The Importance of Managing White Blood Cell Count in Polycythemia Vera

Dr Thomas LeBlanc discusses leukocytosis as a clinically meaningful risk signal in polycythemia vera and the importance of assessing white blood cell count as part of comprehensive disease control.

Hello, and welcome.

I'm Tom LeBlanc, and I am a myeloid malignancies specialist from North Carolina. I've been seeing and treating patients with polycythemia vera for about 15 years.

And polycythemia vera (or PV) is a chronic myeloproliferative neoplasm characterized by an overproduction of red blood cells, white blood cells, and platelets. The elevated blood cell counts increase blood viscosity, raising the risk of thrombosis, cardiovascular complications, and long-term complications, such as myelofibrosis (or MF) and acute myeloid leukemia (or AML).

In this video, we will discuss the importance of white blood cell control in PV and why a more comprehensive view of disease control may be clinically meaningful in managing PV.

Mutations in the Janus tyrosine kinase 2 (or JAK2), particularly, JAK2 V617F, are found in nearly all cases of PV and drive overproduction of blood cells, which increases procoagulant activity and raises the risk of thrombosis.

Maintaining hematocrit control below 45% is the primary treatment goal in PV and is a proven strategy for reducing thrombotic risk.

However, a patient may meet hematocrit targets yet still have persistent leukocytosis, thrombocytosis, splenomegaly, ongoing symptoms, or a continued need for intervention. That broader clinical picture has become increasingly important in routine practice.

In that setting, hematocrit remains an essential target, but hematocrit alone does not fully capture overall disease control.

White blood cell count is a key component of that broader assessment. Elevated white blood cell counts have been associated with increased risk of thrombotic events in PV, including in settings where hematocrit is controlled.

In the REVEAL study, a prospective observational study of 2271 patients with PV, an elevated WBC count of >11 × 10⁹/L was significantly associated with an increased risk of thrombotic events (with a P value of < 0.0001), and this association was observed in both low-risk and high-risk PV. An elevated WBC count of >12 × 10⁹/L was associated with increased risk of thrombotic events even when hematocrit was controlled at ≤45% (with a P value of 0.0300).

A risk-adapted approach reflects these data. In patients with low-risk PV (meaning less than 60 years of age with no history of thrombosis), features such as leukocytosis, inadequate hematocrit control with phlebotomy alone, PV-related symptoms, and elevated cardiovascular risk may warrant initiation of cytoreductive therapy.

Indication  

BESREMi is indicated for the treatment of adults with polycythemia vera.

Boxed Warning  

WARNING: RISK OF SERIOUS DISORDERS

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.

Ropeginterferon alfa-2b (or BESREMi) is a single-site monopegylated interferon and a preferred first-line cytoreductive treatment option for the treatment of both low-risk symptomatic and high-risk PV in the NCCN Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms.

BESREMi has demonstrated its effectiveness in controlling hematocrit, white blood cells, and platelets in multiple clinical trials.

Let’s first consider the pivotal trial for BESREMi, PEGINVERA.

PEGINVERA was a multicenter, single-arm study designed to assess the dosing, tolerability, and efficacy of BESREMi in patients with PV over 7.5 years.

Among the 51 patients enrolled, which included both low- and high-risk patients with PV, BESREMi achieved an 80% complete hematologic response rate. Complete hematologic response was defined as no phlebotomy within the prior 2 months, hematocrit below 45%, leukocyte count at or below 10 x 10⁹/L, and platelet count at or below 400 x 10⁹/L.

Comprehensive disease control was achieved by 61% of patients and was defined as no phlebotomy within the prior 2 months, hematocrit below 45%, leukocyte count at or below 10 x 10⁹/L, platelet count at or below 400 x 10⁹/L, normal spleen size, and no thromboembolic events.

In PEGINVERA, 95% of adverse reactions were Grade 1 or 2. The most frequently reported adverse reactions included influenza-like illness, arthralgia, fatigue, and pruritus.

Together, these findings support BESREMi as an important first-line cytoreductive treatment option across different PV patient populations.

Now, let’s turn to the Low-PV study, which focused specifically on low-risk patients. 

The Low-PV study was a phase-2, open-label, parallel-group, randomized trial comparing the efficacy and safety of BESREMi in combination with standard phlebotomy and low-dose aspirin versus phlebotomy and low-dose aspirin alone in 127 low-risk PV patients. These results support a broader view of disease control as an important component of PV management.

In terms of its primary endpoint, 81% of patients treated with BESREMi plus phlebotomy and aspirin achieved hematocrit control with no disease progression at 12 months, compared with 51% in the phlebotomy and aspirin group. These results were sustained at 24 months: 83% of patients who received BESREMi plus phlebotomy and aspirin achieved the composite endpoint, compared with 59% in the phlebotomy and aspirin group.

The Low-PV study also evaluated white blood cell control because of the known relationship between WBC count and thrombotic risk. WBC count decreased among patients with PV treated with BESREMi plus phlebotomy and aspirin or who switched to BESREMi plus phlebotomy and aspirin after 12 months, compared with those not receiving BESREMi.

These findings support a more comprehensive assessment of response in PV.

Safety and tolerability also remain an essential part of treatment decision-making. In the Low-PV study, grade 3 and grade 4 adverse events were reported in 9% of patients treated with BESREMi plus phlebotomy and aspirin. Eight percent of patients receiving BESREMi plus phlebotomy and aspirin discontinued treatment due to hypertransaminasemia, neutropenia, persistent itching, nausea or asthenia, metrorrhagia, and hyperthyroidism.

Hematocrit control remains central in PV; however, treatment assessment in PV increasingly extends beyond hematocrit alone. Blood cell counts beyond hematocrit, including white blood cell count, symptoms, splenomegaly, and phlebotomy requirements can all contribute to the clinical picture.

A broader assessment of all blood counts and symptom burden may provide a more complete picture of disease control and risk. 

White blood cell count adds important information about ongoing disease activity and thrombotic risk, and persistent leukocytosis may indicate suboptimal disease control. White blood cell count is an important risk factor to consider when making clinical treatment decisions.

INDICATION 

BESREMi is indicated for the treatment of adults with polycythemia vera. 

IMPORTANT SAFETY INFORMATION 

WARNING: RISK OF SERIOUS DISORDERS 

Interferon alfa products may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping therapy.  

CONTRAINDICATIONS 

• Existence of or history of severe depression, suicidal ideation, or suicide attempt 

• Hypersensitivity to interferons or any inactive ingredients 

• Moderate or severe hepatic impairment 

• History or presence of active serious or untreated autoimmune disease 

• History of transplantation and receiving immunosuppressant agents 

WARNINGS AND PRECAUTIONS 

• Depression and Suicide: Closely monitor patients for any symptoms of psychiatric disorders and, if needed, consider psychiatric consultation and treatment or dosage modifications as listed in the full prescribing information. 

• Endocrine Toxicity: Do not use BESREMi in patients with active serious or untreated endocrine disorders associated with autoimmune disease. Evaluate thyroid function in patients who develop symptoms suggestive of thyroid disease during BESREMi therapy. Discontinue BESREMi in patients who develop endocrine disorders that cannot be adequately managed during treatment with BESREMi. 

• Cardiovascular Toxicity: Patients with a history of cardiovascular disorders should be closely monitored for cardiovascular toxicity during BESREMi therapy. Avoid use of BESREMi in patients with severe or unstable cardiovascular disease or recent stroke or myocardial infarction. 

• Decreased Peripheral Blood Counts: Monitor complete blood counts at baseline, during titration, and every 3-6 months during the maintenance phase. 

• Pancreatitis/Colitis/Pulmonary Toxicity: Interrupt BESREMi treatment in patients with possible pancreatitis, colitis, or pulmonary toxicity and evaluate promptly. Consider discontinuation of BESREMi in patients with confirmed pancreatitis or who show signs or symptoms of serious ulcerative or hemorrhagic colitis, or who develop pulmonary infiltrates or pulmonary function impairment. 

• Ophthalmologic Toxicity: Advise patients to have eye examinations before and during treatment. Discontinue BESREMi in patients who develop new or worsening eye disorders. 

• Hyperlipidemia/Hepatotoxicity/Renal Toxicity: Monitor serum triglycerides, liver enzymes, hepatic function, and serum creatinine at baseline and during therapy. Avoid use of BESREMi in patients with eGFR <30 mL/min. Discontinue BESREMi in patients with persistently marked elevated triglycerides, evidence of hepatic decompensation, or if renal impairment develops during treatment. 

• Dental and Periodontal Toxicity: Patients should have good oral hygiene and regular dental examinations. 

• Dermatologic Toxicity: Consider discontinuation of BESREMi if clinically significant dermatologic toxicity occurs. 

• Driving and Operating Machinery: BESREMi may impact the ability to drive and use machinery. Patients should not drive or use heavy machinery until they know how BESREMi affects their abilities. Patients who experience dizziness, somnolence, or hallucination during BESREMi therapy should avoid driving or using machinery. 

• Embryo-Fetal Toxicity: Based on the mechanism of action, BESREMi can cause fetal harm when administered to a pregnant woman. Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with BESREMi. Advise females of reproductive potential to use an effective method of contraception during treatment with BESREMi and for at least 8 weeks after the final dose. Advise women not to breastfeed during treatment and for 8 weeks after the final dose. 

ADVERSE REACTIONS 

The most common adverse reactions reported in >40% of patients were influenza-like illness, arthralgia, fatigue, pruritus, nasopharyngitis, and musculoskeletal pain. 

DRUG INTERACTIONS 

Patients on BESREMi who are receiving concomitant drugs which are CYP450 substrates with a narrow therapeutic index should be monitored to inform the need for dosage modification. Avoid use with myelosuppressive agents, narcotics, hypnotics, or sedatives, and monitor patients receiving the combination for effects of excessive CNS toxicity. 

To report SUSPECTED ADVERSE REACTIONS, contact PharmaEssentia at 1-800-999-2449 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 

Please see full Prescribing Information, including Boxed Warning at besremihcp.com.