Clinical Pearls & Morning Reports

Posted by Carla Rothaus, MD

Published February 21, 2024


Was rusfertide an effective therapy for polycythemia vera in this trial?

Kremyanskaya et al. conducted a phase 2 trial to evaluate the safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera. Read the NEJM Original Article here.

Clinical Pearls

Q: Describe some of the features of polycythemia vera.

A: Polycythemia vera is a myeloproliferative neoplasm that is characterized by erythrocytosis and variable increases in leukocyte and platelet counts. Most patients with polycythemia vera have a constitutively activating somatic mutation in JAK2, which leads to the overproduction of terminally differentiated hematopoietic cells. The incidence of thromboembolic events is higher among patients with polycythemia vera than among persons without polycythemia vera — a finding that has primarily been attributed to erythrocytosis, although some trials have suggested that leukocytosis, thrombocytosis, or both could also be important risk factors. Polycythemia vera is accompanied by systemic symptoms, including pruritus, night sweats, difficulty concentrating, and fatigue.

Q: What therapeutic options are available to treat polycythemia vera?

A: The therapeutic approach in polycythemia vera is to reduce the risk of thromboembolic events by maintaining a hematocrit of less than 45%. Current treatments for polycythemia vera are based on a risk assessment for thrombosis and include aspirin and phlebotomy in low-risk patients and the addition of cytoreductive agents, such as hydroxyurea, ruxolitinib, and interferon alfa, in high-risk patients (those who are ≥60 years old, had previous thrombosis, or both). Rusfertide is an injectable, peptide hepcidin–mimetic compound with a mechanism of action similar to that of endogenous hepcidin.

Morning Report Questions

Q: Why might a hepcidin mimetic be an effective treatment for polycythemia vera?

A: Hepcidin, a peptide hormone produced in the liver, is a master regulator of iron trafficking and is up-regulated by circulating iron levels and inflammatory cytokines and down-regulated by bone marrow erythroid hyperplasia. Hepcidin binds to ferroportin, which blocks the export of intracellular iron to the blood and leads to reduced levels of serum iron and transferrin saturation. Reduced export of iron results in functional iron deficiency and decreased erythropoiesis. Preclinical models suggest that increasing the hepcidin activity in patients with polycythemia vera could be effective in controlling erythrocytosis and might alleviate symptoms.

Q: Was rusfertide an effective therapy for polycythemia vera in this trial?

A: Part 1 of the trial was a 28-week, open-label, dose-finding period (baseline to week 29) in which rusfertide was added to the patient’s ongoing therapy (phlebotomy alone or cytoreductive therapy with supplemental phlebotomy). Rusfertide was administered subcutaneously weekly, and the dose was adjusted to maintain a hematocrit of less than 45%. Part 2 was a 12-week, double-blind, randomized withdrawal period (weeks 29 to 41) in which patients were assigned, in a 1:1 ratio, to receive rusfertide or placebo. The primary efficacy end point was a response during the randomized withdrawal period. Patients were considered to have had a response if they had hematocrit control, did not undergo phlebotomy, and completed the 12-week trial regimen during part 2. In the trial, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. A response occurred in 60% of the patients in the rusfertide group and in 17% of those in the placebo group (P=0.002). In part 1, rusfertide treatment was associated with a lower severity of disease-related symptoms, which included fatigue, early satiety, night sweats, problems with concentration, inactivity, and itching, in patients with moderate or severe symptoms at baseline.

Browse more Clinical Pearls & Morning Reports »