Treatment Options for Patients with Myelofibrosis: Pacritinib, Fedratinib, and Ruxolitinib


Stephen Oh, MD, PhD, gives a comprehensive review of the available treatment options for myelofibrosis.


Stephen Oh, MD, PhD: [As far as] currently approved therapies for myelofibrosis, we can take these agents one by one. First let's talk about pacritinib. Pacritinib is a JAK2, IRAK1, and now recognized to be an ACVR1 inhibitor. This drug is currently FDA approved for patients with myelofibrosis for initial treatment with platelet count less than 50,000. This approval is based on data from the PERSIST-2 study, as well as the other studies conducted with pacritinib, clearly demonstrating activity for pacritinib in terms of spleen response. And now, as presented at ASH, anemia benefits and in particular, patients with low platelets. It seems to have relatively minimal negative impact on the platelet count, and that is why it can be used safely in patients with platelet count less than 50,000. This is where the approval is, and where it would be appropriate to use as a first-line agent. But keep in mind that in the second-line setting, it is a relevant choice for a patient who has already been treated with one prior JAK inhibitor with any platelet count. Here in that sense, it could have activity and it could be useful when another agent has already been tried.

The data that we presented at ASH this year reinforced that pacritinib does provide anemia benefit, and the mechanism of that is thought now to be primarily related to ACVR1 and a production of hepcidin. That link was solidified and presented in conjunction with further analysis of the PERSIST-2 data showing that pacritinib does provide transfusion independence benefit in a way that is clearly superior to, from that study, patients who were in the best available therapy arm. This now becomes more of a consideration as to the potential use of pacritinib in patients with anemia.

Turning now to fedratinib, fedratinib is primarily a JAK2 and FLT3 inhibitor. It does have some modest activity against JAK1, but primarily JAK2 and FLT3. This drug has been approved now for a couple of years based on the JAKARTA studies, and it can be used in the first- or second-line setting. But in my view, its primary role is in the second-line setting for patients who have been previously treated with ruxolitinib or another JAK inhibitor. The data to support that are strong, that it could be a viable option specifically in the second-line setting after patients have been previously treated with ruxolitinib, with the goal of achieving symptom and spleen response in such patients.

In the first-line setting, the question is whether fedratinib has any distinction as a choice vs ruxolitinib. The drugs are certainly not identical, but it's not entirely clear that there is a specific justification or rationale or setting for where fedratinib would be a superior choice in the first-line setting. There is some emerging analysis that suggests that fedratinib does not cause weight gain, and this is something that certainly occurs with ruxolitinib.

Let's turn to the third approved JAK inhibitor, ruxolitinib. This drug, of course, was the first JAK inhibitor to be approved, based on the 2 phase 3 randomized COMFORT studies. The data from those 2 studies in which patients were randomized to ruxolitinib vs either placebo or best available therapy quite clearly demonstrated superior spleen and symptom benefit with ruxolitinib in those 2 settings. For that reason, ruxolitinib for many years now has been the standard of care for initial treatment for patients with myelofibrosis, and we know that we can expect symptom and spleen benefit. In other words, patients feel better when they're on treatment with ruxolitinib. For many years, that has been the only option. And while we have used it extensively, now we have the option of 2 other JAK inhibitors, as I outlined, and we can choose another JAK inhibitor when appropriate. While in previous times we might have stuck with ruxolitinib for patients who are having progressive cytopenias and platelet count, thrombocytopenia, now we have pacritinib in that setting. And also, a consideration of anemia as outlined before with regard to pacritinib.

Transcript edited for clarity.

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