Ep. 1: Clinical Insights: New Approaches to Hematocrit Control in Polycythemia Vera
Key Points
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Standard polycythemia vera (PV) management remains focused on maintaining hematocrit below 45%, but phlebotomy-driven iron deficiency contributes to persistent symptom burden.
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Rusfertide, a hepcidin mimetic, targets iron homeostasis to achieve sustained hematocrit control without direct myelosuppression.
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The VERIFY trial data demonstrate reduced phlebotomy requirements, improved patient-reported outcomes, and durable efficacy with rusfertide.
Rusfertide and Emerging Strategies in Polycythemia Vera
At the 2025 ASH Annual Meeting (ASH 2025), evolving strategies for the management of myeloproliferative neoplasms (MPNs) were highlighted, including new approaches in PV. In this Clinical Insights discussion, Oncology Brothers hosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, moderated a panel focused on contemporary standards of care and emerging clinical trial data.
The panel included Talha Badar, MBBS, MD, of Mayo Clinic; Aaron Gerds, MD, of Cleveland Clinic; and Andrew Kuykendall, MD, of Moffitt Cancer Center. The discussion centered on treatment goals in PV, challenges associated with phlebotomy-based management, and data from the VERIFY trial evaluating the hepcidin mimetic rusfertide.
Current Treatment Paradigm and Unmet Clinical Needs
Management of PV remains grounded in maintaining a hematocrit level below 45% and the routine use of low-dose aspirin, supported by prior randomized trials. Low-risk patients are typically managed with phlebotomy and aspirin alone, while high-risk patients often receive cytoreductive therapy to reduce thrombotic risk and improve long-term outcomes.
Despite improved survival compared with historical cohorts, limitations persist. Frequent phlebotomies can lead to iron deficiency, contributing to fatigue and neuromuscular symptoms, while hematocrit fluctuations may limit consistent thrombotic risk reduction. As emphasized by the panel, symptom burden in PV does not always correlate with hematocrit control, and repeated health care visits for phlebotomy may further affect quality of life. These challenges underscore the need for therapies that provide durable hematocrit control while minimizing treatment-related morbidity.
VERIFY Trial and the Role of Hepcidin Mimicry
Rusfertide is a subcutaneously administered hepcidin mimetic designed to target iron metabolism rather than directly suppress hematopoiesis. Hepcidin regulates iron absorption and mobilization by inhibiting ferroportin-mediated iron transport. In PV, iron deficiency paradoxically coexists with excessive erythropoiesis, effectively sustaining excessive red blood cell production. By mimicking a high-hepcidin state, rusfertide restricts iron delivery to the bone marrow, enabling hematocrit control while potentially allowing systemic iron stores to recover.
The phase 2 VERIFY trial enrolled patients with PV who required ongoing phlebotomy, regardless of concurrent cytoreductive therapy. Participants were randomized to rusfertide or placebo while continuing background treatments, most commonly hydroxyurea, with smaller numbers receiving interferon or ruxolitinib. After a dose-titration period, hematocrit control and phlebotomy requirements were assessed between weeks 20 and 32.
Rusfertide met the primary end point, significantly reducing phlebotomy needs and improving hematocrit control compared with placebo. Key secondary end points, including patient-reported outcomes, also favored rusfertide. Longer-term data presented at ASH 2025 demonstrated durability of benefit in patients continuing therapy, as well as clinical improvement in those crossing over from placebo. Importantly, rusfertide was not associated with clinically meaningful leukopenia or thrombocytopenia, reflecting its distinct mechanism compared with cytoreductive agents.