Advances in PV Management Increase Hepcidin Levels and Improve Disease Burden

Interferons and hepcidin mimetics are ushering in a new era of polycythemia vera (PV) management by targeting JAK2 and reducing phlebotomy needs, respectively; however, comprehensive treatment gaps remain for patients with this multifaceted disease, according to Naseema Gangat, MBBS.

In an interview with OncLive®, Gangat, a professor of medicine and a consultant in hematology at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, discussed agents that have been shown to reduce JAK2 allelic burden in patients with PV, the current role of rusfertide for decreasing phlebotomy needs, and how future research may uncover disease-modifying PV management approaches. 

She offered insights on the current and future states of the myelofibrosis treatment paradigm in another article.

OncLive: What are some of the key treatments within the current PV treatment paradigm?

Gangat: Ropeginterferon alfa-2b-njft [Besremi], which is a long-acting interferon preparation, has produced a reduction in JAK2 allelic burden and potential disease modification. Ruxolitinib [Jakafi] has also generated a reduction in JAK2 allele levels in the phase 2 MAJIC-PV study [ISRCTN61925716]; that agent fits into the treatment paradigm for patients who are in the process of transforming to myelofibrosis and who have significant constitutional symptoms and splenomegaly. Rusfertide, a hepcidin mimetic, is being developed to eliminate phlebotomy needs in patients with PV.

How has rusfertide emerged as an agent with the potential to eliminate phlebotomy needs in patients with PV?

Rusfertide is an interesting agent. It’s a subcutaneous injection that is given once per week. In PV, there is inappropriately increased red blood cell [RBC] production, [leading to] low hepcidin levels. This hepcidin mimetic increases hepcidin levels and blocks ferroportin, which is the protein that regulates the release of iron in [blood] circulation. [This restricts] access to iron and [causes] less RBC production. That’s how hepcidin mimetic agents came into development for PV.

Phlebotomies are cumbersome. If a patient goes into [the clinic] for repeated phlebotomies to keep their hematocrit levels at the goal level, which is below 45%, they become depleted in iron, which can cause symptoms of iron deficiency. Patients don’t feel good with severe iron deficiency.

Rusfertide is filling that void. In [part 2 of the phase 2 REVIVE] trial [NCT04057040], it eliminated phlebotomy needs in [69.2%] of patients.1 It is an agent that just targets the hematocrit [levels]; it doesn’t target other aspects of the disease. Although [PV is characterized by] elevated hemoglobin and hematocrit levels, patients can also have high white blood cell or platelet counts, a big spleen, or other symptoms. Rusfertide does not address those aspects of the disease. It is just used to cut down on phlebotomy needs. It may have a role in low-risk patients who are not being considered for other chemotherapy agents because if a patient is already receiving other agents, those agents can also help bring down hemoglobin and hematocrit levels, specifically chemotherapies like hydroxyurea or interferon.

Is there any other ongoing research in PV that you would like to highlight?

PV is an exciting disease [to manage]. Patients have a long history with it. The unmet need continues to be [the discovery of a] disease-modifying therapy. There are data emerging showing that long-term treatment with interferons, [such as] ropeginterferon alfa-2b, reduces JAK2 allelic burden and may cause disease modification. Since PV is a disease with a long natural history, we don’t know if [the activity of interferons] translates into a reduced risk for disease transformation to myelofibrosis or leukemia. Those [answers] will be learned in the near future.

It is also an exciting time that phlebotomy is an archived procedure. There are several agents in development other than rusfertide that [may] modulate hepcidin access. Those agents may not need to be given every week. They may be given once every 3 to 6 months, depending on the technology that is being applied to increase hepcidin.

Reference

1. Kremyanskaya M, Kuykendall A, Pemmaraju N, et al. Targeted therapy of uncontrolled erythrocytosis in polycythemia vera with the hepcidin mimetic, rusfertide: - blinded randomized withdrawal results of the REVIVE study. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract LBA2710.