What is the treatment for polycythemia vera?

Treatment of Polycythemia Vera

Universal First-Line Therapy for All Patients

All patients with polycythemia vera require phlebotomy to maintain hematocrit strictly below 45% combined with low-dose aspirin (81-100 mg daily) unless contraindications exist. 1, 2, 3

• The hematocrit target of <45% is based on the CYTO-PV study, which definitively demonstrated increased thrombotic risk at levels of 45-50%. 1
• Women and African Americans may require lower hematocrit targets (approximately 42%) due to physiological differences. 1
• Phlebotomy should be performed with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease. 1
• Low-dose aspirin significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism. 1, 2
• Aggressive management of all cardiovascular risk factors is mandatory, including smoking cessation, hypertension control, and management of hyperlipidemia and diabetes. 1

Risk Stratification

Risk stratification determines whether cytoreductive therapy is needed beyond phlebotomy and aspirin. 1, 2

High-risk patients are defined as:

• Age ≥60 years and/or history of thrombosis 1, 2, 3

Low-risk patients are defined as:

• Age <60 years with no history of thrombosis 1, 2

Treatment Based on Risk Category

Low-Risk Patients

• Phlebotomy and low-dose aspirin are generally sufficient. 1
• Monitor every 3-6 months for new thrombosis, bleeding, or disease progression. 1

High-Risk Patients

High-risk patients require phlebotomy, low-dose aspirin, PLUS cytoreductive therapy. 1, 2, 3

Additional indications for cytoreductive therapy in any patient include: 1, 2

• Poor tolerance or frequent phlebotomy requirement
• Symptomatic or progressive splenomegaly
• Severe disease-related symptoms
• Platelet count >1,500 × 10⁹/L (due to bleeding risk from acquired von Willebrand disease)
• Progressive leukocytosis

Cytoreductive Therapy Selection

First-Line Cytoreductive Agents

Hydroxyurea (starting dose 500 mg twice daily):

• First-line cytoreductive agent with Level II, A evidence for patients >40 years old. 1, 2
• Should be used with caution in patients <40 years due to potential leukemogenic risk with prolonged exposure. 1
• Resistance/intolerance is defined as: need for phlebotomy to keep hematocrit <45% after 3 months of at least 2 g/day, uncontrolled myeloproliferation, failure to reduce massive splenomegaly, or cytopenia/unacceptable side effects at any dose. 1, 2

Interferon-α (starting dose 3 million U subcutaneously 3 times weekly):

• First-line alternative with Level III, B evidence, particularly preferred for: 1, 2
  • Younger patients (<40 years)
  • Women of childbearing age
  • Pregnant patients (interferon-α is the ONLY cytoreductive agent safe in pregnancy)
  • Patients with intractable pruritus
• Achieves up to 80% hematologic response rate and is non-leukemogenic. 1
• Can reduce JAK2V617F allelic burden. 1

Critical pitfall to avoid: Never use hydroxyurea in pregnant patients; interferon-α is the only acceptable cytoreductive option. 1, 2

Critical pitfall to avoid: Avoid chlorambucil and ³²P in younger patients due to significantly increased leukemia risk. 1

Second-Line Cytoreductive Agents

Ruxolitinib (JAK1/2 inhibitor):

• Indicated for patients with inadequate response or intolerance to hydroxyurea, with Level II, B evidence from the RESPONSE phase III study. 1
• Particularly effective for: 1, 4
  • Protracted pruritus unresponsive to other therapies
  • Marked splenomegaly not responding to hydroxyurea
  • Symptoms reminiscent of post-PV myelofibrosis

Busulfan:

• Consider only in elderly patients >70 years due to increased leukemia risk in younger patients. 1, 2

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 these platelet-mediated microvascular symptoms. 1

Monitoring and Follow-Up

• Monitor for new thrombosis or bleeding 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
• 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

Special Populations

Pregnancy

• Interferon-α is the cytoreductive agent of choice; hydroxyurea is contraindicated. 1, 2

Extreme Thrombocytosis (>1,500 × 10⁹/L)

• Consider cytoreductive therapy even in otherwise low-risk patients due to bleeding risk from acquired von Willebrand disease. 1

Prognosis and Disease Transformation

• Median survival exceeds 10 years with aggressive phlebotomy, compared to <4 years historically with inadequate phlebotomy. 1
• 10% risk of transformation to myelofibrosis in the first decade. 1
• 5% risk of acute leukemia, with progressive increase beyond the first decade. 1
• Median survival ranges from 14.1 to 27.6 years depending on age at diagnosis. 3