What is the treatment for CALR (Calreticulin) mutation thrombocytosis?

Treatment for CALR Mutation Thrombocythemia

The treatment for CALR mutation thrombocythemia should be risk-stratified, with low-risk patients receiving observation alone and high-risk patients receiving low-dose aspirin plus cytoreductive therapy. 1

Risk Stratification

Risk assessment is essential for determining appropriate treatment:

• Very Low Risk: Age ≤60 years, no JAK2 mutation (CALR-positive), no prior thrombosis 1
• Low Risk: Age ≤60 years, JAK2 mutation positive, no prior thrombosis 1, 2
• Intermediate Risk: Age >60 years, no prior thrombosis 1
• High Risk: Prior history of thrombosis and/or age >60 years 1

Treatment Recommendations by Risk Category

Very Low/Low Risk CALR-Positive Patients

• Observation alone is appropriate for very low-risk patients (CALR-positive, age ≤60, no thrombosis history) 1, 3
• Avoid aspirin in low-risk CALR-mutated patients as it does not reduce thrombosis risk but may increase bleeding risk (12.9 versus 1.8 episodes per 1000 patient-years) 4, 5
• Monitor for new thrombosis, acquired von Willebrand disease, and disease-related bleeding every 3-6 months 1, 3
• Manage cardiovascular risk factors aggressively if present 3

Intermediate Risk Patients

• Low-dose aspirin (81-100 mg/day) for vascular symptoms 1
• Monitor for thrombosis, acquired von Willebrand disease, and disease-related bleeding 1
• Consider cytoreductive therapy if platelet count exceeds 1,000 × 10^9/L 1, 3

High Risk Patients

• Cytoreductive therapy plus low-dose aspirin (81-100 mg/day) is recommended 1
• First-line cytoreductive options:
  • Hydroxyurea (most commonly used) 1
  • Interferon alfa-2b, peginterferon alfa-2a, or peginterferon alfa-2b (preferred for younger patients and pregnant patients) 1
• Second-line options if intolerant or resistant to first-line therapy:
  • Anagrelide 1
  • Interferon (if not used first-line) 1

Special Considerations for CALR-Mutated Thrombocythemia

• Lower thrombotic risk: CALR-mutated patients have lower thrombotic risk compared to JAK2-mutated patients 4, 6
• Higher bleeding risk with aspirin: CALR-mutated patients may have higher bleeding risk when treated with aspirin compared to JAK2-mutated patients 4, 5
• Extreme thrombocytosis: CALR-mutated patients often require cytoreduction earlier to control extreme thrombocytosis 4, 7
• Better long-term survival: Median survival of approximately 20 years has been reported for CALR-mutated cases 6

Pregnancy Considerations

• Pre-conception evaluation by high-risk obstetrician is recommended 1
• Low-risk pregnancy: Low-dose aspirin (50-100 mg/day) throughout pregnancy and for six weeks postpartum 1
• High-risk pregnancy: Consider prophylactic LMWH with low-dose aspirin throughout pregnancy and for six weeks postpartum 1
• Interferon should be considered if cytoreductive therapy is necessary during pregnancy 1

Monitoring and Follow-up

• Regular monitoring of disease-related symptoms every 3-6 months 1, 3
• Assess need for cytoreductive therapy if symptoms progress 1
• Evaluate for disease progression with bone marrow aspirate and biopsy as clinically indicated 1
• Monitor for thrombotic complications, acquired von Willebrand disease, and disease-related bleeding 1, 3

Common Pitfalls and Caveats

• Avoid aspirin in low-risk CALR-mutated patients due to increased bleeding risk without thrombotic benefit 4, 5
• Consider twice-daily aspirin regimen in patients with persistent thrombocytosis despite treatment, as once-daily dosing may not provide 24-hour coverage 5
• Discontinue aspirin one week prior to surgical procedures and restart 24 hours after surgery 1, 8
• Monitor for extreme thrombocytosis (>1,000 × 10^9/L), which may require cytoreduction due to increased bleeding risk rather than thrombosis risk 3, 4
• Be aware that CALR-mutated patients may require cytoreduction earlier than JAK2-mutated patients to control extreme thrombocytosis 4