Taking into account the three JAK inhibitors, ruxolitinib, fedratinib, and pacritinib, experts reflect on the appropriate use of each agent in myelofibrosis.
Stephen T. Oh, MD, PhD: As far as how to choose which of the available JAK inhibitors to use, we have ruxolitinib, which has been available for over a decade; fedratinib, which was approved a couple of years ago; and pacritinib, which was recently approved. We have 3 available JAK inhibitors. They’re similar in that they’re all JAK inhibitors, but they’re also somewhat distinct in certain ways. For instance, fedratinib is a little more specific for JAK2, but it also inhibits FLT3. Because FLT3 is an additional target, this means the drug is associated with some GI [gastrointestinal] adverse effects: nausea, diarrhea, etc. The same is true with pacritinib, which also inhibits JAK2 and FLT3.
In the case of fedratinib, it’s approved for use in myelofibrosis in the first- or second-line setting. But in my experience, it’s particularly positioned as an option after patients have been treated with ruxolitinib. If they have either problem with ruxolitinib or after achieving an initial response to ruxolitinib, if their symptoms or their spleen regrow, choosing fedratinib is particularly appropriate. Pacritinib, [which has just been] recently approved, is a drug that’s unique among the 3 JAK inhibitors that are now available. It doesn’t really cause significant thrombocytopenia, and it has specifically been studied in patients with severe thrombocytopenia with FLT3 count less than 50. That’s where using something like ruxolitinib or fedratinib isn’t feasible because, particularly with ruxolitinib, lowering the platelet count is a problem in terms of achieving an effective dose of ruxolitinib in patients with severe thrombocytopenia. In contrast with that, pacritinib can be used in those patients with very low platelet count. That’s specifically what FDA approval was for: patients with a platelet count of less than 50 per mm3.
Ruben Mesa, MD: The adverse effect profile of each JAK inhibitor is slightly different. With fedratinib, we monitor for cytopenias, for GI adverse effects, and rare issues with Wernicke encephalopathy or thymine deficiency. With ruxolitinib, there can be cytopenia, anemia, or thrombocytopenia, but it’s the main dose-limiting toxicity. There can be increase in liver function tests. There’s an increased risk of nonmelanoma skin cancers, as well as an increase in herpes zoster virus. I frequently will consider for individuals to receive the inactivated shingles vaccine as part of receiving the medication. Similarly, although pacritinib is safe for individuals with thrombocytopenia, cytopenias can still occur, although [that is] less of a factor. There can be GI adverse effects, as there can be with fedratinib, so we’ll typically have patients on an antinausea medicine and antidiarrheals so we can monitor as needed. In the trials, if individuals are thrombocytopenic and have risk of bleeding, we continue to monitor for all that closely, as well as cardiovascular risk. Studies don’t suggest that there’s an incremental risk from the medication, but this tends to be a fairly high-risk group of individuals. Those things need to be monitored carefully.
Transcript edited for clarity.