Disease State Update: Polycythemia Vera Disease State Hub

Polycythemia vera (PV) is a type of myeloproliferative neoplasm (MPN), a group of clonal malignancies characterized by excess hematopoiesis in myeloid cell lineages[GT1] .^1,2 The other 3 types of MPNs are essential thrombocythemia (ET), primary myelofibrosis (MF), and unclassifiable MPN.¹ PV is primarily characterized by erythrocytosis, also known as polycythemia, meaning a high concentration of red blood cells in the blood, along with other systemic symptoms.³  

Notably, patients with PV can often be asymptomatic. For patients who are symptomatic, classic symptoms presented are pruritis, headaches, fatigue, chest pain, splenomegaly, superficial thrombophlebitis, minor mucocutaneous bleeding, or thrombosis. A distinguishing symptom is erythromelalgia, which is characterized by erythema, warmth, and pain in distal areas such as the hands and feet.¹ Splenomegaly is likely to be associated with advanced disease, affecting an estimated 30% to 40% of patients with PV.⁸

Patients with PV have a median survival of 12.4 to 20 years,⁴ and tend to experience an increased incidence of thrombotic events, or blood clotting, which represents the main cause of mortality.^3,4 Disease progression to primary MF, known as “post-PV myelofibrosis,” occurs in approximately 15% of patients with PV. There is also a risk of disease progression to acute myeloid leukemia (AML) over time.¹

The prevalence of PV in the United States is estimated at 44 to 57 per 100,000 people, with its prevalence increasing over time, and⁵ and incidence rate of 1.57 per 100,000 people, with higher rates for patients 60 years or older, as well as male versus female patients.⁶ The median age of diagnosis is 61 years and 10% of patients with PV present below age 40.¹ It is possible that genetic factors could play a role in the development of PV and acquired gene mutations, as familial cases have occurred, although they have been rare.⁷

Development of PV is linked to a malignant change within a single cell of the bone marrow.⁷ The pathophysiology of PV is predominantly driven by Janus kinase (JAK) 2 mutations, with the JAK2 V617F (exon 14) mutation estimated to occur in 97% of patients and the remaining 3% of patients having other JAK mutations such as JAK2 exon 12.^1,8 The type of JAK2 mutation and allele burden play a role in clinical and phenotypic features, despite being similar to one another prognostically.^1,9 Patients with a higher amount of JAK2 V617F alleles tend to experience pruritis, fibrotic transformation, and venous thrombosis.¹ An increased JAK2 V617F allele burden has also been associated with an increased risk of thrombotic events and disease progression.¹⁰

As an example, JAK2 V617F homozygosity has been proposed to be associated with stimulated erythropoiesis and myelopoiesis, lower platelet count, a higher incidence of splenomegaly, a larger spleen size, and a greater proportion of patients requiring cytoreductive therapy. Patients with JAK2 V617F homozygosity also tend to experience an increased incidence of pruritis. JAK2 exon 12 mutations are characterized by erythroid-dominant myeloproliferation, subtler tri-lineage hyperplasia in the bone marrow (BM), and younger age.[GT1] ⁸ Additional driver mutations have been identified in patients with PV, occurring on the TET2, DNMT3a, and ASXL1 genes. Recent studies have shown that modifications to the NF-E2 and LNK (SH2B3) genes could also be involved in the development of PV.⁷

Determining which mutations are present can help aid in diagnosis, as different types of MPN harbor varying mutations. In addition to PV, the JAK2 V617F mutation also occurs in ET and PMF, highlighting the importance of correct diagnosis of disease. Meanwhile, the JAK2 exon 12 mutations that are seen in PV are rare in ET and PMF.⁹ The absence of a JAK2 mutation signifies that a diagnosis of PV is unlikely.¹

There are 2 classifications systems for diagnosis of PV, the International Consensus Criteria (ICC) criteria and the World Health Organization (WHO) criteria.¹ Diagnosis requires all 3 major criteria, or the first 2 major criteria in addition to the minor criterion for a diagnosis of PV (Table 1).^1,11

Table 1. The ICC and WHO diagnostic criteria for PV¹¹

^aA bone marrow biopsy may not be required in patients with sustained absolute erythrocytosis (hemoglobin concentrations of > 18.5 g/dL in men or > 16.5 g/dL in women and hematocrit values of > 55.5% in men or > 49.5% in women) and the presence of a JAK2 V617F or JAK2 exon 12 mutation.
^bIt is recommended to use highly sensitive assays for JAK2 V617F (sensitivity level <1%) and CALR and MPL (sensitivity level 1% to 3%) in negative cases. Consider searching for non-canonical or atypical JAK2 mutations.

BM = bone marrow, CALR = calreticulin, Hct = hematocrit, JAK = Janus kinase, MPL = myeloproliferative leukemia.

Patients with PV are at a higher risk for arterial and venous thrombosis, with the likelihood of thrombotic complications after a median follow-up period of 20 years estimated to be 26%. Advanced age, history of thrombosis, and treatment with phlebotomy alone have been cited as the main risk factors for thrombosis. Patients with PV can be categorized as low- or high-risk for thrombosis, with high-risk patients having an age greater than 60 years or a history of thrombosis and low-risk patients having none of these factors.^1,11

Patients with PV are more prone to develop post-PV myelofibrosis, a more advanced form of myelofibrosis, or AML.^1,12 Unfortunately, current therapies have not been shown to prevent disease transformation from PV to post-PV or AML.¹ Thus, the primary goal of therapy is to manage symptoms and decrease the risk of thromboembolic events by ensuring that a patient’s hematocrit level is < 45%, regardless of individual risk status.^1,3,4 To achieve this, all patients with PV, regardless of risk status, should be treated with daily aspirin (81 mg/day) and periodic phlebotomy to ensure a hematocrit level < 45%. Evidence supports the use of phlebotomy in preventing thrombotic events.¹

Generally, low-risk patients do not need to be treated additionally with cytoreductive agents. However, for those patients finding regular phlebotomies inconvenient, suffering from phlebotomy-induced side effects, or experiencing uncontrolled symptoms such as severe pruritis, cytoreductive agents can be considered.¹

For low-risk patients (age < 60 years and no prior history of thrombosis), the National Comprehensive Cancer Network (NCCN) guidelines recommend aspirin 81 to 100 mg daily, phlebotomy to maintain a hematocrit level < 45%, and the management of cardiovascular risk factors. While a hematocrit level of < 45% is the average recommendation, it is important to note that a lower hematocrit level may be targeted depending on a patient’s individual symptoms. For low-risk symptomatic patients and high-risk patients (age > 60 years and/or prior history of thrombosis), the NCCN recommends other treatments in addition to aspirin and phlebotomy (Table 2).¹¹

Table 2. NCCN Recommendations for Cytoreductive Therapy¹¹

Medications are recommended in addition to aspirin 81 to 100 mg daily + phlebotomy.
^aThe use of peginterferon alfa-2a is noted as an option for younger patients or pregnant patients needing cytoreductive therapy.

Interferon alfa (IFNα) treatments have been shown to be successful in certain patients, selectively decreasing the malignant stem cell pool and inducing durable molecular remissions.

Ropeginterferon alfa-2b is a mono-pegylated IFNα that consists of a single positional isomer, which enables this therapy to have an extended elimination half-life and improved tolerability.¹³ The safety and efficacy of ropeginterferon alfa-2b were assessed first in the PEGINVERA phase 2/3 prospective, open-label, multicenter, dose-escalation study.¹⁴ Data from the PEGINVERA study ultimately led to the US Food and Drug Administration (FDA) approval of ropeginterferon alfa-2b in 2021.¹⁵ Follow-up studies evaluated efficacy and safety in 2 randomized, multicenter, open-label, active-controlled, head-to-head phase 3 trials, PROUD-PV and its extension study, CONTINUATION-PV.¹⁴

PEGINVERA Study

PEGINVERA was a multi-center, open-label, single-group assignment study. The first part of this study, phase 1, was a dose-escalation study to determine the maximum tolerated dose (MTD) of ropeginterferon alfa-2b. The MTD was further defined to be the highest dose at which no more than 1 of 6 patients experienced a dose-limiting toxicity. The primary endpoints for the phase 2 portion of PEGINVERA were hematologic complete response and molecular response.¹⁴

Eligibility criteria included patients aged 18 years or older with a confirmed diagnosis of PV according to the current WHO criteria or the PV study group criteria. A JAK2 mutation presence was required to enroll in the study. Patients currently or previously treated with hydroxyurea failing to control their hematocrit level with phlebotomy or other symptoms were eligible to enroll as well. Patients previously exposed to IFNα treatment or other cytoreductive therapies for PV were deemed ineligible.¹⁴

Phase 1 began with 3 patients per cohort, for a total of 25 patients, to determine the MTD. Ropeginterferon alfa-2b was administered subcutaneously biweekly. Dose levels explored throughout the course of this study ranged from 50 μg to 540 μg. At the start of the study, 3 patients were treated with the lowest dose and monitored for toxicity concerns over a 2-week period. Following this, the dose was gradually increased for the remaining cohorts. Once the MTD was confirmed, a new cohort consisting of 26 patients was enrolled for the phase 2 portion of the study to evaluate efficacy and safety.¹⁴

Phase 2 enrolled an additional 26 patients, for a total of 51 patients, in the study period of 12 months. While still administered subcutaneously biweekly, the dose administered for this portion of the study was dependent on efficacy rather than tolerability. After 12 months, 74% of patients achieved a hematocrit level < 45% without the need for phlebotomy. Additionally, after 12 months of treatment, 89% of patients had platelet levels < 400 g/L and 92% of patients had leukocyte levels < 10 g/L. Spleen size trended downward over time. A significant linear reduction of JAK2 V617F allele burden over time was observed, with each month of treatment resulting in a 1.2% decrease.¹⁴

A total of 744 adverse events were observed throughout this study, with 330 defined as treatment-related. The greatest number of adverse events occurred within the first 3 months of the study and declined over time. All treatment-related adverse events were known toxicities associated with the use of α-interferons and, unless leading to discontinuation, were manageable with dose adjustments or other supportive therapies. The discontinuation rate due to adverse events was 20%.

Psychiatric adverse events, a known safety concern of interferon treatment, occurred in 31% of patients. Events included acute stress disorder, aggression, apathy, depression, and insomnia, among others. Only 2 patients discontinued the study due to these psychiatric events, as the majority of symptoms were mild. Thyroid-related adverse events resulted in the discontinuation of 2 patients, with events including autoimmune thyroiditis (2 patients), latent hyperthyroidism (1 patient), and elevated antithyroid antibodies (4 patients).¹⁴

Overall, PEGINVERA showed that ropeginterferon alfa-2b was safe, effective, and well-tolerated. No dose-limiting toxicities occurred from the dosages explored. The observed decrease in JAK2 allelic burden confirms how α-interferons such as ropeginterferon alfa-2b treat PV by selectively working at the malignant clone of the disease.

The FDA granted approval for ropeginterferon alfa-2b in November 2021. This treatment had originally been granted orphan status for the treatment of PV by both the FDA and European Medicines Agency prior to its approval.¹⁴ This treatment was the first FDA-approved therapy for patients with PV that can be administered regardless of the patient’s treatment history. It was also the first interferon therapy to be specifically approved to treat PV.¹⁵ In the NCCN guidelines for PV, ropeginterferon alfa-2b is currently listed as one of the first-line preferred regimens for both symptomatic low-risk and high-risk patients with PV.¹¹

As there is no cure for PV, treatment is focused on managing symptoms and reducing the risk of thrombotic events. Providers also need to monitor patients for disease progression to post-PV MF or AML. For low-risk patients, treatment with aspirin and phlebotomy are sufficient to maintain low hematocrit levels necessary for decreasing the risk of thrombotic events.

For symptomatic low-risk or high-risk patients, however, cytoreductive therapy is often needed in addition to these agents. For many years, hydroxyurea was the standard of care for patients requiring cytoreductive therapy. Over the years, our understanding of effective treatments for this disease has evolved.^{1, 14,16} Current NCCN guidelines for treatment now include options such as ropeginterferon alfa-2b, peginterferon alfa-2a, and ruxolitinib, in addition to hydroxyurea.¹¹ 

The impact of targeting the JAK2 V617F mutation continues to be researched. While hypothetically, a reduction or elimination of this driver mutation could have the potential to slow disease progression and minimize disease-related symptoms, this has not been proven yet. Peginterferon alfa-2a and ropeginterferon alfa-2b are the only treatments thus far that have been demonstrated to target JAK2 V617F, leading to molecular remission or even elimination of the driver mutation. The role of acquired somatic mutations in disease progression or leukemic transformation is also being investigated.¹⁰ This will be an important area of research for the future of treating and modifying the disease progression of PV.

1. Tefferi A, Barbui T. Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(9):1465-1487. doi:10.1002/ajh.27002
2. Landtblom AR, Bower H, Andersson TM, et al. Second malignancies in patients with myeloproliferative neoplasms: a population-based cohort study of 9379 patients. Leukemia. 2018;32(10):2203-2210. doi:10.1038/s41375-018-0027-y
3. Kremyanskaya M, Kuykendall AT, Pemmaraju N, et al. Rusfertide, a hepcidin mimetic, for control of erythrocytosis in polycythemia vera. N Engl J Med. 2024;390(8):723-735. doi:10.1056/NEJMoa2308809
4. Verstovsek S, Pemmaraju N, Reaven NL, et al. Real-world treatments and thrombotic events in polycythemia vera patients in the USA. Ann Hematol. 2023;102(3):571-581. doi:10.1007/s00277-023-05089-6
5. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma. 2014;55(3):595-600. doi:10.3109/10428194.2013.813500
6. Verstovsek S, Yu J, Scherber RM, et al. Changes in the incidence and overall survival of patients with myeloproliferative neoplasms between 2002 and 2016 in the United States. Leuk Lymphoma. 2022;63(3):694-702. doi:10.1080/10428194.2021.1992756
7. Regimbeau M, Mary R, Hermetet F, Girodon F. Genetic background of polycythemia vera. Genes (Basel). 2022;13(4):637. doi:10.3390/genes13040637
8. Iurlo A, Cattaneo D, Bucelli C, Baldini L. new perspectives on polycythemia vera: from diagnosis to therapy. Int J Mol Sci. 2020;21(16):5805. doi:10.3390/ijms21165805
9. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599-1613. doi:10.1002/ajh.26008
10. Waksal JA, Wagner NE, Mascarenhas JO. Risk factors for disease progression and treatment goals in polycythemia vera. Clin Adv Hematol Oncol. 2024;22(1):31-42.
11. NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms (Version 2.2024). National Comprehensive Cancer Network. August 8, 2024. Accessed August 18, 2024. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
12. Yoon SY, Won JH. Novel therapeutic strategies for essential thrombocythemia/polycythemia vera. Blood Res. 2023;58(S1):83-89. doi:10.5045/br.2023.2023013
13. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
14. 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
15. FDA approves treatment for rare blood disease. US Food and Drug Administration. Published November 12, 2021. Accessed August 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-rare-blood-disease
16. Raedler LA. Jakafi (ruxolitinib): First FDA-approved medication for the treatment of patients with polycythemia vera. Am Health Drug Benefits. 2015;8(Spec Feature):75-79.