has different signs and symptoms, but the 3 classic ones are, No. 1, bone marrow failure that represents itself with anemia in particular. No. 1 is the anemia. The second one is the symptomatic splenomegaly. In about 80% of patients, a big spleen develops. In about 40% of patients, a big liver develops, and they become symptomatic. Symptomatic splenomegaly is the No. 2 factor. Lastly, the No. 3 factor is general bad quality of life. I’m talking about systemic myelofibrosis-related symptoms: night sweating, low-grade fevers, fatigue, itching, weakness, body wasting, decreased performance status, bone aches and pains. Thus, these are parts of the disease spectrum that we are talking about, anemia, symptomatic splenomegaly, and general bad quality of life. Those are the 3 leading problems and 3 leading reasons for trying different therapies to counteract those signs and symptoms of myelofibrosis in everyday practice.

Once we establish the diagnosis of myelofibrosis, the next question is what’s the risk? The risk that we are talking about is the risk of dying. There are prognostic factors that can be used to assess the risk of dying. The primary goal is to say, who has a life expectancy of less than 5 years, and to refer those patients to a bone marrow transplant department and try to save the life of the patients with that relatively invasive procedure. For those who have a life expectancy of more than 5 years, we don’t do that, because the transplant is risky on its own. Once we are done with prognostication, we move on to identify symptoms and signs that require therapy. If there are no significant symptoms and signs, for example, no significant anemia, no significant symptomatic splenomegaly, or no significant issue with quality of life, then sometimes we observe the patient. The low-risk patients usually are like that. We may observe them. As they progress through life with the disease, they become high risk because they develop anemia and the symptoms, for example, these are their prognostic factors. There is overlap between the risk of dying prematurely and the initiation of therapy. For the lower risk therefore, we would occasionally need therapy, and occasionally treat patients for symptomatic splenomegaly, or bad quality of life. Or occasionally for some other reasons, like very high platelets, or very high white blood cell count, to decrease this myeloid proliferation. For high-risk patients, we certainly would treat the patients, and this is where symptom burden comes in. Symptomatic splenomegaly, or general systemic symptoms, are 2 out of the 3 major problems. Also, it is many times tied to the risk of dying. Thus, standard practice would be, if the patient is symptomatic, occasionally in low-risk patients, but normally present in high-risk patients, to utilize the JAK inhibitors. We have a couple of JAK inhibitors, ruxolitinib and fedratinib, that are approved as a therapy for patients who are symptomatic, and who are intermediate or high risk. One or the other are listed in national guidelines as a choice.

Srdan Verstovsek, MD, PhD, describes the classic signs and symptoms of primary myelofibrosis (PMF), along with goals of therapy.

Aaron Gerds, MD, MS, Cleveland Clinic

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