What are the current guidelines for diagnosis and treatment of Essential Thrombocythemia (ET)?

Essential Thrombocythemia (ET): Current Guidelines for Diagnosis and Treatment

The diagnosis of Essential Thrombocythemia requires a sustained platelet count ≥450 × 10^9/L, bone marrow showing megakaryocytic proliferation, exclusion of other myeloid neoplasms, and demonstration of JAK2, CALR, or MPL mutations (or absence of reactive thrombocytosis if no mutation is found). 1 Treatment should be risk-stratified, with low-dose aspirin for low-risk patients and cytoreductive therapy added for high-risk patients 1.

Diagnostic Criteria

According to the World Health Organization (WHO) revised criteria, diagnosis of ET requires all four of the following:

1. Sustained platelet count ≥450 × 10^9/L

2. Bone marrow biopsy showing:

   • Proliferation mainly of megakaryocytic lineage
   • Increased numbers of enlarged, mature megakaryocytes with deeply lobulated nuclei
   • No significant increase in neutrophil granulopoiesis or erythropoiesis

3. Not meeting criteria for other myeloid neoplasms:

   • Polycythemia vera (PV)
   • Primary myelofibrosis (PMF)
   • Chronic myeloid leukemia (CML)
   • Myelodysplastic syndromes (MDS)

4. Presence of clonal marker or exclusion of reactive thrombocytosis:

   • JAK2V617F mutation (found in ~60% of ET cases)
   • CALR mutation (found in 60-80% of JAK2-negative cases)
   • MPL mutation (found in 3-5% of cases)
   • If no mutation is found ("triple negative"), reactive thrombocytosis must be excluded 1, 2

Risk Stratification

Risk assessment is crucial for treatment decisions and is based on:

Thrombotic Risk Categories:

• High-risk:

  • Age >60 years OR
  • History of thrombosis

• Low-risk:

  • Age ≤60 years AND
  • No history of thrombosis 1

Some newer risk stratification models include additional factors:

• JAK2V617F mutation status
• Cardiovascular risk factors
• White blood cell count 3

Treatment Recommendations

Low-Risk Patients:

• Low-dose aspirin (81-100 mg/day) 1, 2
• Observation may be appropriate for very low-risk patients (JAK2-negative) 3
• Caution: Aspirin should be used carefully in patients with extreme thrombocytosis (>1500 × 10^9/L) due to risk of acquired von Willebrand syndrome and bleeding 2

High-Risk Patients:

• Cytoreductive therapy plus low-dose aspirin 1
• First-line cytoreductive options:
  • Hydroxyurea (drug of choice, especially in older patients)
  • Interferon-α (preferred in younger patients and pregnant women) 4, 5
• Second-line options (for hydroxyurea resistance/intolerance):
  • Anagrelide
  • Busulfan (mainly in elderly patients) 3

Monitoring and Response Evaluation

Follow-up visits should be scheduled:

• Low-risk ET: Every 6-12 months
• High-risk ET on cytoreduction: Every 3-4 months
• More frequent visits during initial management until stable control is achieved 1

Response criteria according to European LeukemiaNet:

• Complete response: Resolution of disease-related symptoms, normalization of blood counts (platelets ≤400 × 10^9/L, WBC <10 × 10^9/L), no thrombotic/hemorrhagic events, and bone marrow histological remission
• Partial response: Same as complete but without bone marrow histological remission 1

Special Considerations

Hydroxyurea Resistance/Intolerance

Defined as:

• Platelet count >600 × 10^9/L and WBC <2.5 × 10^9/L at any dose, OR
• Platelet count >400 × 10^9/L and hemoglobin <10 g/dL at any dose, OR
• Presence of leg ulcers or other unacceptable mucocutaneous manifestations, OR
• Hydroxyurea-related fever 1

Pregnancy Management

• Low-risk: Low-dose aspirin throughout pregnancy and prophylactic LMWH post-partum
• High-risk: Consider LMWH throughout pregnancy and/or interferon-alpha 6

Disease Progression

ET may transform to:

• Post-ET myelofibrosis: Characterized by bone marrow fibrosis, anemia, leukoerythroblastosis, increasing splenomegaly, and constitutional symptoms
• Acute leukemia: Rare transformation (<1% at 10 years) 3

Key Pitfalls to Avoid

1. Misdiagnosis: Ensure thorough exclusion of reactive thrombocytosis and other myeloproliferative neoplasms
2. Undertreatment: Failure to provide cytoreductive therapy to high-risk patients increases thrombotic risk
3. Overtreatment: Unnecessary cytoreductive therapy in low-risk patients may increase risk of leukemic transformation
4. Inadequate monitoring: Regular follow-up is essential to detect disease progression and treatment complications

The management of ET requires a careful balance between preventing thrombotic complications and avoiding treatment-related toxicity, with decisions guided by individual risk assessment 5, 6.