Since the US Food and Drug Administration (FDA) approval of ruxolitinib for the treatment of myelofibrosis approximately 10 years ago, several additional agents have become available. There are differences among these agents that may aid in the individualization of therapy based on patient-specific criteria. Further trials and clinical experience are needed to solidify disease- and patient-related factors that can be used to individualize treatment selection.

Now that momelotinib has been FDA approved, there are currently 4 JAK inhibitors that are available for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib. Ruxolitinib has been FDA approved for more than 10 years, so there is familiarity with its toxicity profile, and physicians are comfortable using this medicine. For now, it is the go-to therapy for previously untreated patients, unless there is a compelling reason not to use it, such as in moderate to severe thrombocytopenia or anemia. In the absence of cytopenias, ruxolitinib is standard of care for patients prior to allogeneic stem cell transplant, and in the transplant-ineligible setting.

The ruxolitinib package insert states that the drug is indicated for intermediate- or high-risk myelofibrosis, but as it improves symptomology and may suppress the malignant clone more effectively in less evolved disease, I tend to be more aggressive with the initiation of therapy, even in Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) lower-risk patients, especially, if they have higher-risk mutations (eg, ASXL1) not measured by DIPSS/DIPSS-Plus. Conceptually, the idea is to reduce clonal burden, and this is hard to prove in clinical trials that are targeting higher-risk, more genetically evolved myelofibrosis, such as the COMFORT trials. In early-stage myeloproliferative neoplasms, which are more commonly driven by single aberrations in the JAK/STAT pathway, we may start to see this earlier. And, while there is a natural selection bias when retrospectively analyzing long-term patients from early ruxolitinib studies, there are reductions in clonal burden in patients who are on therapy for long periods of time.

The treatment of patients with an inadequate response to ruxolitinib is an interesting issue. There are very few patients who truly abjectly fail ruxolitinib, but there may be patients who demonstrate less than an International Working Group-Myeloproliferative Neoplasms Research and Treatment response. I tell patients that myelofibrosis is akin to being in a stagecoach pulled by a team of horses that can start to gallop out of control. In this analogy, adding ruxolitinib is like putting reins on the horses, which allows better control moving forward. When the drug ultimately begins to lose effectiveness, the reins start to break, and you lose control of some of the horses. However, it is usually not the case that you lose all the reins, and increased dosing, or, in this analogy, reining in, is often better than abandoning the reins altogether. That is why it is difficult to do studies of second-line treatment after partial, but inadequate, response to ruxolitinib—it is not a binary success vs failure. Given that it is a continuum, it can be difficult to remove ruxolitinib, even after loss of International Working Group response, but the arrival of more FDA-approved options does change this calculus.

For patients with low platelet counts, I had previously tended to use ruxolitinib as first-line treatment, and, if thrombocytopenia is mild, I may still do this if I can deliver an effective dose safely. When the platelets drop closer to 50,000, I usually use pacritinib. We have clinical trial data and considerable post-approval experience showing that pacritinib increases platelets, and, as we gain more and more clinical experience with this agent, we will get a clearer answer regarding the best thresholds for use.

For some patients with mild or moderate anemia, one may be able to use ruxolitinib successfully. For other patients with less reserve and more severe anemia, ruxolitinib is not the right choice for newly diagnosed patients. In a situation in which a significant drop of hemoglobin while on ruxolitinib could lead to vascular insufficiency, pacritinib or momelotinib are superior choices. Both pacritinib and momelotinib effectively and potently inhibit ACVR1, thus stimulating erythropoiesis by suppressing hepcidin. Thus, while there are both scientific rationale and clinical evidence that pacritinib may also increase hemoglobin in patients with anemia, momelotinib has been tested more rigorously as an agent to address anemia. As we get more clinical experience with momelotinib and pacritinib in the real world, we will get a better sense of which patients will use ruxolitinib as first-line therapy (eg, patients with only mild anemia) vs the group of patients with less reserve who might be candidates for first-line JAK inhibitor therapy that includes ACVR1 inhibition.