New JAK Inhibitors in Myelofibrosis Treatment

Video

Experts discuss data on the recently approved agents fedratinib and pacritinib for myelofibrosis treatment.

Rami Komrokji, MD: There’s no doubt that ruxolitinib was transformative for our patients. It’s still a mainstay in treatment for many patients, especially upfront, but there are areas of unmet need in patients who are cytopenic. Ruxolitinib failure is still an issue for a lot of our patients. Recently it was exciting for our patients that there were 2 new drugs approved: fedratinib, with an interesting comeback, and pacritinib, for which Ruben and I did the phase 1 probably 10 years ago. It took the drug a while to get approved, but it finally is. Ruben, can you walk us through fedratinib and pacritinib and where you see their role now that they’re available for our patients?

Ruben Mesa, MD: Sure. It’s good that we have more options, and exciting that we now have 3 approved drugs in myelofibrosis [MF]. In the…community, we haven’t had an opportunity to use either of these. Let me share a little about what we think about each of them. First, fedratinib is a very good JAK inhibitor—JAK2, FLT-3—approved from the JAKARTA (NCT01437787) and JAKARTA-2 (NCT01523171) studies. JAKARTA studied it front line, and JAKARTA-2 in second line vs placebo in the front line. It was a study almost parallel with the COMFORT study. It’s clearly superior to placebo for improving the spleen and symptoms, and as far as adverse effects, it didn’t cause cytopenias.

The approval of the drug was delayed because there was a very low rate of Wernicke encephalopathy, probably interfering with thiamine metabolism to a small degree. There’s a black box warning that sounds pretty scary but in practice is fairly simple. You check thiamine levels and you replace thiamine, and thiamine is dirt cheap. I give patients a bottle. Then you monitor for Wernicke. That’s pretty small. The more likely adverse effects can be GI [gastrointestinal]. I give some folks some antinausea, some antidiarrhea medications. They can take it. It’s very helpful in the second line.

If they used ruxolitinib and still have [an enlarged] spleen and symptoms, and you don’t have a trial available, fedratinib is a good option. It can be used at full dose in patients with platelets between 50,000 and 100,000 per mm3. I helped present some of those data. It’s a very solid option, with a couple of those small caveats. It was approved in fall of 2019 just before the pandemic, so folks still have less familiarity with it.

Much more recently, pacritinib has a long history. We noticed early on when we did that phase 1—back when it called SB1518—that you could use it irrespective of platelet count. You could use it in marked thrombocytopenia. Over time, a mechanism was found explaining why that could be the case. It inhibits IRAK1. It might be better for patients with cytopenic MF. In critical studies, it could be used safely and effectively in individuals with platelet counts of less than 50,000 per mm3. It’s approved for individuals with marked thrombocytopenia in the front line and second line. It might also help to improve anemia.

It has been approved since February 2022. It’s a good option. It will be used either up front or more frequently in the second line to be that thrombocytopenic. It’s already being woven into the NCCN [National Comprehensive Cancer Network] Guidelines in a group that didn’t have an option before. It will be well positioned for combination strategies. Many of the drugs that have different mechanisms of action also tend to cause thrombocytopenia, so it might be a very nice adjunct for that.

People sometimes say: “Myelofibrosis isn’t that common. Can we have all these drugs?” Yes. The more options we have, the better. These drugs will end up having ranges of use in a range of diseases, including anti-inflammatory diseases, cutaneous diseases, and rheumatologic diseases. You don’t have to worry about the drug not having enough patients. But even though myelofibrosis isn’t common, it can be pretty heterogenous. We have MPN [myeloproliferative neoplasm] and MDS [myelodysplastic syndromes] overlap. We’ve got patients with ET [essential thrombocythemia] and PV [polycythemia vera]. The more options we have, the better.

Rami Komrokji, MD: I absolutely agree. Cytopenic MF is a challenging disease. As you alluded to, most of the time we deal with it later in the course of the disease as a natural history of progression. But there’s a subset of up to 20% of those patients, even upfront, that has limited the use of ruxolitinib in that setting. To your point also, we’ve been exploring those drugs in other diseases. We have ongoing trials in CMML [chronic myelomonocytic leukemia] with JAK2 inhibitors and other types of MDS and MPN. It’s always exciting to have more options that fill different gaps of unmet need for our patients.

Jeanne Palmer, MD: We also know that the role of JAK inhibitors prior to transplant can be very beneficial. It has been studied being used 2 months before transplant up until the time of transplant, and even through transplant up until engraftment or day 30. There’s even 1 study looking at it for 1 year. Additionally, after transplant, these drugs can treat graft-vs-host disease. In some of the studies, there are prophylactic studies using JAK inhibitors for all patients. But it’s a gray area for patients who have myelofibrosis who have been on them, because the worst thing you can do is taper them off their JAK inhibitor right before transplant. That causes them to flare up and have lots of transplant complications.

Rami Komrokji, MD: Before the JAK inhibitor era, we couldn’t take many patients to transplant because of how much they were deconditioned. We used to even talk sometimes about doing splenectomy before transplant. Now, when those drugs work, the patient’s performance improves and their spleen shrinks, so it’s good preparation for the transplant. But to your point, even at our institution, we have a protocol where we don’t stop those drugs. You keep [patients on them] until the transplant because patients will have a quick rebound of their symptoms.

Transcript edited for clarity.

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