The Evolving Treatment Landscape in Myelofibrosis: An Advanced Practice Perspective

Sarah Profitt: Hi everyone and welcome JADPRO's roundtable discussion on myelofibrosis. My name is Sarah Profitt and I'm a clinical pharmacy specialist in adult malignant hematology at Vanderbilt University Medical Center in Nashville Tennessee. And I'm joined today with two wonderful panelists that will introduce themselves to you now.

Kate Kennedy: My name is Kate Kennedy. I'm a nurse practitioner in malignant hematology, also at Vanderbilt University Medical Center, specializing in myeloid disorders.

Jill O'Brien: Hi, I'm Jill O'Brien. I'm a physician assistant at the Cleveland Clinic in Cleveland, Ohio, and I also specialize in malignant hematology with myeloid disorders.

Sarah Profitt: Awesome. Thank you guys. Glad to be with you today. We'd like to start off this roundtable series on myelofibrosis with a comprehensive review of our workhorse medication class, and that is the JAK inhibitors. JAK refers to the Janus family of kinases, and these kinases mediate the signaling of over 50 cytokines and growth factors that are key for hematopoiesis and immune function. JAK signaling involves recruiting stats or signal transducers and activators of transcription to cytokine receptors, activating and relocating those STATs to the nucleus of the cell, leading to modulation of gene expression.

And myelofibrosis is a myeloproliferative neoplasm that is associated with dysregulated JAK1 and JAK2 signaling. So JAK inhibitors are a class that have been utilized to treat a variety of non-malignant autoimmune conditions like ulcerative colitis, rheumatoid arthritis, and many more. But today we're here to talk about the JAK inhibitors that are FDA approved to treat myelofibrosis.

The first JAK inhibitor that was approved to treat MF was ruxolitinib, which was first FDA approved back in 2011 for intermediate- to high-risk myelofibrosis. And over the last 15 years or so, we've had several other JAK inhibitors added to the list of available medications and treatment options for our patients. So we're going to review each of these JAK inhibitors and then talk about selecting between different medications in the class and how we differentiate between these products.

So let's get started with this deep dive into JAK inhibitors from the beginning with ruxolitinib. Ruxolitinib targets JAK1 and JAK2. And early on when JAK inhibitors were being developed, JAK2 V617F-mutant mouse models showed that ruxolitinib improved the splenomegaly associated with the disease process. It decreased the allele burden in cells in the spleen and decreased those inflammatory cytokines.

So fast-forward to ruxolitinib getting FDA approved in 2011, and that was based on two major pivotal clinical trials, COMFORT-1 and COMFORT-2. These were large randomized studies looking at patients with intermediate- to high-risk myelofibrosis. We saw early on in these clinical trials that one of the most important clinical outcomes that are used in clinical trials for myelofibrosis are spleen volume reduction. So are the medications that we're giving able to shrink the spleen and therefore help our patients with symptoms?

So what we saw in those early COMFORT-1 and COMFORT-2 studies were that ruxolitinib compared to best available therapy at the time—things like hydroxyurea, steroids, and in some patients just watch and wait—that ruxolitinib was able to improve spleen volume reduction and also help improve quality of life. We were seeing patient-related outcomes being studied in COMFORT-1 and COMFORT-2.

The most common toxicities that are associated with ruxolitinib are hematologic, so anemia most commonly followed by thrombocytopenia. These toxicities we tend to see are dose dependent, so they're usually able to be managed with dose reductions. And in fact, we have recommendations in the package labeling for ruxolitinib doses based on a patient's baseline blood counts, including their platelets. Some other non-hematologic toxicities include non-melanoma skin cancers and opportunistic infections, things like viral reactivation, fungal infections, so those are really important to keep in mind.

One clinical pearl I want to talk with you all about, Jill and Kate, is a really important one for JAK inhibitors and myelofibrosis, and that is the withdrawal syndrome. So this is a lesson we learned early on from early clinical trials. And while it wasn't reported in COMFORT-1 and COMFORT-2, it was reported in the literature that same year back in 2011. And the withdrawal syndrome is characterized by a rebound increase in splenomegaly, return of cytopenias, and a rapid return in these constitutional symptoms that patients experience. And sometimes even those withdrawal symptoms ended up leading to hospitalization or were even fatal events.

So I think the number one lesson for this syndrome, this withdrawal phenomenon, is to educate our patients on what it looks like, why it's so important, and how important it is to refill their medication on time, call us in advance if you're going to run out, make sure you bring your medication with you when you travel. This withdrawal syndrome can occur as quickly as 24 hours off medication, so I know it's really something we try to educate our patients on.

Kate, do you have any experience in your clinical practice preventing the withdrawal syndrome or managing patients that might be experiencing withdrawal symptoms?

Kate Kennedy: Yeah, actually recently we had a patient who we were titrating off of their JAK inhibitor for surgery, and while we tapered slowly, she still had rebound symptoms and wound up with really massive splenomegaly. So her spleen grew from something like 22 cm to 29 cm or thereabouts in about a week and a half or so as we tapered down. So obviously lots of pain with that. We did try and prevent that with steroids, but unfortunately it didn't... I mean, I don't know how bad it would've been without steroids, but unfortunately didn't completely stop it. We managed that. We wound up, once we were able to restart the JAK inhibition, we restarted the JAK inhibition, and then we used narcotics or opioids. I think she wound up on Dilaudid specifically and dexamethasone to help with that capsular pain.

Sarah Profitt: Wow. Thank you. Jill, anything to add? Have you also used steroids or other kind tapering strategies in your practice?

Jill O'Brien: Yes, we do a similar practice of if they have to come off of their ruxolitinib for one reason or the other, we taper them off. And then just utilizing steroids as well, that's also one of the older treatments back in the day, so you can hopefully never go wrong with steroids in one of these instances.

Sarah Profitt: Absolutely. Thank you all.

So we're going to shift next to our second FDA approved JAK inhibitor called fedratinib. This is a multi-kinase inhibitor but it has increased selectivity for JAK2 in particular. It was FDA approved several years later in 2019 for intermediate- and high-risk myelofibrosis based on two major clinical trials, JAKARTA1, JAKARTA2, and the FREEDOM study. And similar to COMFORT-I, JAKARTA1 was a study comparing the JAK inhibitor, in this case the fedratinib, to placebo. And JAKARTA2 was actually looking at patients who had already had ruxolitinib exposure. So we're starting to investigate the use of JAK inhibitors even if someone has failed or been intolerant to a prior JAK inhibitor, which was really nice to see.

And we see the same clinical endpoints as COMFORT-I and COMFORT-II in spleen volume reduction being primary endpoints in these trials. But in addition to improving spleen volume reduction, fedratinib improved patients' total symptom score, so made patients feel better, improved that health-related quality of life, even in patients who had prior exposure to ruxolitinib.

The most common adverse effects that we see with fedratinib include GI toxicities, so diarrhea was reported upwards of 60% of patients, nausea and vomiting in about half of patients. Albeit low grade, these can still be really significant symptoms that we should educate patients on and make sure we have medications available as needed to treat these toxicities.

Cytopenias are something we see commonly with pretty much all the JAK inhibitors, so anemia and thrombocytopenia were reported with fedratinib as well. Some laboratory abnormalities like elevations in AST, ALT, and lipase also occurred in JAKARTA1 and JAKARTA2. Luckily the most kind of problematic toxicities for patients, those GI toxicities tend to occur early on in treatment and tend to get better over time, so that's an important and hopefully helpful counseling point we can give to our patients.

One severe toxicity or a significant toxicity that actually led to a black box warning in fedratinib's package labeling is Wernicke's encephalopathy. Cases of – even fatal cases of – Wernicke's encephalopathy occurred early on in clinical trials with fedratinib. So we do have recommendations to assess patient's baseline thiamine level prior to even starting treatment, repleting that level if needed before starting, and then even supplementing thiamine while on therapy.

So Jill, in your clinical practice, have you seen patients who require thiamine repletion prior to starting fedratinib? Is that something that you've encountered?

Jill O'Brien: So I've been fortunate that we haven't had any patients that needed thiamine repletion, but definitely before we start fedratinib, we always check their levels. And we actually supplement regardless of what their levels are just to prevent against Wernicke's encephalopathy. I don't know. Have you had this issue of it being low and causing a delay in treatment in your practice?

Kate Kennedy: I don't think we've seen a patient who initially was low on thiamine, which delayed treatment. I think we have seen some patients get low while on treatment, which has led to a similar practice of us just kind of [saying], everybody who goes on fedratinib gets placed on thiamine.

Sarah Profitt: Awesome, thanks. Let's switch gears. Next, let's talk about our next JAK inhibitor that was approved in 2022 and that is pacritinib. This medication is also a multi-kinase inhibitor with high selectivity for JAK2, and it's approved for intermediate- to high-risk myelofibrosis in patients with thrombocytopenia, or platelet count less than 50,000. So definitely a niche indication for this medication in the drug class. The FDA approval was based on PERSIST-1 and PERSIST-2, which were both large phase 3 randomized studies, one in JAK inhibitor-naive patients and one compared to best available therapy including ruxolitinib, so a head-to-head comparison, specifically looking at patients that had cytopenias at baseline showing that pacritinib was able to provide durable responses and spleen volume reduction even in patients with low blood counts.

Some common toxicities or adverse effects that are seen with pacritinib are GI toxicity, cardiac events, QTc prolongation, hemorrhage, including post-procedural hemorrhage leading to a recommendation in the package labeling to hold pacritinib prior to any surgeries or invasive procedures. But definitely a niche indication here for patients with baseline thrombocytopenia.

Kate, how helpful has pacritinib's use in patients with thrombocytopenia been for your patients and your practice?

Kate Kennedy: I think it's been hugely helpful. So with ruxolitinib and fedratinib, those have dose reductions based on platelet counts, so we were maybe not able to get the full benefit from the medications as we tapered down on the ruxolitinib to get to a spot where their platelets could handle it. So having this drug available that doesn't necessarily require dose reductions for thrombocytopenia has been extremely helpful.

Sarah Profitt: Awesome, agreed.

Jill O'Brien: Agreed.

Kate Kennedy: Let's move to our last FDA approved drug in the JAK inhibitor class for myelofibrosis and that's momelotinib. This medication was approved in 2023, so relatively recently, for intermediate- to high-risk myelofibrosis in patients with anemia, so definitely another kind of niche area here for patients with baseline cytopenias, in this case, anemia. This improvement in anemia is a specific mechanism that momelotinib has that the other JAK inhibitors don't.

Momelotinib was approved based on another set of very large phase 3 randomized studies, SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM. These studies were comparative in nature, comparing momelotinib to ruxolitinib, to best available therapy, including prior ruxolitinib exposure, and then MOMENTUM comparing momelotinib to another medication that's commonly used to manage anemia and myelofibrosis, and that's danazol. So momelotinib really showed its ability to reduce patients’ total symptom score, decrease the spleen volume, and had that improvement in transfusion rate and transfusion independence, really helping our patients with baseline anemia.

Some common toxicities with momelotinib that were reported were peripheral neuropathy, GI toxicities like diarrhea and nausea, and cytopenias, of course, in this drug class.

Jill, have you used this newest JAK inhibitor momelotinib frequently in your practice for patients with anemia? What has your experience been like with this medication?

Jill O'Brien: Yes, we've had great success with momelotinib for patients, especially if they're on one of the other JAK inhibitors like ruxolitinib that can cause the anemia. You're always concerned if you do decrease it, you may lose some of the symptom improvement that the patients are experiencing with it. So we've had a lot of good success with switching the patient to momelotinib. And they're getting an improvement in their hemoglobin without having to come for transfusion support or anything like that, and they're still getting the symptom management.

Sarah Profitt: That's awesome. Definitely a quality of life satisfier to decrease transfusion burden.

Hey, speaking of switching in between JAK inhibitors, do you have a practice where you taper patients if you're switching directly from one JAK inhibitor to the other, or are you able to just kind of seamlessly transition patients from one to the other?

Kate Kennedy: Our practice is just to transition the patient from one to another unless there is something that requires some washout, like a clinical trial, but otherwise we just switch.

Sarah Profitt: Absolutely. Awesome. I want to touch briefly on another clinical pearl with JAK inhibitors. We just kind of alluded to it a little bit with momelotinib, but cytopenias while on JAK inhibitors are very common and unfortunately something that we have trouble managing in these patients. Specifically, managing anemia is an area that's pretty challenging. We know NCCN has some recommendations for adding luspatercept, or ESAs, or danazol, these adjunctive therapies to manage anemia, but switching JAK inhibitors, like, Jill, you alluded to, is another example of a way that we could manage anemia in these patients.

Anything else to add Jill in terms of managing anemia for patients that are taking JAK inhibitors?

Jill O'Brien: No, I think all of those are practices that we do. Adding luspatercept can help give that extra bump, and while it's still additional time coming into the clinic, those are spaced out every 3 to 4 weeks, so it does still allow for some quality of life for the patients.

Sarah Profitt: Awesome. All right, so lastly, we do want to talk about some future directions. Unfortunately, effective disease-modifying therapies for myelofibrosis outside of a transplant are not a present reality for patients with myelofibrosis, and so we heavily prioritize enrollment in clinical trials so that we can learn more about treating myelofibrosis and hopefully have more effective therapies.

The most common clinical trials or new avenues of therapy that I'm seeing are novel JAK inhibitors with maybe improved symptom profile, less cytopenias, maybe they're more selective kinases. But we also have a lot of exciting novel mechanisms that are being investigated in myelofibrosis, telomerase inhibitors, IMiDs. We have clinical trials with BET inhibitors both as monotherapy and in combination with JAK inhibitors that we already have available to us commercially, Aurora kinase inhibitors, just all these wonderful, exciting new mechanisms that are being studied. And I know we as practitioners treating patients with myelofibrosis, we definitely want to see outcomes improve for our patients.

So this concludes our discussion on JAK inhibitors and myelofibrosis. I'd like to thank Kate and Jill for joining me for this discussion. And for more information and to view our other discussions on myelofibrosis, please visit jadpro.com.