What is the treatment approach for a patient diagnosed with polycythemia?

Treatment Approach for Polycythemia Vera

Universal First-Line Therapy for All Patients

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

• Phlebotomy must target hematocrit <45% 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 targets of approximately 42% due to physiological differences in baseline hematocrit values. 1
• Perform phlebotomy with careful fluid replacement to prevent hypotension, particularly in elderly patients with cardiovascular disease where inadequate fluid replacement can precipitate dangerous hypotension. 1
• Low-dose aspirin (81-100 mg/day) significantly reduces cardiovascular death, non-fatal myocardial infarction, stroke, and venous thromboembolism, and does not increase bleeding risk at this dose. 1
• Aggressively manage all cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, and mandate smoking cessation. 1

Risk Stratification

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

• High-risk patients: Age ≥60 years and/or history of thrombosis. 1
• Low-risk patients: Age <60 years and no history of thrombosis. 1

Treatment Based on Risk Category

Low-Risk Patients

Phlebotomy and low-dose aspirin are generally sufficient for low-risk patients. 1

• Monitor every 3-6 months for new thrombosis, bleeding, or signs of disease progression. 1
• Consider cytoreductive therapy if patients develop intolerable phlebotomy requirements, symptomatic or progressive splenomegaly, severe disease-related symptoms, platelet count >1,500 × 10⁹/L, or progressive leukocytosis. 1

High-Risk Patients

High-risk patients require phlebotomy, low-dose aspirin, plus cytoreductive therapy. 1

• Perform bone marrow aspirate and biopsy to rule out disease progression to myelofibrosis prior to initiating cytoreductive therapy. 1

Cytoreductive Therapy Selection

First-Line Cytoreductive Options

Hydroxyurea is the first-line cytoreductive agent with level II, A evidence for most high-risk patients. 1

• Hydroxyurea demonstrates efficacy and tolerability in most patients. 1
• Use hydroxyurea with caution in patients <40 years due to potential leukemogenic risk with prolonged exposure. 1
• Hydroxyurea resistance/intolerance is defined by: 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

Interferon-α is the preferred first-line cytoreductive option for specific patient populations with level III, B evidence. 1

• Interferon-α is particularly preferred for: patients <40 years, women of childbearing age, pregnant patients, and patients with intractable pruritus. 1
• Interferon-α achieves up to 80% hematologic response rate and is non-leukemogenic. 1
• Interferon-α can reduce the JAK2V617F allelic burden. 1

Second-Line Cytoreductive Options

Ruxolitinib is indicated for patients with inadequate response or intolerance to hydroxyurea, with level II, B evidence. 1

• The RESPONSE phase III study showed improved control of hematocrit, reduction in splenomegaly, and symptom burden. 1
• Ruxolitinib is particularly effective for severe and protracted pruritus or marked splenomegaly not responding to other agents. 1

Busulfan may be considered only in elderly patients >70 years due to increased leukemia risk in younger patients. 1

Management of Specific Symptoms

Pruritus

• Selective serotonin reuptake inhibitors are effective for pruritus. 3
• Interferon-α or JAK2 inhibitors (ruxolitinib) are alternatives for refractory pruritus. 1, 3
• Antihistamines are another option. 1

Erythromelalgia

• Low-dose aspirin (81 mg/day) is typically effective for this platelet-mediated microvascular symptom occurring in approximately 3% of patients. 1, 3

Special Populations

Pregnancy

Interferon-α is the cytoreductive agent of choice over hydroxyurea in pregnant patients due to its safer profile. 1

Extreme Thrombocytosis

• Consider cytoreductive therapy for extreme thrombocytosis (>1,500 × 10⁹/L) due to increased bleeding risk from acquired von Willebrand disease. 1

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. 1
• Avoid chlorambucil and ³²P in younger patients as these agents carry significantly increased leukemia risk (13.2% vs 1.5% for phlebotomy alone at 13-19 years). 4, 1
• Do not perform inadequate fluid replacement during phlebotomy as it can precipitate hypotension, particularly in elderly patients with cardiovascular disease. 1
• Do not neglect cardiovascular risk factor modification as failure to address modifiable factors like smoking worsens outcomes. 1, 3

Long-Term Outcomes and Monitoring

• Aggressive phlebotomy has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy. 1
• Monitor for disease transformation: 10% risk of transformation to myelofibrosis in the first decade and 5% risk of acute leukemia. 1
• There is no routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy. 1