Newer-Generation JAK Inhibitors Expand Myelofibrosis Treatment Paradigm

Author(s):

Anthony M. Hunter, MD, discusses the roles for pacritinib, momelotinib, and fedratinib in patients with myelofibrosis; treatment sequencing with newer-generation JAK inhibitors after ruxolitinib; and the importance of having several treatment options in the second-line setting and beyond.

Anthony M. Hunter, MD

The growing array of JAK inhibitors available to patients with myelofibrosis underscores the need for personalized treatment decisions in this patient population, which may depend on baseline cytopenias, disease characteristics, and the availability of second-line options for patients who progress on first-line ruxolitinib (Jakafi), according to Anthony M. Hunter, MD.

The pivotal phase 3 PERSIST-2 trial (NCT02055781) showed that 29% patients who received pacritinib (Vonjo) achieved a spleen volume reduction of at least 35% compared with 3% of those who received best available therapy, which included ruxolitinib.¹ Additionally, momelotinib (Ojjaara), which was approved by the FDA in September 2023 for adult patients with intermediate- or high-risk primary or secondary myelofibrosis and anemia, is the newest JAK inhibitor to be approved for patients in this population.²

“Instead of just giving everybody the same treatment no matter what, we have room to pick and choose who will be a better [candidate] for which drug,” Hunter said in an interview with OncLive^® during the 2023 SOHO Annual Meeting.

In the interview, Hunter discussed the roles for pacritinib, momelotinib, and fedratinib (Inrebic) in patients with myelofibrosis; treatment sequencing with newer-generation JAK inhibitors after ruxolitinib; and the importance of having several treatment options in the second-line setting and beyond.

Hunter is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and medical director of the Immediate Care Center at Winship Cancer Institute of Emory University, both in Atlanta, Georgia.

OncLive: What was the goal of your presentation on choosing and properly using JAK inhibitors in myelofibrosis?

Hunter: The goal [of my presentation] was to discuss the historical and emerging data with JAK inhibitors. We’ve had JAK inhibitors around for approximately 12 years, from the first one, ruxolitinib, but now, [we are] starting to see an increase in that arsenal, and our fourth JAK inhibitor, [momelotinib, was] approved [in September 2023].The goal was to review the data with these different JAK inhibitors we have already available or emerging right now; discuss some of the unique differences between them and where they may fit into specific subgroups of patients; and [discuss] the practical standpoints of how to use these drugs in clinical practice.

Considering the number of JAK inhibitors that are available, what factors guide your treatment decisions?

[We consider several factors] right now. One of the biggest factors we see that distinguishes a couple of the different JAK inhibitors is patients who have low blood counts or cytopenias at baseline. Standard patients with more elevated counts, or at least not significant cytopenias, are still using ruxolitinib, and we have fedratinib as well.

However, cytopenic patients who historically have been a tough group to treat with our original JAK inhibitors, now have some emerging options. Pacritinib is for patients with lower platelet counts, platelet counts of less than 50 x 10⁹/L, who have historically been excluded [from treatment with JAK inhibitors]. In addition, [data are] showing that [pacritinib] has the potential [to improve] anemia as well. Additionally, momelotinib, [which was approved by the FDA in September 2023, is] an active agent in the setting of these anemic patients, with the potential to improve outcomes.

One of the biggest factors for choosing between these options is the presence of baseline cytopenias. All [these agents] show good activity in the settings of spleen responses and symptom reductions. [We don’t have a lot of] clear data about which subgroups of patients, aside from cytopenic patients in the front line, we should switch between [JAK inhibitors]. Otherwise, the rest of these [agents] are certainly options still. Then, certainly in the second-line setting, we have data with pacritinib, momelotinib, and fedratinib all having some activity after progression on ruxolitinib.

How might the use of pacritinib expand to benefit patients with higher platelet counts?

The National Comprehensive Cancer Network Guidelines for Myeloproliferative Neoplasms have been updated and have included pacritinib as an option for patients with a platelet count of over 50 x 10⁹/L. In more anemic patients, we see anemia responses with pacritinib, so it has a role in that population. A sometimes tougher group is patients with a platelet count between 50 x 10⁹/L and 100 x 10⁹/L, who are able to use drugs like ruxolitinib or fedratinib.

When we start to see thrombocytopenia develop on treatment, [these agents may] start to hit those low platelet levels as well. It’s hard to maintain continuous and effective dosing with some of these patients. Even in patients with more modest levels of thrombocytopenia, there may be some role for pacritinib.

How are JAK inhibitors currently sequenced after ruxolitinib in the first-line setting?

We have seen with ruxolitinib, in multiple real-world cohorts and clinical trials, that outcomes once patients have progressed on ruxolitinib, whether that be [because of] intolerance or resistance to treatment, are quite poor, with survival in the 12- to 16-month range in most studies. Historically, there have not been great data about how to treat these patients. Studies suggest that novel agents, which have included second-line JAK inhibitors, have shown more promise than conventional agents like hydroxycarbamide. The [phase 3] MOMENTUM [NCT04173494] and SIMPLIFY 2 [NCT02101268] studies with momelotinib, PERSIST-2 and other studies with pacritinib, and the [phase 2] JAKARTA-2 study [NCT01523171] with fedratinib are all clinical trials that investigated these agents in patients who had previously been exposed, or at least included patients who had been exposed, to prior ruxolitinib.

We see activity with all those different agents. More advanced patients potentially get more cytopenias and anemias. Some of these newer agents that are a bit more designed for that patient population may have a bigger role there, but certainly fedratinib has also [been associated with] great data in the second-line setting in this population.

What is your main message for colleagues regarding the use of JAK inhibitors in myelofibrosis?

We have options now. For a long time, we only had 1 agent, for the most part. We’ve now had a couple more approved in the past few years, so we’re starting to get to a point now where we can pick and choose a little. We can match [treatments] to clinical features, like cytopenias, potentially, as well as comorbidities and other disease- or non-disease–related aspects that will give us more leeway to treat patients more effectively in a more personalized approach. Also, [there is the] potential to sequence these options, so we have more effective options for patients who progress on first-line treatment.