Therapy in Myelofibrosis: Fedratinib and Ruxolitinib Strategies
EP: 1.Overview on Essential Thrombocythemia and Polycythemia Vera Management
EP: 2.Role of Symptom Burden in Thrombocythemia and Polycythemia Vera
EP: 3.Novel Therapy in Myelofibrosis: Momelotinib
EP: 4.Therapy in Myelofibrosis: Pacritinib
EP: 5.Myelofibrosis: Nuancing the Potential of Disease Modification
EP: 6.Therapy in Myelofibrosis: Fedratinib and Ruxolitinib Strategies
EP: 7.What is the Role of Transplant in Managing Patients With Myelofibrosis?
EP: 8.Myeloproliferative Neoplasms: Targeting CALR With Novel Therapy
EP: 9.An Expanding Armamentarium in MPNs: Therapeutic Strategies Under Investigation
EP: 10.Sequencing and Managing Combination Therapy in Myeloproliferative Neoplasms
EP: 11.Myeloproliferative Neoplasm Management: Future Directions in Care
Transcript:
Naveen Pemmaraju, MD: We have a couple of other JAK inhibitors to talk about. I’m going to ask Ruben to comment on fedratinib. I’ll talk a little about ruxolitinib, and Dr Palmer is going to talk about the only curative modality so far, which is allogeneic transplant. Ruben, what’s your take on the second improved JAK inhibitor, fedratinib? Give a general overview of that agent. Where does it stand after ASH [American Society of Hematology Annual Meeting]?
Ruben Mesa, MD: First, I’ll put this out there in a provocative way: fedratinib is underutilized. This is a drug that can help patients with myelofibrosis, and I don’t think it’s being prescribed enough. It’s a very good JAK inhibitor. We have good data compared with placebo, as a frontline and second-line therapy for MF [myelofibrosis]. It can have GI [gastrointestinal] adverse effects. It has the same cytopenia profile as ruxolitinib, and we need to be mindful of thiamin when prescribing it. But why is it underutilized? There are patients we’d love to have join a clinical trial, but they’re not because of travel expenses or other things. They have adequate counts but an inadequate response to ruxolitinib. These people are candidates for fedratinib. They might get a good response.
We’re inclined to use our clinical trials because they’re an option. We’re trying to move the field forward, but when the pandemic hit, we did not have that as an option. We put a lot of patients on fedratinib, and responses in the second-line setting were good. It’s a good option that people need to consider. This data at this meeting further reinforce the ability to use it. They were presented by Vikas Gupta. The adverse effects are manageable. There can be GI adverse effects. If you think about every other medicine in MF, other than ruxolitinib, they all have GI adverse effects. If you look at it across the board—the dozen new mechanisms of action, the other JAK inhibitors—everything has some GI adverse effects. It’s relatively easy to consider. With most of them, some amount of supportive antinausea and antidiarrheals are manageable. Where is it a deal killer? With fedratinib that’s the case. But the data from postapproval trials show the ability that it can be managed and that patients can remain on it.
There was sensitivity around Wernicke encephalopathy. If you want to throw a curveball to hematology doctors, give us a toxicity that we’re not used to seeing. Nausea, vomiting, diarrhea, cytopenia? We all yawn. But give us a neurological adverse effect, and we’re scrambling for our old copy of Harrison’s [Principles of Internal Medicine]. What is this again? Thiamin? In the trials, there’s a delayed identification that some patients were having Wernicke. To be honest, as hematologists, people were missing it. The drug has some impact on thiamin metabolism in a small amount; some patients had their thiamin go down, and some had preexisting Wernicke.
The guidance is valid, based on the data at ASH. First, check the thiamin level. You can order [a test] through your lab. It’s simple enough. If it’s low, replace it before the patient starts on fedratinib. This is off-label but simple: you can get a jug of thiamin at CVS for $10. I give everyone thiamin who’s on it—end of story. I check ahead of time to be sure that it’s being adequately replaced, but the mitigation strategy in the abstract has not been an issue. I haven’t heard of any documented case of fedratinib postapproval that it’s been an issue. I don’t want to scare anyone. These are sick patients. They need a second-line therapy, so these patients need real medicines. The thiamin thing can be overcome. It’s underutilized. If you’ve got a patient in clinic, and they’ve got a big spleen, and you’ve got them on 15 mg of ruxolitinib twice a day and they’re not getting better, think about fedratinib.
Naveen Pemmaraju, MD: What a wonderful academic and practical update, Ruben. That’s great. Just to bring the JAK inhibitor discussion home, the original JAK inhibitor is approaching its 10-year anniversary. Ruxolitinib was the first in class. There were a couple of interesting abstracts at ASH. The categories are: JAK inhibitor single-agent, including the newer ones coming; JAK inhibitors in combination—if you have a JAK inhibitor with a suboptimal response, you add in a second drug; and then at the end we’ll discuss some of the novel agents you’re excited about.
In summary, ruxolitinib is being used as the backbone for the combination therapy era, and our colleagues updated the 3 most advanced data sets. In the first 1, pelabresib, bromodomain, or a BET inhibitor, which many of you have worked on, is being combined with ruxolitinib, amazingly in the frontline setting in patients who’ve never seen myelofibrosis therapy before. Dr Joe Scandura showed updated data in our oral session [at ASH], showing not only the continued safety and efficacy but detailed cytokine and inflammatory benefits that this program is giving. I appreciated his discussion because we’re trying to understand deeper this concept of disease modification.
Importantly, that program is actively enrolling in phase 3. This is a manifest phase 2 program that’s now in phase 3, a randomized multicenter study, and we eagerly wait those data. No. 2 is the ruxolitinib plus navitoclax, which is BCL-XL inhibition. Dr [Francesco] Passamonti showed that in the ongoing frontline phase 2 cohort, which is 32 patients, the drug combination is safe and efficacious, and there’s starting to be a suggestion of disease modification. Some anemia improvement…that needs to be tracked over time. This has already moved into large, randomized phase 3 trials, TRANSFORM-1 and TRANSFORM-2 in the frontline and relapse setting. Those data are eagerly awaited.
Finally, Dr Abe [Abdulraheem] Yacoub updated the third advanced data: ruxolitinib with the PI3 kinase inhibitor parsaclisib, showing safety and feasibility of this novel approach. This is heading into phase 3 randomized up-front frontline trials. Dr Palmer, before we go into the transplant discussion, what’s your take on all this? Five years ago we didn’t have any of these clinical trials. What’s your feeling as you see our field rapidly increase?
Jeanne M. Palmer, MD: It’s very exciting to have different drugs that we can offer patients. When I meet with people and give them the long look about what’s going to happen, especially for patients who aren’t transplant candidates, it’s nice to say that there are things coming down the pipeline that could be very helpful. It also brings up some very compelling academic questions. How do we define disease modification? That catch phrase has been used in different talks, but how do we define it? Do we define it as a decrease in the allele burden? Do we define it as a decrease in fibrosis or as changes in blood counts? What does that look like? In multiple discussions, we’ve batted it back and forth. At the end of the day, we need to find that surrogate marker and change that tells us they’re going to live longer. That’s what patients care about. They want to live longer. We’re trying to parse what the specifics are. How do we predict if these agents are going to help somebody survive longer? That’s the next big question, and that’s going to be hard to answer. We have a lot of work to do. It’s very exciting to have that information for patients.
Some of these new drugs are being tested. When Dr Scandora presented his abstract, he had a very new marker to look at. A lot of times, we look at fibrosis and allele burden, but he looked at changes in the morphology suggesting that the megakaryocytes, which historically have been very clustered, become unclustered and dispersed, like in a normal marrow. Is that something that can indicate it? He correlated it along with spleen response and anemia response, so he showed that if these changes occurred, they might be a marker of response. Does that mean somebody is going to live longer down the road? We don’t know. The same thing applies for interferon. We’re getting more mature data with interferon and its usage, primarily in polycythemia vera, showing that long-term benefit is going to be very important. It’s very challenging. When you look at interferon data, which are some of the best we have in terms of long-term data, it takes years to see these changes. To have a clinical trial that runs for that long monitors people for that long, that’s hard to do.
Transcript edited for clarity.
