John Mascarenhas, MD, Icahn School of Medicine at Mount Sinai, New York, New York, shares highlights from a discussion on the utilization and selection of optimal JAK inhibitor therapies for the treatment of patients with myelofibrosis (MF). 

This research was presented at the 2024 Annual Society of Hematologic Oncology (SOHO) meeting in Houston, Texas.

Transcript:

I'm John Mascarenhas from the Icahn School of Medicine at Mount Sinai. Another discussion that occurred at SOHO 2024 in the [myeloproliferative neoplasm] (MPN) space was the utilization and selection of JAK inhibitors in myelofibrosis, which has been a significant contribution to tailoring therapy and personalizing the approach.

Now that we have ruxolitinib, fedratinib, pacritinib, and momelotinib all approved, all share 1 thing in common: they're JAK-2 inhibitors. But, due to differences in the kinome profile, relative sparing of JAK-1 with pacritinib to some extent fedtratinib, as well as FL-3 inhibition with pacritinib and fedratinib explaining some toxicity profile differences like GI toxicity, and then, ACVR1 inhibition that's shared between pacritinib and momelotinib, likely, underlying some of the anemia responses we could see with these 2 drugs. And the fact that pacritinib is the only drug that's an IRAK1 inhibitor, allows for a more tailored approach for the treatment of myelofibrosis.

The treatment, still first and foremost for most patients, could be ruxolitinib. I think the exception to that upfront might be patients with extreme thrombocytopenia platelets below 50,000, or even below 100,000 by the PERSIST-2 study for pacritinib. Or even patients who come in treatment-naive with significant anemia and transfusion dependence one might even consider momelotinib upfront. The phase 3 studies that have provided data all allow for the use of these drugs, particularly in the second-line we can use pacritinib in patients with thrombocytopenia and anemia, and momelotinib in patients, where anemia is a significant issue.

I still think fedratinib is the agent that is often forgotten—approved in 2019 with the ability to have significant benefit on symptom and particularly spleen for those patients on ruxolitinib who have resistant spleen or progressive spleen, fedtratinib should remain one of those drugs to consider particularly in the second-line setting from data from the JAKARTA-2 study. There's a, a lot of data that provides confidence in selecting these drugs. The only drug that has a black box warning is fedratinib with warnings of encephalopathy, so check that vitamin B1 thiamine level and replete as needed.

Be aware that, as I mentioned, fedratinib and pacritinib do have GI toxicity, more so than the other drugs. So antiemetics, it's usually low-grade in the first month or 2, and easy to tolerate and easy to manage. Rarely a reason for discontinuation. I will point out pacritinib may have a higher rate of bleeding tendency, irrespective of the platelet count. So be aware of that and to correct coagulopathies when possible to perhaps [those] avoid with anticoagulation. Don't allow washouts between the drugs. You can really switch these drugs from one day to the next. Follow the patients carefully for their blood counts, and temper expectations. It's unlikely that patients will feel fantastic, or have improvements in their numbers immediately. It can take months in some cases. So tempering expectations, providing supportive care, transfusing as needed, I think is key to success when transitioning from one JAK inhibitor to the other.

As I presented previously, we're also moving into the stage of combination therapies. A study that will likely result in 2025 is going to be the independent study looking at luspatercept, Activin-ligand trap  that's approved for the treatment of lower-risk MDS in myelofibrosis patients on JAK inhibitors wit, anemia might be a nice way of capturing the anemia aspect, while allowing the JAK inhibitor to maintain spleen and symptom benefit.

So as this field moves forward, we'll have to figure out how best to combine some of these novel agents in development. But for the time being, we have 4 very active JAK inhibitors that can really allow for a personalized approach in 2024. Thanks very much.