Selecting a JAK Inhibitor Therapy for Patients With Myelofibrosis

At the Society of Hematologic Oncology (SOHO) 2023 Annual Meeting in Houston, Texas, Anthony Hunter, MD, Emory University, Atlanta, Georgia, discusses the process of selecting and properly using a JAK-inhibitor for the treatment of patients with myelofibrosis.

Transcript:

I'm Anthony Hunter, I'm an assistant professor at the Winship Cancer Institute of Emory University, particularly focused in treating myeloproliferative neoplasms (MPN). I presented the talk entitled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis” at the SOHO Conference in 2023 in early September. 

The talk really covered inhibitor use in myelofibrosis. JAK inhibitors have become the mainstay in myelofibrosis therapy, and this is due to the key role that activation and JAK signaling plays in MPNs in general, including myelofibrosis. We spent some time reviewing the data with our available JAK inhibitors. 

Obviously, ruxolitinib has been our most commonly used agent here. It's been approved for over a decade now based on the COMFORT studies, which really shows significant improvements in splenomegaly as well as symptomatology and higher-risk myelofibrosis patients, but certainly does have some data in lower-risk patients as well.

I did discuss some of the challenges with using agents like ruxolitinib as well as fedratinib, which both can lead to quite a bit of myelosuppression including anemia and thrombocytopenia. We do see this relatively early on in the treatment course with these agents, in the first 12 weeks or so, with some improvements in anemia over time, although the thrombocytopenia is generally sustained. So, it can be a challenge, and an important thing to monitor during treatment. But certainly, particularly with ruxolitinib, which is dose-based on platelet counts, certainly the dosing and ultimate titration does impact response rates with this agent. So, important to try to maximize dosing as much as able. 

We do have a number of other agents that recently come out. In fact, momelotinib was actually approved since the talk, a couple of weeks ago here. Pacritinib and momelotinib are 2 of the newest JAK inhibitors that we have available. 

Pacritinib was approved about a year and a half ago now, studied in multiple lines of therapy, but has really been focused for its developments and for the use of patients with more of thrombocytopenia, and was FDA-approved specifically for patients with a platelet count of less than 50. This is due to data during its development, showing it's safe for use in this population, and does cause less myelosuppression as well. So, it was approved specifically in this more difficult to treat population, who have really been hard to treat with JAK inhibitors like fedratinib and ruxolitinib in the past. So, really expanding the benefit of JAK inhibitors in these patients.

We also have momelotinib, which again was just approved in the last 2 weeks or so here. The big improvement or change that we see with momelotinib is that it inhibits a receptor called ACVR1. This is a receptor in the BMP and SMAD signaling pathway, which is an important regulator of hepcidin. This is upregulated in patients with myelofibrosis and contributes to anemia. So, by inhibiting this pathway, we’re really able to overcome some of the iron-restricted erythropoiesis that we see contributing to anemia in myelofibrosis patients.

Momelotinib has been in development for quite a while now and initially studied in the SIMPLIFY-1 and SIMPLIFY-2 studies, both larger randomized phase 3 studies, and then very recently in the MOMENTUM study, which compared it to danazol and JAK-inhibitor-exposed patients, where it did show benefits in symptom improvement, which was a primary endpoint but also in spleen improvement, as well as anemia. So, really targeting the 3 key domains and symptomatology of myelofibrosis patients and anemia constitutional symptoms and splenomegaly. This agent really is adding to our arsenal of JAK inhibitors now, and really, potentially beneficial for these patients who are more anemic at baseline in particular.

Pacritinib has also been recently shown to inhibit this ACVR1 pathway. So, a very good option in a more cytopenic patients that not only has this safety data in thrombocytopenic patients but also has some potential to improve anemia that we see as well looking back in some of these studies. 

The changes we're seeing is that we're moving from having just one option available with ruxolitinib for a long time to now having multiple potential JAK inhibitors that we can pick from. So, we can use these agents and pick from them based on multiple factors from patient comorbidities, in particular, baseline cytopenias.

I think ruxolitinib is still really the standard of care right now in more proliferative disease, patients with higher counts and significant splenomegaly and symptomatology. But certainly, these patients who also have baseline anemia at the time that we’re starting JAK inhibitor use, agents like momelotinib and pacritinib are really becoming emerging options here. Also, certainly pacritinib in our patients with significant thrombocytopenia.

We'll also just add that historically, ruxolitinib usage, duration of therapy has been a lot shorter in clinical practice than what we've seen in clinical trials, like the COMFORT study is really just about a year to a year and a half, than most real world cohorts. Certainly outcomes historically have been quite poor, usually just a little over a year overall survival once patients have failed ruxolitinib, regardless of whether that was due to intolerance or through resistance.

Now, multiple of these agents have shown second-line data after ruxolitinib use. We see that probably some of the best spleen responses with fedratinib in the JAKARTA-2 study with about 30% of patients who did show significant spleen reductions as well as improvement in symptoms. And then certainly both pacritinib and momelotinib have been studied in multiple studies in the second-line setting, as well, and certainly have data here as well. 

So, not only improving our options in the frontline setting, but now multiple options as well with data in the second-line setting for monotherapy JAK inhibitor use, with certainly a number of clinical trials that are ongoing right now, exploring a number of combination therapies and utilizing non-JAK-inhibitor treatments often in combination with the JAK inhibitor as the backbone of that treatment.

Source:

Hunter A. Choosing and Properly Using a JAK Inhibitor in Myelofibrosis. Presented at 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.