Management of Polycythemia Vera
All patients with polycythemia vera require phlebotomy to maintain hematocrit strictly below 45% and low-dose aspirin (81-100 mg daily), with high-risk patients (age ≥60 years or prior thrombosis) additionally requiring cytoreductive therapy with either hydroxyurea or interferon-α. 1, 2
Risk Stratification
Risk stratification determines treatment intensity and must be performed at diagnosis:
- Low-risk patients: Age <60 years AND no history of thrombosis 1
- High-risk patients: Age ≥60 years OR history of thrombosis 1
Universal Treatment for All Patients
Phlebotomy
- Maintain hematocrit strictly <45% in all patients regardless of risk category 1, 3
- Consider lower targets of approximately 42% for women and African Americans due to physiological hematocrit differences 1, 4
- The CYTO-PV trial definitively demonstrated that maintaining hematocrit <45% versus 45-50% reduced cardiovascular death and major thrombosis by nearly 4-fold (hazard ratio 3.91, P=0.007) 3
- Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease 1
Aspirin Therapy
- Administer low-dose aspirin 81-100 mg daily for all patients without contraindications 1, 2
- Aspirin significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 1
Cardiovascular Risk Factor Management
- Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, and diabetes 5, 1
- Mandatory smoking cessation counseling and support 5, 1
Treatment Based on Risk Category
Low-Risk Patients
- Phlebotomy plus low-dose aspirin is generally sufficient as initial therapy 1, 4
- Cytoreductive therapy is NOT recommended as initial treatment 4
- Consider adding cytoreductive therapy if: 5
- Poor tolerance of phlebotomy or frequent phlebotomy requirement
- Symptomatic or progressive splenomegaly
- Severe disease-related symptoms
- Platelet counts >1,500 × 10⁹/L
- Progressive leukocytosis
High-Risk Patients
First-Line Cytoreductive Therapy Options
Hydroxyurea
- First-line cytoreductive agent with Level II, A evidence 1
- Use with caution in young patients (age <40 years) due to potential leukemogenic risk 5
- Approximately 1 in 4 patients develops resistance or intolerance 6
Resistance/intolerance to hydroxyurea is defined as: 5
- Need for phlebotomy to keep hematocrit <45% after 3 months of at least 2 g/day hydroxyurea, OR
- Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L AND WBC >10 × 10⁹/L) after 3 months of at least 2 g/day, OR
- Failure to reduce massive splenomegaly by >50% or relieve splenomegaly symptoms after 3 months of at least 2 g/day, OR
- Absolute neutrophil count <1.0 × 10⁹/L OR platelet count <100 × 10⁹/L OR hemoglobin <10 g/dL at lowest dose required for response, OR
- Presence of leg ulcers or other unacceptable toxicities (mucocutaneous manifestations, GI symptoms, pneumonitis, fever)
Interferon-α (Including Pegylated Forms)
- First-line cytoreductive option with Level III, B evidence 1
- Particularly preferred for: 5, 1
- Younger patients (age <40 years)
- Pregnant patients (ONLY cytoreductive option safe in pregnancy)
- Patients with pruritus
- Achieves up to 80% hematologic response rate 5
- Non-leukemogenic, making it the preferred second-line agent after hydroxyurea failure 5
- Can induce molecular responses with decreased JAK2V617F allele burden 5
Agents to Avoid
- Never use chlorambucil or ³²P in younger patients due to significantly increased leukemia risk 1
- Busulfan may be considered only in elderly patients (age >70 years) 5
Second-Line Cytoreductive Therapy
Ruxolitinib (JAK1/2 Inhibitor)
- Indicated for patients who are resistant to or intolerant of hydroxyurea 6, 2
- Provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms 6
- Particularly effective for alleviating pruritus and decreasing splenomegaly 2
Interferon-α as Second-Line
- Should be strongly considered as second-line therapy because it is non-leukemogenic, unlike some other agents administered after hydroxyurea 5
Symptom Management
Pruritus
Extreme Thrombocytosis
- Consider cytoreductive therapy for platelet counts >1,500 × 10⁹/L due to increased bleeding risk from acquired von Willebrand disease 1, 2
Monitoring and Follow-Up
- Monitor for new thrombosis or bleeding events 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 progression to myelofibrosis prior to initiating cytoreductive therapy 1
- Monitor hematocrit levels regularly to maintain target values 4
- No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 5
Critical Pitfalls to Avoid
- Do not accept hematocrit targets of 45-50%—the CYTO-PV trial definitively showed increased thrombotic risk at these levels 1, 3
- Do not use routine transfusions, which would counteract the therapeutic goal of maintaining hematocrit <45% 7
- Avoid inadequate fluid replacement during phlebotomy, which can precipitate hypotension in elderly patients with cardiovascular disease 1
- Do not withhold cytoreductive therapy in high-risk patients, as phlebotomy and aspirin alone are insufficient 1, 2
Special Populations
Pregnancy
- Interferon-α is the ONLY cytoreductive therapy recommended during pregnancy 1
- Continue low-dose aspirin and phlebotomy as needed 1
Perioperative Management
- Continue low-dose aspirin therapy during the perioperative period to reduce thrombotic risk 7
- Maintain hematocrit <45% before elective surgeries 7
Prognosis
- Median survival from diagnosis ranges from 14.1 to 27.6 years 2
- Approximately 12.7% of patients develop myelofibrosis and 6.8% develop acute myeloid leukemia 2
- Arterial thrombosis occurs in 16% and venous thrombosis in 7% of patients prior to or at diagnosis 2
- Aggressive phlebotomy approach has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy 1