Hydroxyurea Treatment for Essential Thrombocythemia
Hydroxyurea is the first-line cytoreductive therapy for high-risk essential thrombocythemia patients, with a target platelet count below 400 × 10⁹/L to prevent thrombotic complications. 1
Risk Stratification and Treatment Indications
High-risk patients requiring hydroxyurea include those who are:
- Age ≥60 years 1, 2
- History of prior thrombosis at any age 1, 2
- Platelet count >1,500 × 10⁹/L (due to increased bleeding risk) 1, 3
Low-dose aspirin (81-100 mg daily) should be added for high-risk patients, particularly those ≥60 years when combined with cytoreductive therapy, as this reduces major thrombosis risk despite a compensatory increase in bleeding risk. 1, 2 In JAK2V617F-mutated patients specifically, aspirin reduces venous thrombosis without increasing bleeding, while CALR-mutated patients show increased bleeding without thrombosis benefit. 1
Cytoreductive drugs are not indicated for low-risk patients with well-controlled cardiovascular risk factors. 1
Dosing and Administration
Start hydroxyurea with the following approach:
- Standard dosing: 2 g/day 1, 3, 4
- For patients >80 kg: 2.5 g/day 3, 4
- Titrate to achieve platelet count <400 × 10⁹/L 3, 2
The evidence supporting hydroxyurea's efficacy is strong: a landmark randomized trial demonstrated that hydroxyurea reduced thrombotic episodes from 24% to 3.6% in high-risk ET patients over 27 months of follow-up. 5
Monitoring Response
Evaluate treatment response using these parameters:
- Platelet count <400 × 10⁹/L 3, 2
- WBC count <10 × 10⁹/L 3, 2
- Resolution of disease-related symptoms 3
- Monitor complete blood counts every 4-8 weeks once stabilized 3
No routine bone marrow monitoring is needed for clinical follow-up. 1, 3 Bone marrow examination is reserved only for assessing transformation to myelofibrosis or acute leukemia. 1, 3
Recent data shows that achieving complete hematological response (CHR) with hydroxyurea in high-risk patients reduces arterial thrombosis risk by 65% (HR: 0.35) and shows a trend toward lower venous thrombosis. 6 CHR is also associated with longer survival and lower myelofibrosis incidence. 6
Defining Resistance and Intolerance
Resistance to hydroxyurea is defined by:
- Platelet count >600 × 10⁹/L after 3 months of ≥2 g/day (or 2.5 g/day if >80 kg) 1, 3, 4
- Platelet count >400 × 10⁹/L with hemoglobin <10 g/dL at any dose 1, 3
- Platelet count >400 × 10⁹/L with absolute neutrophil count <1.0 × 10⁹/L at the lowest effective dose 1, 3
Intolerance is defined by:
- Leg ulcers or unacceptable mucocutaneous manifestations 1, 3, 4
- Hydroxyurea-related fever 1, 4
- GI symptoms, pneumonitis at any dose 1
Second-Line Therapy
When resistance or intolerance develops:
- Anagrelide is the recommended second-line therapy for ET 1, 3
- Interferon-alpha (rINFα) is an alternative second-line option 1, 3
The 2018 European LeukemiaNet guidelines reached consensus on both hydroxyurea and interferon-alpha as first-line options, but did not reach consensus on anagrelide as first-line due to concerns about evidence quality and risk-benefit ratio from the PT-1 trial. 1 However, the ANAHYDRET trial showed anagrelide was non-inferior to hydroxyurea for preventing thrombotic complications, though this evidence was rated as moderate quality. 1
Critical Safety Considerations
Use hydroxyurea with extreme caution in patients <40 years old due to long-term leukemogenic risk. 1, 3, 4 For young patients requiring cytoreduction, interferon-alpha should be strongly considered as an alternative. 1, 2
Mandatory dose reduction or discontinuation criteria:
Patients receiving multiple cytotoxic agents have significantly higher risk of developing acute myeloid leukemia/myelodysplastic syndromes, making the choice of second-line therapy critical. 1 This is why non-leukemogenic agents like anagrelide or interferon are preferred after hydroxyurea failure. 1
For pregnant patients requiring cytoreduction, interferon-alpha should be used instead of hydroxyurea. 3, 2
Additional Management
All patients with ET should have: