Hematocrit Control, QOL Are Priorities in Low-Risk Polycythemia Vera

Polycythemia vera (PV) is a myeloproliferative neoplasm associated with overactivation of the JAK2-STAT pathway resulting in increased production of progenitor cells and increased numbers of blood cells. The current state of treatment for low-risk and high-risk PV was explored in a recent in-person Community Case Forum event in Santa Monica, California, moderated by Mojtaba Akhtari, MD, professor of medicine at Loma Linda University. Akhtari discussed the data supporting the treatment goals of cytoreductive therapy with patients with low-risk disease by treating symptomatic patients appropriately to reduce the need for phlebotomy and minimizing other impacts of the disease.

How do you decide how patients with low-risk PV should be treated?

Mojtaba Akhtari, MD: The NCCN guidelines for low-risk PV [say that] everybody should be on [81 mg] aspirin.¹ We do phlebotomy; the goal is to keep hematocrit below 45%. If they are asymptomatic, there are no indications for cytoreductive treatment and [one should] continue aspirin and phlebotomy, but if they become symptomatic, then you need to decide. They recommend ropeginterferon alfa-2b [Besremi] or clinical trial. They also talk about hydroxyurea or Peg-IFN [Pegasys], but the preferred regimen is ropeginterferon alfa-2b. [PV] can progress to myelofibrosis, and then you have to treat along myelofibrosis paradigms.

Describe the trial that led to the use of ropeginterferon alfa-2b in low-risk PV.

The PEGINVERA trial [NCT01193699] was a prospective, open-label, multicenter, phase 1/2 dose-escalation study with ropeginterferon alfa-2b. It has a longer elimination half-life and is administered every 2 weeks. They wanted to find the maximum tolerated dose, safety, and efficacy, starting with 50 μg and up to 540 μg with no dose-limiting toxicities. The overall response rate [ORR] was 90%, with 47% complete responses and 43% partial responses.² It takes time; it's not [like] hydroxyurea where changing the dose…can bring the [blood cell] counts down quickly. It works through the immune system, so it takes time. Looking at the adverse events [AEs], it gets better over the course of time; patients get used to it. I ask patients to [take ropeginterferon] on Friday night or Saturday night, have acetaminophen and diphenhydramine, and then 15 minutes later, have the shot and go to bed.

What data support the preference for ropeginterferon alfa-2b vs the previous standard in this setting?

The Low-PV study [NCT03003325] was a randomized, multicenter, open-label 2-arm study. These were 127 adult patients with PV between the age of 18 to 60. They had low-risk PV. They had a JAK2 mutation. They had done a bone marrow biopsy [within 3 years] and had no history of blood clots. One arm was ropeginterferon. They started at 100 μg; if they are not on hydroxyurea, the starting dose is 100 μg every 2 weeks plus standard of care. The opposite arm was standard-of-care phlebotomy plus low-dose aspirin. The primary end point was if they could get the hematocrit below 45% maintained over 12 months in the absence of progressive disease, and then they looked at hematologic response; getting the hematocrit below 45%, white blood cell count below 10,000/μL, and platelets below 400,000/μL. [Other secondary end points included] shrinking of the spleen, quality of life [QOL], JAK2 V617F allele burden, number of phlebotomies, and safety.

In the group which received ropeginterferon alfa-2b, the response rate was 84% [vs 60% in the standard group] for the composite primary end point of getting not only hematologic response but also shrinking the spleen.³ The hematocrit control was 84% [vs 66%, respectively], and patients needed less phlebotomy.

[At 12 months], the treatment response was 81.3% for the ropeginterferon alfa-2b arm and the hematocrit control was 81.3%.⁴ Nobody had disease progression on ropeginterferon [vs 12.7% with standard care], and the number of phlebotomies per patient per year was 2.9 [vs 4.2 with standard care]. If patients are getting less phlebotomy, it means that the disease is under control. If a patient’s hematocrit stays below 45%, it means that disease is under control. If you are able to shrink the spleen, that's something important to remember. On this study, they didn't look at the thrombosis [because] it was low-risk disease. It was looking at hematocrit control and hematologic response, and then the number of the phlebotomies.

Most [AEs] are grade 1 and 2. It can cause cytopenias [including] neutropenia. You can have elevated liver enzymes, flu-like symptoms, and depression. If you are going to use ropeginterferon alfa-2b, make sure that the patient is not depressed, and if the patient has history of depression, get a [psychiatrist] to see the patient.

The final report looking at the ropeginterferon [showed] the rate of response to treatment was 81%, phlebotomy need was 2.9 per year, and complete hematological response rate was 28%.⁵ Patients continued having the response; out of 64, 52 stayed on treatment. The [AE-related] discontinuation rate was 16%.

Looking at the quality of life [QOL], JAK1 is associated with overproduction of inflammatory cytokines [leading to symptoms of] night sweats, fever, pruritus, fatigue, and tiredness. In the ropeginterferon arm it was at baseline moderate to severe in 39%but at 24 months, it dropped to 33%. In the standard treatment arm at baseline, it was 43% but at 24 months it went up to 64%.⁴

How does hematocrit relate to risk of thrombosis and cardiovascular events in this patient population?

The CYTO-PV trial [NCT01645124] had 365 adult patients at least 18 years old with confirmed PV. One group was very strict control, keeping hematocrit below 45% plus standard cytoreduction. The opposite arm was what I would call liberal management, with hematocrit between 45% to 50%. The median follow-up was 31 months. Looking at time to cardiovascular or major thrombotic events, the group that had liberal management had 4-fold higher rate of cardiovascular death and major thrombosis. This presentation made 45% the new standard of care for patients with PV.⁶ The same group published [data showing that] with white blood cell count of more than 11,000/μL, those patients had more thrombotic events, so it's not only about hematocrit, but also white blood cell count and platelet count.^7,8

DISCLOSURES: Akhtari previously reported consulting or advisory roles with Abbvie, BMS, Incyte, Karyopharm Therapeutics, Pfizer, and Takeda; and speakers' bureau with Incyte; Jazz Pharmaceuticals, and Novartis.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2025. Accessed June 16, 2025. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf

2. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, et al. Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126(15):1762-1769. doi:10.1182/blood-2015-04-637280

3. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021;8(3):e175-e184. doi:10.1016/S2352-3026(20)30373-2

4. Barbui T, Vannucchi AM, De Stefano V, et al. Ropeginterferon versus standard therapy for low-risk patients with polycythemia vera. NEJM Evid. 2023;2(6):EVIDoa2200335. doi:10.1056/EVIDoa2200335

5. Barbui T, Vannucchi A, De Stefano V, et al. Ropeginterferon alfa-2b versus standard therapy for low-risk patients with polycythemia vera. final results of Low-PV randomized phase ii trial. Blood. 2022;140(suppl 1):1797-1799. doi:10.1182/blood-2022-157255

6. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500

7. Barbui T, Masciulli A, Marfisi MR, et al. White blood cell counts and thrombosis in polycythemia vera: a subanalysis of the CYTO-PV study. Blood. 2015;126(4):560-561. doi:10.1182/blood-2015-04-638593

8. Tashi T. Hematocrit, white blood cells, and thrombotic events in the veteran population with polycythemia vera. Fed Pract. 2022;39(suppl 2):S43-S46. doi:10.12788/fp.0243