Although the number of agents available to treat myelofibrosis has increased in recent years, many patients continue to have a substantial disease burden. Work is being done to both build upon existing treatment regimens and evaluate novel agents that modify the disease trajectory in hopes of improving long-term outcomes for individual patients with myelofibrosis.

In the hope of modifying the patient’s disease trajectory, I think that we tend to focus on epiphenomena that may or may not be related to disease modification, and bone marrow fibrosis in myelofibrosis is a key example. But, to me, the meaningful and functional definition of a disease-modifying agent is an agent that allows the patient to live a close-to-normal life span with minimal symptoms or cytopenias.

JAK inhibitors may have an effect on survival in patients with myelofibrosis based on the results of several studies, and this effect on survival partially meets the criteria for disease modification. Momelotinib and pacritinib can certainly help with anemia. So, we have agents that I think fall under the umbrella of disease-modifying therapies, but, for the majority of patients with myelofibrosis, we currently lack drugs that fit all the criteria for disease modification. I think something that we as a field have to be careful of is that trials are often read out at 6 months. However, the meaningful data with regard to disease modification are really going to be the long-term data showing the overall impact on the risk of disease progression and survival, which take years to read out.

Agents such as JAK inhibitors may help some patients with myelofibrosis have a good quality of life, but, for other individuals, they do not provide a long-term benefit and are not curative. Available data suggest that patients with intermediate- to high-risk myelofibrosis will benefit the most from a transplant. Nico Gagelmann, MD, et al put together different models to try to better delineate which patients should receive a transplant and at what time, and these data were presented at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition. I think something that individuals in the field have to think about is when to prioritize a transplant. Is it at the time of best response? Is it early in the disease, or perhaps even prior to a patient being on a JAK inhibitor or other therapy?

There are exciting mechanism-based agents in clinical trials that are showing early evidence of activity. For example, the combination of pelabresib and ruxolitinib is being evaluated vs ruxolitinib alone in the phase 3 MANIFEST-2 trial, and, in a presentation at ASH 2023, we reported that this regimen showed clinical activity. An updated trial readout at ASH 2024 showed a deepening of response over time with the combination, which I think is encouraging.

We also have some newer agents that have emerged, such as the PIM1 kinase nuvisertib, which is showing activity in a phase 1/2 clinical trial, and this is exciting for a single-agent, non–JAK inhibitor. I think that the same thing is true of navtemadlin, an MDM2 inhibitor for which there are strong preclinical data. For example, data were presented at ASH 2024 showing some strong clinical activity of the drug in the phase 3 BOREAS trial. Selinexor is also in a phase 3 trial, and data from the phase 1/3 XPORT-MF-034 trial evaluating selinexor in combination with ruxolitinib that were previously reported at ASH 2023 also showed clinical activity. Other exciting agents in development include newer selective JAK2 inhibitors. So, I think that there are reasons to be optimistic about the direction the field is heading.