What is the treatment for polycythemia vera?

Treatment for Polycythemia Vera

All Patients Require Phlebotomy and Aspirin

Every patient with polycythemia vera must receive therapeutic phlebotomy to maintain hematocrit strictly below 45% combined with low-dose aspirin 81-100 mg daily, unless aspirin is contraindicated. 1, 2 This approach is based on the landmark CYTO-PV trial, which definitively demonstrated that maintaining hematocrit <45% versus 45-50% reduced cardiovascular death and major thrombosis by nearly 4-fold (hazard ratio 3.91) 3. The ECLAP study further confirmed that low-dose aspirin significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 1.

Specific Hematocrit Targets by Demographics

• Men: Maintain hematocrit <45% 1, 2
• Women and African Americans: Target approximately 42% due to physiological differences in baseline hematocrit values 1
• Critical threshold: Hematocrit values >44% are associated with progressive increases in vascular occlusive episodes and suboptimal cerebral blood flow 1

Phlebotomy Safety Considerations

• Perform phlebotomy with careful fluid replacement to prevent hypotension or fluid overload, particularly in elderly patients with cardiovascular disease 1
• Inadequate fluid replacement can precipitate dangerous hypotension, especially in elderly patients 1
• Aggressive phlebotomy has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy 1

Risk Stratification Determines Additional Treatment

Low-Risk Patients (Age <60 Years AND No Prior Thrombosis)

Phlebotomy plus aspirin is generally sufficient for low-risk patients. 1, 2 Real-world data from 453 low-risk patients treated with phlebotomy alone showed a thrombosis incidence rate of only 0.8% per year, with 10-year survival probability of 97% 4. However, only 32-44% of patients maintained adequate hematocrit control at 12-24 months with phlebotomy alone 4.

High-Risk Patients (Age ≥60 Years OR Prior Thrombosis)

High-risk patients require cytoreductive therapy in addition to phlebotomy and aspirin. 1, 2

Additional Indications for Cytoreductive Therapy (Regardless of Age/Thrombosis History)

• Poor tolerance or frequent phlebotomy requirement (≥3 phlebotomies per year) 2, 5
• Symptomatic or progressive splenomegaly 1, 2
• Severe disease-related symptoms 1, 2
• Extreme thrombocytosis (platelet count >1,500 × 10⁹/L) due to acquired von Willebrand disease bleeding risk 1, 6
• Progressive leukocytosis 1, 2

Important caveat: Patients requiring ≥3 phlebotomies per year while on hydroxyurea have a 3.3-fold increased thrombosis risk (20.5% vs 5.3% at 3 years) compared to those requiring ≤2 phlebotomies annually, indicating inadequate disease control 5.

First-Line Cytoreductive Agent Selection

Hydroxyurea for Older Patients

Hydroxyurea (starting dose 500 mg twice daily) is the first-line cytoreductive agent for patients >40 years old. 1, 2 This recommendation carries Level II, A evidence for efficacy and tolerability 1. However, use hydroxyurea with extreme caution in patients <40 years due to potential leukemogenic risk with prolonged exposure 1.

Hydroxyurea resistance/intolerance is defined as:

• Need for phlebotomy to maintain hematocrit <45% after 3 months of ≥2 g/day 1, 2
• Uncontrolled myeloproliferation 1, 2
• Failure to reduce massive splenomegaly 1, 2
• Cytopenia or unacceptable side effects at any dose 1, 2

Interferon-α for Younger Patients and Special Populations

Interferon-α (starting dose 3 million units subcutaneously 3 times weekly) is preferred for patients <40 years, women of childbearing age, and pregnant patients. 1, 2 This agent carries Level III, B evidence and achieves up to 80% hematologic response rate while being non-leukemogenic 1. Interferon-α can reduce the JAK2V617F allelic burden and is particularly effective for refractory pruritus 1.

Absolute preference for interferon-α over hydroxyurea:

• Pregnant patients 1
• Patients <40 years old 1, 2
• Women of childbearing age 1, 2
• Patients with intractable pruritus 1

Agents to Avoid

• Never use chlorambucil or ³²P in younger patients due to significantly increased leukemia risk 1
• Busulfan should only be considered in elderly patients >70 years due to increased leukemia risk 1, 2

Second-Line Therapy

Ruxolitinib is indicated for patients with inadequate response or intolerance to hydroxyurea. 1 The RESPONSE phase III study demonstrated improved hematocrit control, reduction in splenomegaly, and decreased symptom burden with Level II, B evidence 1. Ruxolitinib is particularly effective for alleviating pruritus and decreasing splenomegaly 6.

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 platelet-mediated microvascular symptoms, occurring in approximately 3% of PV patients 1

Cardiovascular Risk Factor Management

Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, and diabetes, with mandatory smoking cessation counseling. 1 Arterial hypertension significantly increases the probability of arterial thrombosis, while high JAK2V617F allele burden trends toward higher venous thrombosis risk 4.

Monitoring Strategy

• Monitor for new thrombosis or bleeding every 3-6 months 1, 7
• Assess symptom burden regularly 1, 7
• Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy 1, 7
• Regular monitoring of hematocrit levels to maintain target values 1
• No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 1

Disease Progression Risks

• 10% risk of transformation to myelofibrosis in the first decade 1
• 12.7% develop myelofibrosis overall 6
• 5% risk of acute leukemia in the first decade, with progressive increase beyond 1
• 6.8% develop acute myeloid leukemia overall 6
• Median survival from diagnosis ranges from 14.1 to 27.6 years across cohorts 6