What is the treatment for polycythemia?

Treatment of Polycythemia Vera

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

Risk Stratification

Risk stratification determines treatment intensity and guides therapeutic decisions:

• Low-risk patients are defined as age <60 years with no history of thrombosis 3, 1
• High-risk patients are defined as age ≥60 years and/or any history of thrombosis 3, 1
• This stratification is critical because high-risk patients have significantly elevated thrombotic risk requiring more aggressive intervention 2

Universal First-Line Treatment (All Patients)

Phlebotomy

• Maintain hematocrit strictly <45% through therapeutic phlebotomy 1, 4
• The CYTO-PV randomized trial definitively demonstrated that hematocrit <45% resulted in significantly lower cardiovascular death and major thrombosis (2.7%) compared to hematocrit 45-50% (9.8%), with hazard ratio 3.91 (95% CI 1.45-10.53, P=0.007) 4
• Female patients may require lower targets around 42% due to physiological hematocrit differences 3, 1
• 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 to all patients without contraindications 1, 2
• Aspirin significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism 1
• Avoid aspirin if platelet count >1,500 × 10⁹/L due to increased bleeding risk from acquired von Willebrand disease 1, 2

Cardiovascular Risk Factor Management

• Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, and diabetes 1
• Mandatory smoking cessation counseling and support 1

Treatment by Risk Category

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

• Phlebotomy plus low-dose aspirin is generally sufficient 3, 1
• Monitor for new thrombosis or bleeding every 3-6 months 3, 1
• Cytoreductive therapy is not recommended as initial treatment 3

Indications to add cytoreductive therapy even in low-risk patients:

• Frequent phlebotomy requirement with poor tolerance 3, 1
• Symptomatic or progressive splenomegaly 3, 1
• Severe disease-related symptoms (pruritus, night sweats, fatigue) 3, 1
• Progressive leukocytosis 3, 1
• Platelet count >1,500 × 10⁹/L (extreme thrombocytosis) 1

High-Risk Patients (Age ≥60 or Prior Thrombosis)

• Add cytoreductive therapy to phlebotomy and aspirin 1, 2
• Perform bone marrow aspirate and biopsy to rule out progression to myelofibrosis prior to initiating cytoreductive therapy 3, 1

Cytoreductive Therapy Selection

First-Line Cytoreductive Agents

Hydroxyurea:

• Recommended as first-line cytoreductive agent with Level II, A evidence 1
• Starting dose: 500 mg twice daily, titrate to effect 5
• Use with caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure 1, 6
• Monitor for myelosuppression, which is the most common toxicity 6

Interferon-α:

• Preferred for patients <40 years, women of childbearing age, and pregnant patients with Level III, B evidence 1
• Starting dose: 3 million units subcutaneously 3 times weekly 5
• Achieves up to 80% hematologic response rate 1
• Non-leukemogenic and can reduce JAK2V617F allelic burden 1
• Particularly effective for refractory pruritus 1
• Interferon-α is the only cytoreductive agent recommended in pregnancy 1

Critical pitfall: Never use chlorambucil or ³²P in younger patients due to significantly increased leukemia risk 1

Defining Hydroxyurea Resistance/Intolerance

Hydroxyurea resistance or intolerance is defined by:

• Need for phlebotomy to maintain hematocrit <45% after 3 months of at least 2 g/day 1, 5
• Uncontrolled myeloproliferation despite adequate dosing 1, 5
• Failure to reduce massive splenomegaly or relieve splenomegaly-related symptoms 1, 5
• Development of cytopenia or unacceptable side effects at any dose 1, 5

Second-Line Cytoreductive Therapy

Ruxolitinib:

• Indicated for patients with inadequate response or intolerance to hydroxyurea with Level II, B evidence 1
• The RESPONSE phase III study demonstrated improved hematocrit control, reduction in splenomegaly, and decreased symptom burden 1
• Particularly effective for alleviating pruritus and decreasing splenomegaly 2

Busulfan:

• May be considered only in elderly patients (>70 years) 1
• Generally avoided due to leukemogenic potential 1

Management of Specific Symptoms

Pruritus

• Selective serotonin receptor antagonists 1
• Interferon-α or JAK2 inhibitors 1
• Antihistamines as alternative option 1

Splenomegaly

• Cytoreductive therapy with hydroxyurea or interferon-α 3, 1
• Ruxolitinib for refractory cases 1, 2

Special Populations

Pregnancy

• Interferon-α is the cytoreductive agent of choice due to safety profile 1
• Never use hydroxyurea in pregnancy due to teratogenic risk 1
• Continue phlebotomy and consider low-dose aspirin based on risk-benefit assessment 1

Young Patients (<40 Years)

• Prefer interferon-α over hydroxyurea to avoid potential long-term leukemogenic risk 1
• If hydroxyurea is necessary, use lowest effective dose and monitor closely 1

Monitoring Strategy

• Assess for thrombosis or bleeding every 3-6 months or more frequently if clinically indicated 3, 1
• Monitor hematocrit levels regularly to maintain target values 1
• Assess symptom burden regularly using standardized tools 3, 1
• No routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy 1
• Perform bone marrow biopsy if clinical suspicion for progression to myelofibrosis or acute leukemia 3, 1

Critical Pitfalls to Avoid

• Never accept hematocrit targets of 45-50% as the CYTO-PV trial definitively showed increased thrombotic risk at these levels 1, 4
• Never administer folic acid before or without treating B12 deficiency if present, as folate can mask anemia while allowing irreversible neurological damage 7
• Avoid inadequate fluid replacement during phlebotomy as it can precipitate hypotension, particularly in elderly patients 1
• Do not use live vaccines in patients taking hydroxyurea 6
• Avoid chlorambucil and ³²P in younger patients due to significantly increased leukemia risk 1