Background
Randomized, open-label, controlled trial. 809 patients with high-risk essential thrombocythemia (ET), defined as requiring cytoreductive therapy. All received low-dose aspirin (100 mg/day). Patients were assigned to cytoreductive therapy with either hydroxyurea (HU) or anagrelide. Primary endpoint was vascular event outcomes. UK multicenter (PT1 = Primary Thrombocythemia 1). Median follow-up 39 months.
Interventions and follow up
Arm A: Hydroxyurea (titrated to platelet control) + low-dose aspirin 100 mg/day (n=405)
Arm B: Anagrelide (titrated to platelet control) + low-dose aspirin 100 mg/day (n=404)
Primary endpoint: Composite of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from thrombotic/hemorrhagic cause
Median follow up: 39 months
Arm B: Anagrelide (titrated to platelet control) + low-dose aspirin 100 mg/day (n=404)
Primary endpoint: Composite of arterial thrombosis, venous thrombosis, serious hemorrhage, or death from thrombotic/hemorrhagic cause
Median follow up: 39 months
Results
Primary composite (anagrelide vs HU): OR 1.57 (95% CI 1.04–2.37), P=.03 — anagrelide INFERIOR
Arterial thrombosis: More with anagrelide, P=.004
Serious hemorrhage: More with anagrelide, P=.008
Transformation to myelofibrosis: More with anagrelide, P=.01
Venous thromboembolism: LESS with anagrelide vs HU, P=.006
Platelet count control: Equivalent between arms
Withdrawals from assigned treatment: More with anagrelide, P<.001
Arterial thrombosis: More with anagrelide, P=.004
Serious hemorrhage: More with anagrelide, P=.008
Transformation to myelofibrosis: More with anagrelide, P=.01
Venous thromboembolism: LESS with anagrelide vs HU, P=.006
Platelet count control: Equivalent between arms
Withdrawals from assigned treatment: More with anagrelide, P<.001
Adverse events
Anagrelide: Higher rates of arterial thrombosis, serious hemorrhage, and MF transformation; more frequent treatment withdrawals due to intolerance
Hydroxyurea: Higher rate of venous thromboembolism versus anagrelide
Hydroxyurea: Higher rate of venous thromboembolism versus anagrelide
Conclusions
Hydroxyurea + low-dose aspirin is superior to anagrelide + low-dose aspirin for high-risk ET, with significantly lower rates of arterial thrombosis, serious hemorrhage, and MF transformation. Anagrelide was associated with lower venous thromboembolic events but overall outcomes were worse. HU + aspirin is the established standard of care for high-risk ET.
Key Limitations
Open-label design may introduce bias in event reporting and treatment adjustment. Anagrelide-treated patients withdrew more often, introducing potential selection bias in long-term follow-up. The higher VTE rate with HU is a notable safety signal. Newer agents (pegylated interferon) were not compared. Risk-stratification criteria were pre-CALR-era and are less precise than modern molecular stratification (JAK2/CALR/MPL status).
Clinical Context
PT1 established hydroxyurea + aspirin as the standard first-line cytoreductive therapy for high-risk ET, a position that remains unchanged over 20 years later. Anagrelide is retained as a second-line option (e.g., HU intolerance). Pegylated interferon alfa-2a is recommended by ELN and ESMO for younger high-risk ET patients due to potential molecular remission induction. JAK2 V617F status, CALR mutation type, and age are now incorporated into modern ET risk stratification beyond traditional criteria.
References