What You Should Know
- Rusfertide, a newly FDA‑approved hepcidin mimetic, is now an NCCN Category 1 option for both low‑ and high‑risk PV, offering patients more consistent hematocrit control and a major reduction in phlebotomy needs — with REVIVE and VERIFY showing strong efficacy and symptom improvement.
- Experts note its clearest role is for patients with persistent erythrocytosis, frequent phlebotomy requirements, or phlebotomy‑related iron deficiency; however, rusfertide is a disease‑control therapy, not disease‑modifying, and does not replace cytoreductive treatment when indicated.
- Safety findings were manageable, with injection‑site reactions and some anemia reported; ongoing questions remain about whether improved hematocrit stability and reduced phlebotomy exposure will ultimately lower thrombotic risk or influence long‑term PV progression.
The treatment landscape for polycythemia vera (PV) has expanded with the FDA’s August 28 approval of rusfertide (Mimrylo), a first-in-class hepcidin mimetic, and its incorporation into the NCCN guidelines as a Category 1 recommendation for both low- and high-risk PV.
The treatment landscape for polycythemia vera (PV) has expanded with the FDA’s August 28 approval of rusfertide (Mimrylo)
Rusfertide mimics hepcidin and inhibits ferroportin, reducing iron availability for erythropoiesis and providing a mechanism to control erythrocytosis without directly targeting the malignant clone. Its clinical role is to improve hematocrit and reduce dependence on phlebotomy.
“This gives patients with PV an alternative to repeated phlebotomy for controlling excess [red blood cell] production. It can help patients avoid the iron deficiency and associated symptoms caused by frequent phlebotomy, while also providing more consistent control of hematocrit over time,” says Angela Fleischman, MD, a hematologist-oncologist at UC Irvine who specializes in myeloproliferative neoplasms.
What Does the Data Say
Efficacy data are supported by the phase 2 REVIVE and phase 3 VERIFY studies. In REVIVE, 60% of patients continuing rusfertide maintained the predefined clinical response during randomized withdrawal compared with 17% receiving placebo.
VERIFY randomized 293 patients with inadequately controlled PV and ongoing phlebotomy requirements despite standard therapy. During weeks 20-32, 76.9% of patients receiving rusfertide achieved the prespecified clinical response versus 32.9% with placebo. In addition, over the full weeks 0-32 treatment period, 62.6% of rusfertide-treated patients maintained hematocrit below 45% without phlebotomy compared with 14.4% receiving placebo. Rusfertide significantly reduced phlebotomy requirements and improved patient-reported fatigue and disease-related symptoms.
“People living with PV are often walking a fine line between maintaining their hematocrit <45% to decrease thrombosis risk, and minimizing therapeutic phlebotomies that can cause significant logistical burdens and bothersome symptoms from iron deficiency,” Dr. Kristen Petit, Clinical Associate Professor of Internal Medicine-Hematology/Oncology at University of Michigan Rogel Cancer Center, tells SurvivorNet Connect.
“The approval of rusfertide (Mimrylo) offers a new option to help with this common challenge. Rusfertide is a novel, first-in-class hepcidin mimetic that targets iron metabolism, allowing patients with PV to achieve and maintain their goal hematocrit levels, while minimizing therapeutic phlebotomy needs and promoting recovery of iron stores,” Dr. Petit adds.
Updated NCCN Recommendations
The NCCN recommendations provide a practical framework for incorporating rusfertide.
Dr. Michael Keng, a UVA Health hematologist, says, “The NCCN’s Category 1 recommendation for rusfertide is an exciting clinical advancement for people living with polycythemia vera. This is especially true for patients who require frequent phlebotomies in the setting of current therapies available.”
In low-risk PV, it may be used instead of or in addition to cytoreductive therapy for frequent phlebotomy requirements or phlebotomy intolerance.
In high-risk PV, it can be added to cytoreductive therapy when patients remain phlebotomy-dependent or have difficulty maintaining hematocrit below 45%. Rusfertide does not replace cytoreductive therapy when otherwise indicated, particularly in patients with high-risk disease, significant leukocytosis or thrombocytosis, symptomatic splenomegaly, or progressive disease.
It should be viewed as a disease-control strategy rather than disease-modifying therapy. Leukocyte and platelet counts were not meaningfully altered in REVIVE, and no data currently show an effect on the underlying PV clone, thrombosis, or progression to myelofibrosis or leukemia. This distinguishes rusfertide from some other therapies where molecular responses and reductions in JAK2 V617F allele burden have been observed.
Safety was generally manageable. Injection-site reactions occurred in 56% of patients, while anemia occurred in approximately 16% versus 4.1% with placebo.
The clearest role for rusfertide is in patients with persistent erythrocytosis despite appropriate management, frequent phlebotomy requirements, or phlebotomy-related iron deficiency and symptom burden. The key unanswered question is whether more durable hematocrit control and reduced phlebotomy exposure will ultimately translate into fewer thrombotic events or modification of long-term PV progression.
