Novel Targets Beyond the JAK-STAT Pathway Aim to Push Myelofibrosis Treatment Forward

Anthony M. Hunter, MD

Ongoing research in myelofibrosis continues to focus on agents directed at novel targets with the hope of expanding treatment options beyond the host of JAK inhibitors used in this treatment paradigm, according to Anthony M. Hunter, MD.

“[There are] a lot of novel agents on the horizon [that could] work in combination with JAK inhibitors to hopefully continue to move that bar forward for patients [with myelofibrosis,” said Hunter, who is an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and the medical director of the Immediate Care Center at Winship Cancer Institute of Emory University in Atlanta, Georgia.

In an interview with OncLive^®, Hunter explained the evolving understanding of the biology of myelofibrosis, detailed the growth of JAK inhibitors being used for the treatment of these patients, and expanded on novel targets and agents currently being tested in clinical trials.

OncLive: How has our understanding of the pathology of myelofibrosis evolved in recent years as more research studies have been conducted?

Hunter: What has been well documented for years now is that the key biologic pathway or cell-signaling pathway actually involved in myeloproliferative neoplasms [MPN] or myelofibrosis is the JAK-STAT pathway. That [understanding] was advanced in 2005 when we found out about the JAK2 mutation in a large percentage of these patients, [and we] subsequently [found out about] the MPL and CALR mutations, as well. We find that in all patients with MPN or myelofibrosis, irrespective of those mutations, we see activation of this JAK-STAT signaling pathway, which has a lot of different effects and we can break those up into effects on hematopoiesis, or how they affect sort of blood cell production.

Then we also see increases in inflammatory cytokine signaling. The JAK/STAT pathway signals through a lot of cytokine and inflammatory receptors, so we see a lot of inflammatory signaling increase in a number of different cytokine levels and in myelofibrosis, which impacts the disease and the symptoms that we see. That has been key to [understanding] the biology [of myelofibrosis] and has led to the development of JAK inhibitors.

We've started to move beyond [the JAK-STAT] pathway a little bit, as well. A lot of the research now and new agents that are being explored in clinical trials are largely looking at non–JAK inhibitor agents, combining other pathways such as BET inhibitors, various other signaling molecules, and anti-fibrotic type compounds. All of those have additional roles, along with the JAK-STAT pathway in myelofibrosis.

What are the challenges and complications associated with cytopenias in patients with myelofibrosis, especially those treated with ruxolitinib? What are the current strategies to manage or mitigate cytopenias?

Ruxolitinib has been available for over a decade now, and it is a very effective drug at improving symptomatology and splenomegaly; however, one of the biggest limitations, especially in routine clinical practice, is cytopenias. We do see a reasonable drop in both hemoglobin and platelet counts in the majority of patients treated with ruxolitinib. Often that hemoglobin will drop up to about 1.5 g in the first 8 to 12 weeks or so, and then stabilize and get slightly better thereafter. However, there is usually some persistent drug-related anemia and a dose-dependent decrease in platelet counts as well in patients treated with ruxolitinib. This can be impactful.

We now think about myelofibrosis in two phenotypes. Patients with a more proliferative phenotype with more splenomegaly and elevated counts, and patients with more cytopenic myelofibrosis, especially those patients with baseline cytopenias. When we're worsening those [cytopenias], it does complicate treatment.

Especially in community practice and real-world studies, we see that cytopenias lead to a lot of dose reductions and a lot of early cessations of therapy, all of which [impact] outcomes and survival in these patients. We know that anemia in myelofibrosis is a big prognostic factor, but drug-related anemia from ruxolitinib doesn't impact survival. Historically, we've tried to power through and support patients, think about adding agents like erythropoiesis-stimulating agents and other anemia-directed agents. [There have] been some studies looking at different dosing strategies for these patients. We start anemic patients more at a dose of 10 mg twice daily, irrespective of their platelet count, and we try to titrate up over time based on their counts. We have various strategies that we have used historically in ruxolitinib-treated patients, but we have tried as best as we can to try to treat through those [cytopenias].

That is changing now with some of the newer JAK inhibitors that we have, thankfully, and we do have more options now. One of the big things that separates out how we use these different JAK inhibitors is the cytopenias that we see. Although we see a lot of drug-related anemia and thrombocytopenia in both ruxolitinib and fedratinib [Inrebic], our newer agents, pacritinib [Vonjo] and momelotinib [Ojjaara], are potentially much more beneficial in these patients with cytopenias, especially those with cytopenias at baseline. We see pacritinib specifically FDA approved for patients with a platelet count of less than 50 × 10⁹/L. Although momelotinib is specifically approved for patients with myelofibrosis with anemia, that degree of anemia is not specified in the FDA label, so [that anemia level] is somewhat debated in practice.

Both [pacritinib and momelotinib] target the ACVR1 pathway, so you see not only less drug-related anemia but true anemia responses, even achievement of transfusion independence in some patients. [These agents] tend to have less of a suppressive effect on platelet counts as well, and nonetheless, they are at least safer in these patients with thrombocytopenias. A lot has changed recently, with more benefit for these patients with cytopenias. We are able to tailor therapy and pick between options that may be best suited to a patient and their features, with cytopenias being a key factor in how we choose between these drugs right now.

Are there any new targets beyond the JAK-STAT pathway that particularly intrigue you?

There are a lot of exciting agents out there right now. We're already excited that we've got four JAK inhibitors to pick from now; however, now [we are] moving beyond that pathway, which is great to try to improve outcomes. We know JAK inhibitors do have their limitations.

The two [novel agents] that have had the most press recently are pelabresib [CPI-0610], which is a BET inhibitor, [in addition to] navitoclax, an inhibitor of BCL2 and BCLXL. [Data from] randomized, phase 3 studies with the agents in combination with ruxolitinib—[the MANIFEST-2 trial (NCT04603495) for pelabresib and the TRANSFORM-1 study (NCT04472598) for navitoclax]—at the 2023 ASH Annual Meeting. Both of these studies did meet their primary end point of spleen volume reduction, although we didn't necessarily see significant improvements in symptomatology. Therefore, more data and longer-term follow-up [will be] needed for some of these agents.

In particular, the BET inhibitors are perhaps a little bit more promising. We do see some anemia benefits from MANIFEST-2 and in prior studies with that agent. A couple of other BET inhibitors that are also in earlier-phase studies [have also shown] some early activity. The BET pathway is an important one, potentially.

Other agents have looked promising thus far. We saw [data from a phase 1/2 trial (NCT04176198) for] a new PIM1 kinase inhibitor [TP-3654] that were presented at ASH. That was early data, but the agent seemed to have not much of an effect on platelet count, which is great, because with a lot of these combination agents—both the BET inhibitors and the navitoclax—we do see some significant thrombocytopenia. The PIM1 kinase inhibitor showed some early promising data at ASH.

There is another phase 3 study ongoing—[the IMpactMF trial (NCT04576156)]—with imetelstat, which is a novel agent that inhibits telomerase. This [agent] has shown some promising phase 1/2 data and is now in a randomized phase 3 study. Importantly, [this is] the first study in a long time to look at overall survival in patients [with myelofibrosis] as a primary end point, and [those end points] are not strictly spleen and symptom responses.

These are all promising agents out there, and there are many more. We have bomedemstat (IMG-7289), an LSD1 inhibitor, showing a lot of activity in multiple MPN disease states in early clinical trials. There are a number of other agents targeting the fibrotic pathway and other things.

Given the ongoing research, how do you see the myelofibrosis treatment paradigm continuing to evolve?

Myelofibrosis treatment is starting to evolve quite a bit. [Although current treatment] predominantly features JAK inhibitors right now, as opposed to having just one agent [used for all patients with myelofibrosis], we have a lot more room to tailor therapy and pick the right treatment for patients [without needing] to power through things like anemia. Tailored treatments may help a little bit with cytopenias, as well.

Most of these agents have demonstrated efficacy in the second-line setting after ruxolitinib failure or intolerance. Historically, that's a space that has poor outcomes. Now we have room to tailor treatment in the first-line setting and sequence these agents to [hopefully] improve outcomes for these patients [in the second line and beyond].