What is the approach to managing polycythemia vera?

Management Approach to Polycythemia Vera

Core Treatment Strategy

All patients with polycythemia vera require phlebotomy to maintain hematocrit strictly below 45% combined with low-dose aspirin (81-100 mg daily), with cytoreductive therapy added for high-risk patients (age ≥60 years or prior thrombosis history). 1, 2

Risk Stratification

Risk stratification determines treatment intensity and guides therapeutic decisions 2:

• Low-risk: Age <60 years AND no history of thrombosis 2
• High-risk: Age ≥60 years OR history of thrombosis 2

Universal First-Line Interventions for All Patients

Phlebotomy Management

• Target hematocrit <45% based on the landmark CYTO-PV trial, which demonstrated that maintaining hematocrit below 45% versus 45-50% reduced cardiovascular death and major thrombosis by nearly 4-fold (2.7% vs 9.8%, hazard ratio 3.91) 3, 2
• Consider lower targets of approximately 42% for women and African Americans due to physiological hematocrit differences 4, 5
• Perform phlebotomy with careful fluid replacement to prevent hypotension or fluid overload, particularly in patients with cardiovascular disease 4, 5
• The aggressive phlebotomy approach has improved median survival to >10 years compared to <4 years historically when inadequate phlebotomy was used 4

Aspirin Therapy

• Low-dose aspirin (81-100 mg daily) for all patients without contraindications significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 1, 2

Risk Factor Management

• Aggressively manage vascular risk factors including smoking cessation 2

Treatment Based on Risk Category

Low-Risk Patients

Phlebotomy plus low-dose aspirin is generally sufficient without cytoreductive therapy as initial treatment 2, 5

High-Risk Patients

Add cytoreductive therapy to phlebotomy and aspirin 2:

First-Line Cytoreductive Agent Selection

• Hydroxyurea (starting dose 500 mg twice daily): Recommended for older patients (>40 years) as first-line cytoreductive option 1, 2
• Interferon-α (starting dose 3 million U subcutaneously 3 times weekly): Preferred for younger patients (<40 years) and women of childbearing age 1, 2

Additional Indications for Cytoreductive Therapy

Beyond high-risk criteria, consider cytoreductive therapy for 1:

• Poor tolerance of phlebotomy or frequent phlebotomy requirement
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms
• Extreme thrombocytosis (platelet count >1,500 × 10⁹/L)
• Progressive leukocytosis

Special Clinical Situations

Pregnancy

• Interferon-α is preferred over hydroxyurea for cytoreductive therapy in pregnant patients 2

Symptom Management

• Pruritus: Selective serotonin receptor antagonists, interferon-α, JAK2 inhibitors, or antihistamines 2
• Extreme thrombocytosis (>1,500 × 10⁹/L): Consider cytoreductive therapy to reduce bleeding risk from acquired von Willebrand disease 2, 6

Monitoring and Follow-Up

• Monitor for thrombosis or bleeding and evaluate for disease progression every 3-6 months 2
• Assess symptom burden regularly 2
• Perform bone marrow aspirate and biopsy to rule out progression to myelofibrosis prior to initiating cytoreductive therapy 2
• Monitor hematocrit levels regularly to maintain target values 5

Defining Treatment Resistance

Hydroxyurea resistance or intolerance is defined as 1:

• Need for phlebotomy to keep hematocrit <45% after 3 months of at least 2g/day of hydroxyurea
• Uncontrolled myeloproliferation
• Failure to reduce massive splenomegaly or relieve splenomegaly-related symptoms
• Cytopenia or unacceptable side effects at any dose

Critical Pitfalls to Avoid

• Do not accept hematocrit targets of 45-50%: The CYTO-PV trial definitively showed increased thrombotic risk at these levels despite older studies suggesting safety up to 50-52% 3, 4
• Avoid chlorambucil and ³²P in younger patients: These agents carry significantly increased leukemia risk (13.2% and 9.6% respectively vs 1.5% with phlebotomy alone at 13-19 years) 4
• Do not withhold aspirin without clear contraindications: The cardiovascular benefit is substantial 2
• Avoid inadequate fluid replacement during phlebotomy: This can precipitate hypotension, particularly in elderly patients with cardiovascular disease 4