What is the treatment for polycythemia vera?

Treatment of Polycythemia Vera

Universal First-Line Therapy for All Patients

All patients with polycythemia vera must receive phlebotomy to maintain hematocrit strictly below 45% combined with low-dose aspirin (81-100 mg daily), as this approach significantly reduces cardiovascular death, myocardial infarction, stroke, and major thrombotic events. 1, 2, 3

• The CYTO-PV randomized trial definitively demonstrated that maintaining hematocrit <45% reduces thrombotic events compared to targets of 45-50% (hazard ratio 3.91 for the higher target group, P=0.007) 3
• Women and African Americans may require even lower hematocrit targets (approximately 42%) due to physiological differences in baseline hematocrit values 1, 4
• Low-dose aspirin (100mg daily) significantly reduces the combined endpoint of cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism based on the ECLAP double-blind, placebo-controlled trial 5, 2
• Phlebotomy should be performed with careful fluid replacement to avoid hypotension or fluid overload, particularly in patients with cardiovascular disease 5, 4

Risk Stratification to Guide Cytoreductive Therapy

High-risk patients—defined as age ≥60 years and/or prior thrombotic event—require cytoreductive therapy in addition to phlebotomy and aspirin. 1, 2, 6

Additional indications for cytoreductive therapy include: 1

• Poor tolerance of phlebotomy or requirement of frequent phlebotomies (>3-5 per year)
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms (pruritus, constitutional symptoms)
• Extreme thrombocytosis (platelet count >1,500 × 10⁹/L)
• Progressive leukocytosis

Low-risk patients (age <60 years without prior thrombosis) should be managed with phlebotomy and aspirin alone initially, as this approach achieves 10-year survival of 97% with thrombosis rates of only 0.8% per year. 2, 7

Selection of Cytoreductive Agent

For patients ≥40-60 years old:

Hydroxyurea is the recommended first-line cytoreductive agent (starting dose 500mg twice daily, titrated to effect). 5, 1, 2

• Hydroxyurea has demonstrated superior safety compared to other cytoreductive agents, with significantly lower rates of acute leukemia/MDS at 20 years compared to pipobroman (24% vs 52%, P=0.004) 5
• The definitive leukaemogenic risk of hydroxyurea remains uncertain after prolonged exposure, but it appears safer than alternatives 5

For patients <40 years old and women of childbearing potential:

Interferon-α is preferred (starting dose 3 million units subcutaneously 3 times weekly) to avoid potential long-term leukaemogenic risks in younger patients. 5, 1, 2

• Interferon-α induces high rates of hematological response and significantly reduces the JAK2V617F mutant allele burden in phase II studies 5
• Interferon-α is the only cytoreductive option safe for use during pregnancy 2

Defining Treatment Failure and Second-Line Options

Resistance or intolerance to hydroxyurea is defined as: 1

• Need for phlebotomy to maintain hematocrit <45% after 3 months of at least 2g/day hydroxyurea
• Uncontrolled myeloproliferation (leukocytosis or thrombocytosis)
• Failure to reduce massive splenomegaly or relieve symptoms
• Development of cytopenia or unacceptable side effects at any dose

Patients requiring ≥3 phlebotomies per year while on hydroxyurea have a 3.3-fold increased risk of thrombosis (HR 3.3,95% CI 1.5-6.9, P=0.002) and should be considered for treatment escalation. 8

For hydroxyurea-resistant or intolerant patients, ruxolitinib (a JAK1/2 inhibitor) provides hematocrit control, reduces spleen size, normalizes blood counts, and improves symptoms 9, 6

Management of Specific Symptoms

Pruritus management: 2

• Selective serotonin receptor antagonists (first-line)
• Interferon-α or JAK2 inhibitors (alternative options)
• Antihistamines (additional option)

Monitoring Strategy

Monitor patients every 3-6 months for: 2

• New thrombotic or bleeding events
• Signs/symptoms of disease progression to myelofibrosis
• Symptom burden assessment
• Hematocrit maintenance at target levels

Perform bone marrow aspirate and biopsy to rule out progression to myelofibrosis prior to initiating cytoreductive therapy. 2

Critical Pitfalls to Avoid

• Do not accept hematocrit targets of 45-50%—the CYTO-PV trial clearly demonstrated increased thrombotic risk at these levels 3
• Do not withhold aspirin without clear contraindications—the ECLAP trial showed definitive benefit 5, 2
• Do not use hydroxyurea as first-line in young patients (<40 years)—consider interferon-α to minimize potential long-term leukaemogenic risk 5, 1
• Do not ignore phlebotomy requirement while on hydroxyurea—needing ≥3 phlebotomies/year signals inadequate disease control and increased thrombotic risk 8
• Aggressively manage all vascular risk factors, particularly smoking cessation 5, 2