Ruben Mesa, MD: Fedratinib is a JAK2 inhibitor. It was tested almost in parallel with ruxolitinib and was approved on the basis of the JAKARTA and the JAKARTA-2 studies. In the JAKARTA study, fedratinib was compared against a placebo in 2 different doses of fedratinib, 400 and 500 mg per day. It was [found to be] vastly superior for improving splenomegaly and symptoms compared to placebo. The 400-mg arm had the best blend of efficacy and safety. The agent was found to have some potential GI [gastrointestinal] adverse effects that were largely manageable. There also was a very rare adverse effect, less than 1%, of a decrease in thiamine levels that was potentially associated with Wernicke encephalopathy in a handful of patients. That led to a black box warning.

With fedratinib, when used, it is recommended to check thiamine levels, replace them before initiating if they are low, and monitor both for thiamine levels and for onset of Wernicke encephalopathy. In my practice, thiamine is inexpensive, it’s pretty nontoxic. We certainly measure it and replace it before initiation, but we typically do have patients on thiamine, given that there’s low risk in doing so in a preventive fashion, particularly if they’re older or things of that nature. It’s a good medicine, and it should be a strong consideration for the second line for those who have failed ruxolitinib therapy, but also as a real consideration in frontline therapy, particularly in individuals with a platelet count of 50,000 to 100,000 [per μL] where ruxolitinib may be less active.

Pacritinib is an agent like fedratinib that I’ve been involved with since its earliest days of testing. We noted in the earlier studies that it could be given to individuals irrespective of thrombocytopenia in a safe way. It was tested first in the PERSIST studies, then PAC203 and PACIFICA, and has the unique differentiator that it was able to achieve improvement of splenomegaly and symptoms. It was found over time to have an optimized dose of 200 mg twice a day, now the FDA-approved dose under its trade name of Vonjo, where it could be given fully at that dose for those individuals with improvement in splenomegaly or symptoms. There was a PERSIST-1 trial, which I led, which was pacritinib vs best alternative therapy, and where it was found to be superior, including in people with thrombocytopenia. It can be helpful even if you don’t have thrombocytopenia, but that is its most unique niche.

Then the PERSIST-2 study that my friend and colleague Srdan Verstovsek [MD, PhD,] ran, included individuals with a platelet count of under 100,000 [per μL]. It is FDA-labeled for anyone under 50,000 [per μL] at any point in time. That’s a strong consideration, 200 mg BID [twice daily], improvement in splenomegaly and symptoms. I think it’s a strong consideration for anyone with a platelet count of under 100,000 [per μL]. If an individual has had the other agents and failed, ruxolitinib and/or fedratinib, I think pacritinib still is active in other individuals and could be a consideration as a second- or third-line JAK inhibitor even in the nonthrombocytopenic patients, but it’s most sweet spot is cytopenic myelofibrosis.

Transcript edited for clarity.