Management of 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), while high-risk patients (age ≥60 years or prior thrombosis) additionally need cytoreductive therapy with hydroxyurea as first-line or interferon-α in specific situations. 1, 2
Risk Stratification Framework
Risk stratification determines treatment intensity and guides cytoreductive therapy decisions 1:
- Low-risk patients: Age <60 years AND no history of thrombosis 1, 3
- High-risk patients: Age ≥60 years OR history of thrombosis 1, 3, 2
Universal First-Line Treatment (All Patients)
Phlebotomy Protocol
- Target hematocrit <45% in men based on the CYTO-PV study, which definitively demonstrated increased thrombotic risk at higher levels 1, 3
- Target approximately 42% for women due to physiological hematocrit differences 1
- Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease 1
- The aggressive phlebotomy approach has improved median survival to >10 years compared to <4 years historically 1
Aspirin Therapy
- Low-dose aspirin (81-100 mg daily) for all patients without contraindications 1, 3, 2
- The ECLAP study demonstrated significant reduction in cardiovascular death, non-fatal myocardial infarction, stroke, and major venous thromboembolism 1
Cardiovascular Risk Factor Management
- Mandatory smoking cessation counseling and support 1
- Aggressively manage hypertension, hyperlipidemia, and diabetes 1, 4
Cytoreductive Therapy Indications
Cytoreductive therapy is indicated for 1, 3:
- High-risk patients (age ≥60 years or prior thrombosis)
- Poor tolerance or frequent phlebotomy requirement
- Symptomatic or progressive splenomegaly
- Severe disease-related symptoms
- Platelet count >1,500 × 10⁹/L
- Progressive leukocytosis
Cytoreductive Agent Selection Algorithm
First-Line: Hydroxyurea
- Hydroxyurea (starting dose 500 mg twice daily) is the first-line cytoreductive agent with level II, A evidence 1, 3
- Preferred for older patients (>40 years) 3
- Use with caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure 1, 3
Hydroxyurea resistance/intolerance is defined as 1:
- Need for phlebotomy to keep hematocrit <45% after 3 months of at least 2 g/day
- Uncontrolled myeloproliferation
- Failure to reduce massive splenomegaly
- Cytopenia or unacceptable side effects at any dose
First-Line Alternative: Interferon-α
Interferon-α (starting dose 3 million U subcutaneously 3 times weekly) is preferred in specific situations 5, 1, 3:
- Younger patients (<40 years) due to non-leukemogenic profile 1, 3
- Women of childbearing age and pregnant patients (safer profile than hydroxyurea) 5, 1, 3
- Intractable pruritus (can reduce JAK2V617F allelic burden) 5, 1
- Achieves up to 80% hematologic response rate 1
Second-Line: Ruxolitinib
- Ruxolitinib is indicated for patients with inadequate response or intolerance to hydroxyurea (level II, B evidence) 1
- The RESPONSE phase III study showed improved hematocrit control, reduction in splenomegaly, and symptom burden 1
- Particularly effective for protracted pruritus and symptoms reminiscent of post-PV myelofibrosis 6
Alternative for Elderly: Busulfan
- Busulfan (initial dosage 4 mg/day) may be considered only in elderly patients (>70 years) 5, 1
- Recognize potential toxicity to lungs (pulmonary fibrosis) and bone marrow (aplasia), although infrequent 5
- Use intermittent treatment with drug holidays 5
Treatment by Risk Category
Low-Risk Patients
- Phlebotomy to maintain hematocrit <45% plus low-dose aspirin is generally sufficient 1, 3
- Add cytoreductive therapy only if symptomatic or meeting other specific indications 1
High-Risk Patients
- Phlebotomy plus low-dose aspirin plus cytoreductive therapy (hydroxyurea or interferon-α) 1, 3
- Consider interferon-α over hydroxyurea in younger high-risk patients to avoid potential long-term leukemogenic risk 1
Management of Specific Symptoms
Pruritus
- Selective serotonin receptor antagonists as first-line 1
- Interferon-α or JAK2 inhibitors (ruxolitinib) for refractory cases 1
- Antihistamines as alternative option 1
Microvascular Disturbances (Erythromelalgia)
- Erythromelalgia occurs in approximately 3% of PV patients and is often associated with thrombocythemia 5
- Low-dose aspirin is typically effective for platelet-mediated microvascular symptoms 5
Monitoring and Follow-Up
- Monitor for new thrombosis or bleeding 1
- Evaluate for signs/symptoms of disease progression every 3-6 months 1
- Assess symptom burden regularly 1
- Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy 1
- Monitor hematocrit levels closely to maintain target values 1
- No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 1
Special Populations
Pregnancy
- Interferon-α is the cytoreductive agent of choice over hydroxyurea due to safer profile 1, 3
- Phlebotomy alone plus low-dose aspirin may be sufficient for low-risk pregnant patients 5
Extreme Thrombocytosis
- Consider cytoreductive therapy for platelet count >1,500 × 10⁹/L due to increased bleeding risk from acquired von Willebrand disease 5, 2
Critical 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
- Avoid inadequate fluid replacement during phlebotomy as it can precipitate hypotension, particularly in elderly patients with cardiovascular disease 1
- Do not use routine transfusions as they counteract the therapeutic goal of maintaining hematocrit <45% 7
Disease Transformation Risk
- 10% risk of transformation to myelofibrosis in the first decade 5
- 5% risk of acute leukemia in the first decade, with progressive increase beyond 5, 2
- Current treatment strategies have not been shown to modify the risk of disease transformation 5
- Median survival ranges from 14.1 to 27.6 years, exceeding 35 years in young patients 6, 2