What is the initial management strategy for patients with myeloproliferative disorders, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis?

Initial Management of Myeloproliferative Disorders

The initial management of myeloproliferative disorders should be risk-stratified, with low-risk patients receiving phlebotomy plus aspirin for polycythemia vera, aspirin alone for essential thrombocythemia, and symptom-directed therapy for primary myelofibrosis, while high-risk patients additionally require cytoreductive therapy, typically with hydroxyurea or interferon-α. 1, 2

Risk Stratification

Polycythemia Vera (PV)

• Risk categories:
  • Low-risk: Age <60 years AND no history of thrombosis
  • High-risk: Age ≥60 years OR history of thrombosis 1, 2

Essential Thrombocythemia (ET)

• Risk categories:
  • Low-risk: Age <60 years AND no history of thrombosis
  • High-risk: Age ≥60 years OR history of thrombosis 1

Primary Myelofibrosis (PMF)

• Risk assessment is more complex and includes:
  • Age
  • Constitutional symptoms
  • Hemoglobin level
  • Leukocyte count
  • Peripheral blood blast percentage
  • Cytogenetics 1

Initial Management Algorithm

Polycythemia Vera

Low-risk PV:

1. Phlebotomy to maintain hematocrit <45% 1, 2

   • Target is based on the CYTO-PV trial showing nearly 4-fold increased risk of cardiovascular events with hematocrit 45-50% compared to <45% 2
   • May need individualization to 42% for women 1

2. Low-dose aspirin (81-100 mg daily) 1, 2

   • The ECLAP trial demonstrated significant reduction in the combined endpoint of nonfatal MI, nonfatal stroke, pulmonary embolism, major venous thrombosis, or cardiovascular death (RR 0.40; 95% CI 0.18-0.91) 1

3. Aggressive management of cardiovascular risk factors 1, 2

   • Smoking cessation
   • Blood pressure control
   • Lipid management
   • Weight management

High-risk PV:

• All measures for low-risk PLUS:
• Cytoreductive therapy with one of the following:
  • Hydroxyurea (first-line for most patients) 1, 2
  • Interferon-α (preferred for younger patients <40 years and women of childbearing age) 1, 2

Essential Thrombocythemia

Low-risk ET:

• Low-dose aspirin (81-100 mg daily) if microvascular symptoms are present 1
• Observation if asymptomatic

High-risk ET:

• Low-dose aspirin 1
• Cytoreductive therapy with hydroxyurea 1
  • The PT-1 trial demonstrated that hydroxyurea plus aspirin reduced thrombotic events compared to anagrelide plus aspirin 1

Primary Myelofibrosis

• Symptom-directed therapy based on disease manifestations:
  • Anemia: Erythropoiesis-stimulating agents, danazol, or immunomodulatory drugs
  • Splenomegaly: Hydroxyurea or ruxolitinib
  • Constitutional symptoms: Ruxolitinib
• Allogeneic stem cell transplantation consideration for eligible intermediate-2 or high-risk patients 1

Additional Indications for Cytoreductive Therapy

Even in low-risk patients, cytoreductive therapy should be initiated if any of the following develop:

• New thrombosis or major bleeding
• Poor tolerance of phlebotomy (PV)
• Symptomatic or progressive splenomegaly
• Platelet count >1,500 × 10^9/L (increased bleeding risk)
• Progressive leukocytosis
• Severe disease-related symptoms (pruritus, night sweats, fatigue) 1

Monitoring Response to Therapy

Polycythemia Vera

• Monitor hematocrit (target <45%)
• Complete blood count every 3-6 months
• Assess for symptoms of disease progression
• Evaluate for signs of transformation to myelofibrosis or acute leukemia 1

Essential Thrombocythemia

• Monitor platelet count (target <400 × 10^9/L with cytoreductive therapy)
• Complete blood count every 3-6 months
• Assess for thrombotic or bleeding complications 1

Special Considerations

Resistance/Intolerance to Hydroxyurea

• For PV: Consider switching to interferon-α if resistance or intolerance develops according to European LeukemiaNet criteria 1
• For elderly patients (>70 years): Busulfan may be considered as second-line therapy 1

Thrombosis Prevention in Myeloproliferative Neoplasms

• The pooled prevalence of thrombosis is 28.6% in PV, 20.7% in ET, and 9.5% in PMF 1
• Thrombosis can precede PV diagnosis by many years 1
• Avoid chlorambucil and phosphorus-32 due to increased risk of leukemic transformation 2

Pitfalls and Caveats

1. Inadequate hematocrit control: Failure to maintain hematocrit <45% significantly increases thrombotic risk 2

2. Underuse of aspirin: Low-dose aspirin is critical for reducing thrombotic events in PV and symptomatic ET 1, 3

3. Overtreatment of low-risk patients: Cytoreductive therapy is not recommended as initial treatment for low-risk patients with well-controlled cardiovascular risk factors 1

4. Inadequate monitoring: Regular assessment for disease progression to myelofibrosis or acute leukemia is essential 1, 2

5. Missing secondary causes: For secondary polycythemia (e.g., testosterone-induced), consider reducing testosterone dosage or switching to transdermal formulation before initiating phlebotomy 2

6. Inappropriate iron supplementation: Iron should only be given in cases of severe symptomatic iron deficiency 2