Emerging Evidence for Earlier Intervention in Low-Risk Polycythemia Vera

During a live event, Kristen M. Pettit, MD, associate professor of medicine at the University of Michigan in Ann Arbor, and participants discussed whether ropeginterferon alfa-2b (Besremi) should be considered earlier in the management of low-risk polycythemia vera (PV), balancing growing evidence of molecular disease modification against the realities of starting injectable therapy in patients who may otherwise feel well.

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CASE SUMMARY

Initial Presentation and Management

• The patient is a 42-year-old woman.
• Asymptomatic at diagnosis
• Regular physical activity
• Body mass index: 23.4 kg/m²
• No significant past medical history
• Abnormal bloodwork at annual physical
• Initial labs: hematocrit (HCT) 52%, hemoglobin 17.2 g/dL, white blood cell count 9.8 × 10⁹/L, platelets 450 × 10⁹/L, erythropoietin 3 mU/mL (low), JAK2 V617F: positive
• Risk assessment: low-risk category; age less than 60 years; no prior thrombosis
• Initial management: phlebotomy (target HCT less than 45%), aspirin 81 mg/day, cardiovascular risk factor management, monitor for progression

Eight-Year Routine Follow-Up Visit

• HCT: 45%
• Presents with left lower leg deep vein thrombosis
• Increased fatigue
• Active treatment: anticoagulation

EVENT RECAP

Participants discussed whether a change in treatment approach was needed after the patient began showing symptoms at routine follow-up 8 years after diagnosis. An HCT level less than 45% is considered low-risk PV, with the National Comprehensive Cancer Network (NCCN) guidelines for low-risk PV recommending phlebotomy to maintain HCT below 45%.¹ Additional NCCN recommendations for low-risk PV include low-dose aspirin (81-100 mg/day) and cardiovascular risk factor management.

The NCCN guidelines list several potential indications for initiating cytoreductive therapy, including intolerance to phlebotomy, progressive leukocytosis or thrombocytosis, splenomegaly, new thrombosis or major bleeding, and disease-related symptoms.¹ The preferred regimens for cytoreductive therapy listed in the guidelines are ropeginterferon alfa-2b or clinical trial.¹

After discussing the parameters for the low-risk PV paradigm, the group examined the results from the Low-PV study (NCT03003325), a randomized controlled trial comparing ropeginterferon alfa-2b combined with standard therapy (phlebotomy plus aspirin) or standard therapy alone in patients with low-risk PV.^2,3

At 12 months, 84% of ropeginterferon-treated patients met the composite end point of HCT control below 45% and absence of disease progression, as compared with 60% of patients in the standard therapy–alone group. There were 4 disease progression events in the standard arm vs none in the ropeginterferon arm. Phlebotomy requirements were significantly lower with ropeginterferon.^2,3

Molecular response data from Low-PV showed that JAK2 V617F variant allele frequency (VAF) declined at 12 and 24 months in the ropeginterferon arm while rising in the standard arm, with reductions deepening further in hematologic responders over time.^2,3 Pettit noted she is increasingly considering serial VAF monitoring as a treatment response tool, citing evidence that baseline VAF above 50% is associated with substantially higher thrombotic risk.

Also in the Low-PV trial, quality-of-life data showed that at 24 months, 67% of patients on standard therapy alone reported moderate-to-severe PV-related symptoms vs 33% on ropeginterferon, with fatigue, spleen-related symptoms, and concentration problems all stable or improved in the ropeginterferon arm.⁴

To further contextualize the potential of ropeginterferon in low-risk PV, the participants discussed long-term data from the PROUD-PV and CONTINUATION-PV trials.^5,6 This phase 3 program compared ropeginterferon with hydroxyurea in cytoreductive therapy–naive patients or those with fewer than 3 years of prior hydroxyurea exposure. Patients were required to be JAK2 V617F mutation–positive. At 72 months of follow-up, low-risk patients treated with ropeginterferon achieved a complete hematological response rate of 73.2% vs 38.3% in the comparator arm (P = .0003). The molecular response rates were 84.4% vs 49.0%, respectively (P = .0009).

Participants came to a consensus that the available clinical trial evidence is strong supporting intervention with ropeginterferon alfa-2b in low-risk PV, even potentially earlier in asymptomatic patients, such as the patient in the case. They did note, however, that subcutaneous injection presents a challenging discussion with asymptomatic patients potentially facing decades of therapy. They agreed that it is at least worth having these discussions, particularly with younger asymptomatic patients compelled by the efficacy QOL data supporting earlier intervention.

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DISCLOSURES: Pettit reported participating in advisory boards for CTI BioPharma, AbbVie, Protagonist Therapeutics, PharmaEssentia, and Kura Oncology.

REFERENCES

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 2.2025. Accessed March 24, 2026.

2. Barbui T, Vannucchi AM, Alvarez-Larran A, et al. Ropeginterferon alfa-2b versus standard therapy for low-risk patients with polycythemia vera. Lancet Haematol. 2021;8(3):e175-e184. doi:10.1016/S2352-3026(20)30373-2

3. Barbui T, Vannucchi AM, Alvarez-Larran A, et al. Long-term results of ropeginterferon alfa-2b in early polycythemia vera. NEJM Evid. 2023;2(6):EVIDoa2200335. doi:10.1056/EVIDoa2200335

4. Guglielmelli P, Loscocco GG, Mannarelli C, et al. JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis. Blood Cancer J. 2021;11(12):199. Published 2021 Dec 11. doi:10.1038/s41408-021-00581-6

5. Gisslinger H, Klade C, Giorgio P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythemia vera (PROUD-PV and CONTINUATION-PV): a prospective, multi-centre, randomised trial. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4

6. Kiladjian JJ, Klade C, Georgiev P, et al. Long-term outcomes of polycythemia vera patients treated with ropeginterferon alfa-2b. Leukemia. 2022;36(5):1408-1411. doi:10.1038/s41375-022-01528-x