What is the management and treatment of Polycythemia Vera?

Management and Treatment of Polycythemia Vera

Core Treatment Strategy

All patients with polycythemia vera require phlebotomy to maintain hematocrit strictly below 45% plus low-dose aspirin (81-100 mg daily), with cytoreductive therapy added for high-risk patients (age ≥60 years or prior thrombosis history). 1, 2, 3

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, 2
• High-risk patients: Age ≥60 years OR history of thrombosis 1, 2, 3

Universal Treatment for All Patients

Phlebotomy

• Target hematocrit <45% in men based on the CYTO-PV study, which definitively showed increased thrombotic risk at levels of 45-50% 2, 3
• Target approximately 42% in women due to physiological hematocrit differences 2
• Perform with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease 2
• This aggressive approach has improved median survival to >10 years compared to <4 years historically 2

Antiplatelet Therapy

• Low-dose aspirin (81-100 mg/day) for all patients without contraindications 1, 2, 3
• The ECLAP study demonstrated significant reduction in cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 2
• Low-dose aspirin does not increase bleeding risk 2

Cardiovascular Risk Management

• Mandatory smoking cessation counseling and support 2
• Aggressive management of hypertension, hyperlipidemia, and diabetes 2, 4

Treatment Based on Risk Category

Low-Risk Patients

Phlebotomy plus low-dose aspirin is generally sufficient 2

High-Risk Patients

Add cytoreductive therapy to phlebotomy and aspirin 1, 2, 3

First-Line Cytoreductive Options

Hydroxyurea:

• Recommended as first-line cytoreductive agent with Level II, A evidence 1, 2
• Efficacious and well-tolerated in most patients 2
• Use with caution in patients <40 years due to potential leukemogenic risk with prolonged exposure 2

Interferon-α:

• Recommended as first-line alternative with Level III, B evidence 1, 2
• Preferred for:
  • Younger patients (<40 years) 1, 2
  • Women of childbearing age 1, 2
  • Pregnant patients 2
  • Patients with intractable pruritus 1, 2
• Achieves up to 80% hematologic response rate 2
• Non-leukemogenic profile 2
• Can reduce JAK2V617F allelic burden 2

Indications for Cytoreductive Therapy Beyond Risk Status

• Intolerance or frequent need for phlebotomy 2
• Symptomatic or progressive splenomegaly 2
• Severe disease-related symptoms 2
• Platelet count >1,500 × 10⁹/L 2
• Progressive leukocytosis 2

Second-Line Cytoreductive Therapy

Ruxolitinib:

• Indicated for patients with inadequate response or intolerance to hydroxyurea 2, 3
• The RESPONSE phase III study showed improved hematocrit control, reduction in splenomegaly, and decreased symptom burden with Level II, B evidence 2
• Particularly effective for alleviating pruritus and decreasing splenomegaly 3

Hydroxyurea resistance/intolerance is defined by:

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

Busulfan:

• Consider only in elderly patients >70 years due to significantly increased leukemia risk in younger patients 2

Management of Specific Symptoms

Pruritus

• Selective serotonin reuptake inhibitors 5, 2
• Interferon-α or JAK2 inhibitors 2
• Antihistamines as alternative option 2

Erythromelalgia

• Low-dose aspirin is typically effective for these platelet-mediated microvascular symptoms 2
• Occurs in approximately 3% of PV patients, often associated with thrombocythemia 2

Microvascular Disturbances

• Often controlled with low-dose aspirin 5

Monitoring and Follow-Up

• Monitor for new thrombosis or bleeding 2
• Evaluate for signs/symptoms of disease progression every 3-6 months 2
• Assess symptom burden regularly 2
• Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy 2
• Regular monitoring of hematocrit levels to maintain target values 2
• No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 2

Special Populations

Pregnant Patients

Interferon-α is the cytoreductive agent of choice over hydroxyurea due to its safer profile 2

Young Patients (<40 years)

Consider interferon-α over hydroxyurea due to concern about possible leukemogenicity with long-term hydroxyurea or busulfan therapy 1, 2

Extreme Thrombocytosis

Consider cytoreductive therapy for platelet count >1,500 × 10⁹/L due to increased bleeding risk from acquired von Willebrand disease 2, 3

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 2
• Avoid chlorambucil and ³²P in younger patients as these agents carry significantly increased leukemia risk 2
• Avoid inadequate fluid replacement during phlebotomy as it can precipitate hypotension, particularly in elderly patients with cardiovascular disease 2

Disease Transformation Risk

• 10% risk of transformation to myelofibrosis in the first decade 2
• 5% risk of acute leukemia, with progressive increase beyond 2
• Overall, 12.7% develop myelofibrosis and 6.8% develop acute myeloid leukemia 3
• No controlled treatment has been shown to influence disease transformation 5

Prognosis

• Median survival from diagnosis ranges from 14.1 to 27.6 years across cohorts 3
• Prior to or at diagnosis, arterial thrombosis occurs in 16% and venous thrombosis in 7% of patients 3
• Thrombotic events can involve unusual sites such as splanchnic veins 3