Pankit Vachhani, MD: We have many JAK inhibitors as options to treat in the frontline setting. For patients without thrombocytopenia, the first-line treatment choice of JAK inhibitor is ruxolitinib in the vast majority of cases. However, for those who have serious thrombocytopenia, pacritinib would be the frontline treatment of choice. One may even consider pacritinib in those who have platelets in the 50-to-100-per-mm3 range. In the event of progression, if the patient continues to be in the chronic phase but has evolved into a scenario where their platelet counts have decreased to 100 per mm3 or less, the use of pacritinib in such a situation may allow for a higher JAK inhibitory dose to be given compared with, say, ruxolitinib. This is especially true if one is unable to keep a ruxolitinib dose of 10 mg 2 times a day or more on a sustained basis.

In fact, according to the NCCN [National Comprehensive Cancer Network] Guidelines, pacritinib could be considered in the second-line setting, irrespective of the platelet counts the patient has. Why is it that a JAK inhibitor followed by another JAK inhibitor may work, but we don’t fully understand why? We have some idea that maybe an alternative pathway inhibition, like the ITK pathway inhibition that comes about with pacritinib, may be a way that pacritinib could be working in patients who’ve been previously exposed to a JAK inhibitor. Not to mention the ACVR1 inhibition that pacritinib has been shown to have and that may help with some anemia and amelioration as well.

Fedratinib is another example that one may consider in the second-line setting if not in the first-line setting. Fedratinib would be an option to use in cases where there’s massive splenomegaly and the blood counts are normal or high, which means not too cytopenic. Data from the JAKARTA2 study support its use in such a setting. Some more data from the FREEDOM analysis also support its use.

Finally, momelotinib, which is also a JAK inhibitor and an ACVR1 inhibitor, has been used and shown to have benefits in the second-line setting as well. Its additional anemia benefits are likely coming from ACVR1 inhibition, and patients who were previously transfusion dependent may become transfusion independent and may even have a survival advantage in some cases.

That’s what one would consider for patients in the chronic phase, but what if the patient happens to have progressed to an accelerated or blast phase disease? First, consider transplantation in such cases. Second, if the patient is evolving or has evolved to accelerated or blast phase disease, consider adding azacytidine therapy on top of, say, JAK inhibitor therapy to slow down the progression. In select cases, intensive chemotherapy in blast phase disease may be very reasonable if the patient is eligible for intensive chemotherapy.

Naveen Pemmaraju, MD: One of the great questions of our time in the MPN [myeloproliferative neoplasm] field is the sequencing of therapies. The great news, compared with 10 years ago, is that we have multiple therapies to talk about in myelofibrosis. The problem is that we don’t know the exact scenarios, and every patient is different. One way to think about sequencing is that we have 4 categories to choose from. No. 1 is sequential JAK inhibitor therapy. At the time of this filming, we don’t have a lot of guidance or biomarkers to determine that sequencing, but based on the approvals and available drugs, we have 3 JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. A fourth, momelotinib, is under review. I challenge our field—our research scientists and everyone out there—to determine if there are biomarkers to determine which patient could match with which JAK inhibitor. In the absence of that, it’s clinical decision-making with the patient and the provider, following FDA approvals, NCCN Guidelines, and other approaches. The sequencing of JAK inhibitors has been studied in the case of several JAK inhibitors, so it’s possible.

The No. 2 category in this would be the so-called add-on, or combination, strategies to the JAK inhibitor. Those are in active clinical trials and feature a number of novel agents. You’re already on the JAK inhibitor. You stay on the JAK inhibitor and add the second agent. A third category is a completely novel approach. Now you’re completely off your JAK inhibitor and you’re looking for a clinical trial, with a completely novel agent that’s beyond a JAK inhibitor. There are a lot of expanding trials in that space.

Finally, a fourth category is adjunctive therapies for specific problems the patient is having. For example, with anemia, you either stay on your JAK inhibitor or you come off, and now you’re directing at a specific problem such as anemia. That’s where you have clinical trials for luspatercept and other agents that are aiming to improve the anemia, either in addition to JAK inhibitor, after, or before. These are some of the categories.

I’ll remind everyone that the only curative strategy for myelofibrosis is an allogeneic stem cell transplant. That’s the only curative approach in 2023. Unfortunately, a lot of patients may not be qualified, eligible, or able to go to a transplant center. We have to keep thinking about the sequencing of agents, particularly as we get to multiple lines of therapy, to see how to give benefit to patients in a personalized, rational way but also keep in mind stem cell transplant for the eligible patient.

Transcript edited for clarity.