What are the treatment options for polycythemia vera?

Treatment 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 cytoreductive therapy added for high-risk patients (age ≥60 years or prior thrombosis history). 1, 2

Risk Stratification

Risk stratification determines treatment intensity and must be performed at diagnosis:

• 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 substantially elevated thrombotic risk requiring cytoreductive therapy, while low-risk patients can often be managed with phlebotomy and aspirin alone. 1

Universal First-Line Treatment (All Patients)

Phlebotomy

• Target hematocrit <45% in men based on the CYTO-PV study, which definitively demonstrated increased thrombotic events at higher targets 1, 2
• Consider lower targets of approximately 42% for women due to physiological hematocrit differences 1, 4
• Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease 1
• The aggressive phlebotomy approach has improved median survival to >10 years compared to <4 years historically when inadequate phlebotomy was used 1

Aspirin Therapy

• Low-dose aspirin (81-100 mg daily) for all patients without contraindications 3, 1, 2
• This significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism based on the ECLAP study 1
• Low-dose aspirin does not increase bleeding risk 1

Cardiovascular Risk Factor Management

• Mandatory smoking cessation counseling and support 1
• Aggressively manage hypertension, hyperlipidemia, and diabetes 1

Treatment by Risk Category

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

Phlebotomy and aspirin are generally sufficient without cytoreductive therapy initially. 3, 1

• Monitor for new thrombosis or bleeding every 3-6 months 3, 1
• Assess symptom burden regularly 3, 1

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

• New thrombosis or disease-related major bleeding 3
• Frequent and/or persistent need for phlebotomy with poor tolerance 3
• Symptomatic or progressive splenomegaly 3
• Symptomatic thrombocytosis 3
• Progressive leukocytosis 3
• Progressive disease-related symptoms (pruritus, night sweats, fatigue) 3
• Extreme thrombocytosis (>1,500 × 10⁹/L) due to bleeding risk from acquired von Willebrand disease 1, 2

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

Add cytoreductive therapy to phlebotomy and aspirin. 3, 1

Cytoreductive Therapy Selection

First-Line Cytoreductive Agents

Hydroxyurea is the preferred first-line cytoreductive agent for most patients:

• Level II, A evidence for efficacy and tolerability 1
• Starting dose typically 500 mg twice daily 4
• Use with caution in young patients (<40 years) due to potential leukemogenic risk with prolonged exposure 1, 5
• Monitor blood counts at baseline and throughout treatment for myelosuppression 5
• Avoid live vaccines during treatment 5

Interferon-α is preferred as first-line for specific populations:

• Younger patients (<40 years) due to non-leukemogenic profile 1, 4
• Women of childbearing age and pregnant patients due to safer profile than hydroxyurea 1, 4
• Patients with intractable pruritus 1
• Achieves up to 80% hematologic response rate 1
• Can reduce JAK2V617F allelic burden 1
• Starting dose typically 3 million units subcutaneously 3 times weekly 4

Critical caveat: Busulfan may be considered only in elderly patients >70 years due to increased leukemia risk in younger patients. 1 Chlorambucil and ³²P should be avoided in younger patients due to significantly increased leukemia risk. 1

Defining Hydroxyurea Resistance or Intolerance

Hydroxyurea resistance or intolerance is defined by any of the following criteria:

• Need for phlebotomy to keep hematocrit <45% after 3 months of at least 2 g/day 1, 4
• Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L and white blood cell count >10 × 10⁹/L) 1
• Failure to reduce massive splenomegaly by >50% or failure to relieve splenomegaly-related symptoms 1
• Cytopenia (absolute neutrophil count <1.0 × 10⁹/L or platelet count <100 × 10⁹/L or hemoglobin <10 g/dL) at any dose 1
• Unacceptable side effects at any dose 1

Second-Line Cytoreductive Therapy

Ruxolitinib (JAK1/2 inhibitor) is indicated for patients with inadequate response or intolerance to hydroxyurea:

• The RESPONSE phase III study demonstrated improved hematocrit control, reduction in splenomegaly, and decreased symptom burden 1
• Level II, B evidence 1
• Particularly effective for severe and protracted pruritus or marked splenomegaly not responding to other agents 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 these platelet-mediated microvascular symptoms 1
• Occurs in approximately 3% of PV patients, often associated with thrombocythemia 1

Special Populations

Pregnancy

• Interferon-α is the cytoreductive agent of choice over hydroxyurea due to its safety profile 1, 4
• Continue phlebotomy and low-dose aspirin if no contraindications 1

Renal Impairment

• Reduce hydroxyurea dose by 50% in patients with creatinine clearance <60 mL/min 5

Monitoring Strategy

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

Disease Transformation Risk

• 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 approximately 14-27 years from diagnosis 2

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
• Never administer folic acid before or without treating B12 deficiency if present, as folate can mask anemia while allowing irreversible neurological damage to progress 7
• Avoid inadequate fluid replacement during phlebotomy as it can precipitate hypotension, particularly in elderly patients with cardiovascular disease 1
• Do not use chlorambucil or ³²P in younger patients due to significantly increased leukemia risk 1