What is the initial management for a patient with Polycythemia Vera?

Initial Management of Polycythemia Vera

All patients with polycythemia vera should receive therapeutic phlebotomy to maintain hematocrit strictly below 45% combined with low-dose aspirin (81-100 mg daily), and high-risk patients (age >60 years or prior thrombosis) require the addition of cytoreductive therapy with either hydroxyurea or interferon-α. 1, 2

Risk Stratification

Risk stratification determines treatment intensity and must be performed at diagnosis:

• High-risk patients are defined as age ≥60 years and/or history of thrombosis 1, 3
• Low-risk patients are age <60 years with no thrombosis history 1, 3

Universal First-Line Treatment (All Patients)

Phlebotomy

• Target hematocrit <45% based on the landmark CYTO-PV trial, which demonstrated a 3.91-fold reduction in cardiovascular death and major thrombosis compared to targets of 45-50% 4, 1, 5
• Induction phase: Remove 300-450 ml weekly or twice weekly until target achieved 4
• Maintenance phase: Same volume per session, with intervals determined by hematocrit monitoring 4
• Lower targets (approximately 42%) should be considered for women and African Americans due to physiological hematocrit differences 1, 6
• Critical safety measure: Perform phlebotomy with careful fluid replacement to prevent hypotension or fluid overload, particularly in elderly patients with cardiovascular disease 1, 7

Aspirin Therapy

• Low-dose aspirin (81-100 mg daily) for all patients without contraindications 4, 1, 2
• This significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 1
• Low-dose aspirin does not increase bleeding risk 1

Cardiovascular Risk Factor Management

• Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, and diabetes 4, 1
• Mandatory smoking cessation counseling and support 1, 8

Risk-Stratified Cytoreductive Therapy

Low-Risk Patients

• Phlebotomy and aspirin are generally sufficient 1, 6
• Additional indications for cytoreduction even in low-risk patients include: 4, 1
  • Poor tolerance to phlebotomy
  • Symptomatic or progressive splenomegaly
  • Severe disease-related symptoms
  • Platelet count >1,500 × 10⁹/L
  • Leukocyte count >15 × 10⁹/L

High-Risk Patients

Cytoreductive therapy is strongly recommended in addition to phlebotomy and aspirin 4, 1

First-Line Cytoreductive Options:

Hydroxyurea:

• First-line agent with Level II, A evidence for efficacy and tolerability 4, 1
• Caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure 4, 1
• Resistance/intolerance defined by: need for phlebotomy after 3 months of ≥2 g/day, uncontrolled myeloproliferation, failure to reduce massive splenomegaly, or cytopenia/unacceptable side effects 1

Interferon-α:

• First-line alternative with Level III, B evidence 4, 1
• Preferred for: 1
  • Younger patients (<40 years)
  • Women of childbearing age
  • Pregnant patients (interferon-α is the only cytoreductive agent safe in pregnancy)
  • Patients with refractory pruritus
• Achieves up to 80% hematologic response rate 1
• Non-leukemogenic and can reduce JAK2V617F allelic burden 1

Monitoring and Follow-Up

• Monitor hematocrit regularly to maintain target values 1
• Evaluate every 3-6 months for new thrombosis, bleeding, signs/symptoms of disease progression, and symptom burden 1
• Bone marrow aspirate and biopsy should be performed prior to initiating cytoreductive therapy to rule out disease progression to myelofibrosis 1
• No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 1

Management of Specific Symptoms

Pruritus

• Selective serotonin receptor antagonists 1
• Interferon-α or JAK2 inhibitors 1
• Antihistamines 1

Erythromelalgia

• Low-dose aspirin is typically effective for these platelet-mediated microvascular symptoms 1

Common Pitfalls to Avoid

• Do not accept hematocrit targets of 45-50%, as the CYTO-PV trial definitively showed increased thrombotic risk at these levels 1
• Avoid chlorambucil and ³²P in younger patients due to significantly increased leukemia risk 1
• Do not use busulfan except in elderly patients >70 years due to increased leukemia risk 1
• Avoid inadequate fluid replacement during phlebotomy, which can precipitate dangerous hypotension, particularly in elderly patients with cardiovascular disease 1

Second-Line Therapy

• Conventional second-line options: Switch between hydroxyurea and interferon-α 4
• Ruxolitinib is indicated for patients with inadequate response or intolerance to hydroxyurea, particularly for severe pruritus or marked splenomegaly not responding to first-line agents 4, 1, 2