Optimizing Treatment Outcomes in Polycythemia Vera

The evolving treatment landscape in polycythemia vera (PV) is shifting from a focus on hematocrit control to a more comprehensive approach involving myelosuppression and symptom management. A number of large-scale studies, including the REVEAL (NCT02252159) and Low-PV (NCT03003325) studies, challenge the current treatment paradigms for both high- and low-risk patients with PV.

Firas El Chaer, MD, MSHCM, chief of leukemia and medical director of infusion services, Baptist Health Miami Cancer Institute, provided his insights and key findings from these trials during a Community Case Forum event in Miami, Florida.

Targeted Oncology: Please provide an overview of the REVEAL study.

Firas El Chaer, MD: REVEAL is the largest prospective observational study of polycythemia vera (PV), published about 2 years ago in the journal Blood.¹

A total of 2500 patients with a physician-determined diagnosis of PV were recruited in this observational study and it was physician choice of therapy—hydroxyurea, pegylated interferon, or enrollment in a clinical trial. Investigators followed these patients for more than 3 years to monitor outcomes, with a specific focus on venous and arterial thrombotic events.

Patients were divided into low-risk and high-risk populations. As expected, therapeutic approaches varied between these groups. Phlebotomy alone was more prevalent in the low-risk population, whereas hydroxyurea was more commonly added for those in the high-risk group. Some patients received combination therapies, while approximately 5% of patients in each arm underwent watchful waiting without any active interventions.

What’s important to note is that venous thromboembolisms and arterial thrombotic events were higher in the higher risk group.

The REVEAL study underscored that hematocrit control is not the only factor in managing thrombotic risk. Subgroup analysis revealed that hematocrit levels greater than 45% were associated with an increased risk of thrombosis. Furthermore, white blood cell counts exceeding 11,000/μL and platelet counts greater than 400,000/μL also conferred a higher risk.

Of particular note, a neutrophil count greater than 7000 /μL increased the risk of thrombosis, even in patients with a total white blood cell count below 11,000/μL. Neutrophils express specific receptors that contribute to high thrombotic risk, with monocytes and macrophages acting as primary drivers of these events. Consequently, these data have shifted the field toward prioritizing the management of broader blood counts beyond hematocrit.

On further covariate analysis, the hematocrit white blood cell count and platelet count was a driver in the patients with high-risk PV and in patients with low-risk PV, an elevated white blood cell count was still a risk factor for thrombosis in these patients.

What is the maximum hematocrit level you would allow before changing your management approach?

The established hematocrit target of less than 45% is primarily supported by data from the New England Journal of Medicine,² which demonstrated superior outcomes compared with a target of 45% to 50%. While some research suggests that a more stringent target of less than 42% may be appropriate for women—potentially due to physiological differences in testosterone levels—the original study enrolled both male and female patients and observed outcomes across the entire cohort.

In clinical practice, tighter hematocrit control is particularly important for younger patients who have decades of life ahead of them, as well as for those with comorbidities such as diabetes, hypertension, or cardiovascular disease. A significant challenge in maintaining these levels is that frequent phlebotomy leads to iron deficiency, which can exacerbate patient symptoms.

The anticipated approval of rusfertide in August 2026 may address this issue by lowering hematocrit through the hepcidin pathway. By blocking iron absorption rather than removing it via phlebotomy, this agent could provide a valuable option for patients with concomitant iron deficiency who cannot receive iron supplementation. It is important to note, however, that this therapy is not intended to replace existing cytoreductive treatments.

What do the National Comprehensive Cancer Network (NCCN) guidelines suggest for low-risk PV and cytoreductive therapy?

The NCCN guidelines specify that both interferon and hydroxyurea (Hydrea) are primary options for cytoreductive treatment. While clinicians may debate whether one is preferred over the other, the current guidelines provide both as valid choices for managing the disease.

A primary indication for initiating or switching therapy is the presence of progressive thrombocytosis or leukocytosis. While the NCCN does not provide a strict definition for ”progressive,” a white blood cell count exceeding 11,000/µL is considered a significant risk factor. It is common for high white blood cell counts to be overlooked in clinical settings as long as the patient's hematocrit remains controlled; however, this elevation, alongside persistent disease-related symptoms like pruritus, often necessitates a change in the treatment regimen.

For low-risk patients, the preferred regimens include clinical trials or the use of ropeginterferon alfa-2b, known by the brand name Besremi. This long-acting interferon represents an advancement over older options like peginterferon alfa-2a (Pegasys). Although older interferons typically require weekly injections, ropeginterferon is initially administered every two weeks. After approximately one year of treatment, if the patient maintains a complete hematologic response on a stable dose, the frequency can be further reduced to a single injection every 4 weeks. This monthly schedule significantly reduces the treatment burden on the patient compared to the weekly requirements of previous therapies.

What patients and clinical factors do you consider in your initial choice of treatment?

For low-risk patients with polycythemia vera, the standard approach traditionally involves phlebectomy and low-dose aspirin. However, for patients who do not tolerate phlebectomy or who exhibit progressive leukocytosis and thrombocytosis, hydroxyurea is not typically the first-line choice because its testing was primarily conducted on high-risk populations. Instead, there are solid data supporting the use of ropeginterferon for this lower-risk population. This clinical preference is supported by the Low-PV study ,³ which was a randomized, multicenter, open-label, two-arm trial.

The study enrolled patients between the ages of 18 and 60 with a confirmed diagnosis of polycythemia vera. These patients were classified as low-risk by definition, as they were under 60 years old and had no history of thrombosis. Participants were required to have a JAK2 mutation and a bone marrow biopsy performed within 3 years of enrollment. The trial divided patients into two groups: one receiving ropeginterferon and the other receiving standard of care, which consisted of phlebectomy and low-dose aspirin.

They followed these patients to monitor several key outcomes over a 12-month period. Investigators specifically evaluated how many patients maintained a hematocrit level below 45% without disease progression. Furthermore, the study assessed the control of blood counts, particularly white blood cell and platelet counts. Beyond clinical markers, the trial also analyzed improvements in quality of life, changes in the JAK2 allele burden, and the total number of phlebectomies required while on the study.

Please describe the safety and toxicity findings.

Clinical concern often arises when prescribing long-term medication to a younger patient population, such as those in their 20s or 30s who may remain on treatment indefinitely. However, data from the Low-PV study revealed no alarming new safety signals in this low-risk group compared to higher-risk populations.

A notable improvement was observed regarding flu-like symptoms. Although older versions of interferon, such as peginterferon alfa-2a [Pegasys], were associated with a 30% incidence of these symptoms, the newer ropeginterferon showed a significantly lower rate of approximately 11%. When these symptoms do occur—including body aches, myalgia, and low-grade fever—they are generally much milder. Clinicians often advise patients to take [acetaminophen] on the morning of the injection, again that night, and the following day, which typically manages these side effects effectively.

Regarding overall tolerability, the Low-PV study reported that 16% of patients discontinued treatment due to adverse events related to the interferon. While some patients experienced adverse events they found intolerable, the majority were able to maintain the regimen without significant safety issues.

REFERENCES

1. Gerds AT, Mesa R, Burke JM, et al. Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL. Blood. 2024;143(16):1646-1655. doi:10.1182/blood.2023020232

2. 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

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