What are the guidelines for managing a patient with polycythemia, including treatment options and monitoring protocols?

Management of Polycythemia Vera

Risk Stratification

All patients with polycythemia vera must be immediately stratified into high-risk (age ≥60 years and/or any history of thrombosis) or low-risk (age <60 years with no thrombosis history) categories, as this determines whether cytoreductive therapy is required. 1

• High-risk patients are defined as those aged ≥60 years or with any prior thrombotic event 1
• Low-risk patients are those aged <60 years without any thrombosis history 1

Universal First-Line Treatment (All Patients, Regardless of Risk)

Every patient with polycythemia vera requires phlebotomy to maintain hematocrit strictly below 45% and low-dose aspirin 81-100 mg daily, unless contraindications exist. 1

Phlebotomy Protocol

• Target hematocrit <45% for men, with lower targets of approximately 42% for women and African Americans due to physiological differences 1
• Perform phlebotomy as frequently as needed to maintain target—there is no absolute limit on frequency 1
• Always provide careful fluid replacement during phlebotomy to prevent hypotension, particularly in elderly patients with cardiovascular disease 1
• The CYTO-PV study definitively showed increased thrombotic risk at hematocrit levels of 45-50%, making strict adherence to the <45% target critical 1
• Aggressive phlebotomy has improved median survival to >10 years compared to <4 years historically with inadequate phlebotomy 1

Aspirin Therapy

• Administer 81-100 mg daily to all patients without contraindications 1
• The ECLAP study demonstrated significant reduction in cardiovascular death, non-fatal myocardial infarction, stroke, and major venous thromboembolism 1
• Low-dose aspirin does not increase bleeding risk 1

Cardiovascular Risk Factor Management

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

Cytoreductive Therapy Decision Algorithm

Low-Risk Patients

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

• Consider cytoreductive therapy only if: 1
  • Intolerance or frequent need for phlebotomy becomes burdensome
  • Symptomatic or progressive splenomegaly develops
  • Severe disease-related symptoms emerge
  • Platelet count exceeds 1,500 × 10⁹/L
  • Progressive leukocytosis occurs

High-Risk Patients

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

First-Line Cytoreductive Options

Hydroxyurea is the preferred first-line cytoreductive agent for most high-risk patients (Level II, A evidence). 1

• Dosing: 2 g/day (2.5 g/day if body weight >80 kg) 1
• Target response: hematocrit <45% without phlebotomy, platelet count ≤400 × 10⁹/L, and WBC count ≤10 × 10⁹/L 1
• Critical caveat: Use hydroxyurea with caution in patients <40 years due to potential leukemogenic risk with prolonged exposure 1

Interferon-α is the preferred first-line alternative in specific situations (Level III, B evidence): 1

• Patients <40 years of age 1
• Women of childbearing age 1
• Pregnant patients (interferon-α is the only cytoreductive agent safe in pregnancy) 1
• Patients with refractory pruritus 1
• Achieves up to 80% hematologic response rate and is non-leukemogenic 1
• Can reduce JAK2V617F allelic burden 1

Defining Hydroxyurea Resistance or Intolerance

Switch to second-line therapy if any of the following occur after 3 months of at least 2 g/day hydroxyurea: 1

• Need for phlebotomy to keep hematocrit <45% 1
• Uncontrolled myeloproliferation (platelet count >400 × 10⁹/L and WBC count >10 × 10⁹/L) 1
• Failure to reduce massive splenomegaly 1
• Development of cytopenia or unacceptable side effects at any dose 1

Second-Line Cytoreductive Options

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

• The RESPONSE phase III study showed improved hematocrit control, reduction in splenomegaly, and decreased symptom burden 1
• Particularly effective for refractory pruritus and symptoms reminiscent of post-PV myelofibrosis 1

Interferon-α as second-line therapy should be considered after hydroxyurea failure because it is non-leukemogenic. 1

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

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

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 platelet-mediated microvascular symptoms 1
• Occurs in approximately 3% of PV patients, often associated with thrombocythemia 1

Monitoring Protocol

Monitor every 3-6 months in stable patients: 1

• Hematocrit levels to maintain target values 1
• Complete blood count 1
• New thrombotic or bleeding events 1
• Signs/symptoms of disease progression 1
• Symptom burden assessment 1

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

There is no routine indication to monitor JAK2V617F allele burden except when using interferon-α therapy. 1

Special Considerations

Pregnancy

Interferon-α is the only cytoreductive agent of choice in pregnancy—never use hydroxyurea. 1

Extreme Thrombocytosis

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

Perioperative Management

• Continue low-dose aspirin during the perioperative period to reduce thrombotic risk 3
• Closely monitor hematocrit levels before, during, and after any procedure 3

Critical Pitfalls to Avoid

• Never accept hematocrit targets of 45-50%—the CYTO-PV trial definitively showed increased thrombotic risk at these levels 1
• Never perform phlebotomy without adequate fluid replacement, especially in elderly patients with cardiovascular disease, as this can precipitate dangerous hypotension 1
• Never use hydroxyurea as first-line therapy in patients <40 years without considering interferon-α due to leukemogenic risk 1
• Never use chlorambucil or ³²P in younger patients due to significantly increased leukemia risk 1
• Blood transfusions are generally contraindicated in polycythemia vera as they increase red cell mass and exacerbate hyperviscosity, potentially increasing thrombotic risk 3

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 ranges from 14.1 to 27.6 years depending on age at diagnosis 2