There have been significant improvements in the management of myelofibrosis with the availability of therapies that can improve symptoms and certain complications, such as anemia. Advances in our understanding of molecular genetics are also allowing us to identify patients with a higher risk of developing aggressive disease, and such information is helping with the development of targeted therapies.

At a high level, the unmet need in the management of myelofibrosis is the lack of a curative therapy to deplete malignant stem cells. Current therapies are good at shrinking the spleen and alleviating symptoms, but they do not prevent disease progression or produce a functional cure. The fundamental goal is to allow patients to live the longest life possible, free of symptom burden as much as possible. Our current therapies are adequate in this regard, but we need to continue building off of them.

The development of cytopenias is not inevitable for patients with myelofibrosis, but it is certainly a major part of the disease process. Myelofibrosis itself can cause progressive cytopenias, and the therapies that we give, such as JAK inhibitors, can also cause cytopenias. Of course, these things are not mutually exclusive, and both can contribute, which can lead to a challenging additive effect. Fortunately, we have therapies, including JAK inhibitors, that seem to alleviate anemia in a proportion of patients. We also have luspatercept, which is US Food and Drug Administration (FDA) approved for the treatment of anemia in patients with myelodysplastic syndromes, and it has shown some efficacy in treating anemia among patients with myelofibrosis. Unfortunately, these therapies do not work in the majority of patients, so there is still much work to be done. For those who develop thrombocytopenia, therapies such as pacritinib may be helpful, but, again, there is a significant need for additional tools.

One area where we have barely scratched the surface is sorting patients for their risk of progression and their risk of becoming resistant to therapy based on their molecular status. These outcomes may be molecularly driven, and some mutation profiles can identify patients who are more likely to have aggressive disease progression. For the most part, however, we do not conduct clinical trials based on this information. Rather, we put all the patients into 1 pot to evaluate outcomes, so this is an area where we need to evolve in the field. I think that we should be designing trials to evaluate patients with very high-risk disease that is molecularly defined.

It is important to keep in mind that a patient’s molecular status can shift over time. We often do somatic mutation sequencing in the initial workup, but we should be advocating for somatic sequencing on a serial basis. That could give us more information about the risk of disease progression and could potentially allow us to predict when the disease is going in that direction sooner.

Finally, a greater understanding of the molecular characteristics of myelofibrosis has allowed us to begin exploiting genetic alterations. A key example is IDH2 mutations, which confer a worse prognosis for patients with myelofibrosis and are targetable by an FDA-approved drug. The Myeloproliferative Neoplasm Research Consortium recently completed a trial combining a JAK inhibitor plus an IDH2 inhibitor in patients with IDH2-mutated myeloproliferative neoplasms. Although we do not have a lot of targeted therapies for other myelofibrosis-related mutations yet, there are some promising candidates, and this type of approach is where we need to go as a field.