Addressing Anemia in Patients With Myelofibrosis
Anemia is a well-recognized complication in patients with myelofibrosis, and it is linked to a poor prognosis. Based on an increased understanding of the pathologic pathways that are associated with anemia, new classes of agents that may demonstrate significant improvement in anemia-related outcomes have been developed and are being evaluated.
Most patients with myelofibrosis will likely eventually develop anemia, including many who will become transfusion dependent, and the presence of anemia is a well-recognized adverse prognostic marker in patients with myelofibrosis. It is incorporated into nearly every prognostic modeling tool that we use.
Established treatment options for anemia in these patients include erythropoiesis-stimulating agents, danazol, and immunomodulatory agents such as thalidomide and lenalidomide. These therapies have demonstrated anemia response rates of 20% to 30% or so, but the responses that are seen are often not durable and may co-occur with drug toxicities. Thus, the effective management of anemia in patients with myelofibrosis remains a substantial unmet need.
We now have 4 JAK inhibitors that are approved by the US Food and Drug Administration (FDA) in this therapeutic area. From the anemia perspective, what is important to understand is that not all JAK inhibitors are created equal. There has been ongoing work to develop JAK inhibitors that might provide splenic symptom benefit but that might also be less myelosuppressive and more likely to stabilize the hemoglobin or even improve the hemoglobin, perhaps even keeping patients out of the transfusion suite. This is where pharmacologic differences might come into play.
Ruxolitinib is a JAK1/2 inhibitor while fedratinib is more of a JAK2 inhibitor that also has activity against FLT3. Both ruxolitinib and fedratinib are associated with drug-induced anemia, thrombocytopenia, and worsening transfusion requirements. Pacritinib inhibits JAK2, spares JAK1, and inhibits FLT3, and it is also an IRAK1 inhibitor. Momelotinib inhibits JAK1/2 and also blocks ACVR1. Mechanistically, both pacritinib and momelotinib exert an ACVR1 inhibitory effect, which is important because this is linked to anemia responses.
ACVR1 inhibition upregulates the expression of genes that control erythropoiesis maturation, leading to improved red blood cell maturation. This process is thought to be mediated by a reduction in hepatocyte hepcidin production. Hepcidin is considered the master regulator of iron availability. These therapies downregulate ACVR1-mediated hepcidin, which can be upregulated in patients with myelofibrosis. This opens up access to iron availability in the bone marrow and iron absorption in the gut, thereby stimulating erythropoiesis.
Momelotinib was the first to demonstrate anemia responses in myelofibrosis, and it was recently approved by the FDA in September 2023 for the treatment of intermediate- or high-risk myelofibrosis in adults with anemia regardless of prior myelofibrosis therapy. The approval was based on the results of the phase 3 MOMENTUM trial, which found that momelotinib significantly improved the primary end point of Myelofibrosis Symptom Assessment Form Total Symptom Score response at week 24 vs those who were randomized to danazol. Momelotinib also met key secondary end points, demonstrating statistically significant responses with respect to constitutional symptoms, splenic response, and transfusion independence.
Pacritinib is FDA approved for the treatment of myelofibrosis and severe thrombocytopenia based on the results of the phase 3 PERSIST-2 trial, which evaluated patients with very advanced disease who had platelet counts of 100 x 103/µL or less. This drug has also demonstrated a substantial anemia benefit in clinical trials, including improved transfusion independence; however, it has not been approved for that indication.
From a patient perspective, an improvement in transfusion independence can have meaningful impacts on the disease burden. Transfusion dependence is burdensome not only for the health care system but also for the patient and for their family members. It takes a day out of their life. Some patients have to go to the Emergency Department and do it in the hospital, and it really reduces quality of life and functionality. It takes patients out of their work and social engagements.
Having said that, ruxolitinib is a great drug. We have had it for more than 10 years. It is very effective in addressing the spleen and symptoms in most patients whom we treat, but it does worsen the anemia. I have never seen it really improve the anemia. And, for some patients, that is an issue because they can get spleen and symptom improvement, but they are still left with a certain degree of anemia or even transfusion dependence.
Finally, there are multiple agents that are in development and are being investigated for use in patients with myelofibrosis-associated anemia. For example, luspatercept has demonstrated efficacy in a phase 2 trial, with a 50% reduction in the transfusion burden and 26.3% of patients achieving transfusion independence when used in combination with ruxolitinib. This agent is currently undergoing further evaluation in the phase 3 INDEPENDENCE trial in patients with myelofibrosis and transfusion-dependent anemia who are receiving concomitant JAK2 inhibitor therapy. And there are new agents that are being developed to target this pathway. For example, DISC-0974 is an antihemojuvelin monoclonal antibody that can be administered as a once-monthly, subcutaneous injection and is designed to suppress hepcidin, which, as mentioned, is a critical driver of anemia.
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