Prospective randomized trials have shown that patients with "high-risk" essential thrombocythemia (aged >60, prior thrombotic history and/or cardiovascular risk factors) have a lower thrombotic risk if treated with hydroxycarbamide compared to no cytoreduction, and that hydroxycarbamide reduces risks of major vascular events, arterial thrombosis, serious hemorrhage and post-ET myelofibrosis (PET-MF) compared to anagrelide. However there are no prospective data evaluating the effects of cytoreduction in ET patients lacking high-risk factors. We undertook a prospective, open-label, randomized trial comparing hydroxycarbamide plus aspirin with aspirin alone in patients with "intermediate-risk" ET.


Patients were recruited from 198 hospitals in 5 countries. Intermediate-risk patients were aged 40 to ≤ 59 years and lacked the following high-risk criteria: current or previous platelet count ≥1000x109/l (≥1500x109/l from 06/05/2004); previous ischemia, thrombosis or embolism; hemorrhage due to ET; hypertension or diabetes requiring therapy. 382 patients were randomized between 21/07/1997 and 31/07/2012 in a 1:1 ratio to aspirin alone or aspirin plus hydroxycarbamide; 24 were subsequently identified to be ineligible and excluded (Fig 1A). The composite primary endpoint was time from randomization to arterial or venous thrombosis, serious hemorrhage or death from vascular causes. Secondary endpoints were time to first arterial or venous thrombosis or to first serious hemorrhage; time to death; incidence of transformation to PET-MF, acute myeloid leukemia (AML), myelodysplasia (MDS) or polycythemia vera (PV); and patient-reported quality of life. The required duration of follow-up was calculated as the maximum period of time required for either a significantly different treatment effect or a point estimate for the number needed to treat to prevent one endpoint per year of >100, with a lower limit of the 95% confidence interval (CI) >50. Intention-to-treat analyses were performed.


Median duration of follow-up was 73 months (range, 0 to 187) with total follow-up of 2373 patient-years. 47% of the aspirin alone group started cytoreduction during follow-up whilst 21% of the aspirin plus hydroxycarbamide arm stopped hydroxycarbamide and/or started another cytoreductive agent (Fig 1A). Median time without treatment change was 36 months in the aspirin alone arm and 55 months in the aspirin plus hydroxycarbamide arm (p<0.001). Platelet counts were significantly different between the arms early on and started to overlap 5-6 years after entry (Fig 1B).

The composite primary endpoint of time from randomization to arterial or venous thrombosis, serious hemorrhage or death from vascular causes was not significantly different between the arms (hazard ratio 0.98, 95% CI 0.43-2.27, p=1.0, Fig 1C). The incidence of significant vascular events for the whole study was 0.93 per 100 patient-years (95% CI 0.61-1.41). There was no significant difference in overall survival between the arms (p=0.5, Fig 1D), nor in the composite endpoint of rate of transformation to PET-MF, AML or MDS (p=0.7, Fig 1E). The rate of PV transformation was significantly higher in the aspirin alone arm (p=0.01, Fig 1E), most likely reflecting the non-specific effect of hydroxycarbamide in constraining erythropoiesis. A pre-specified analysis for any major disease-related complication - arterial thrombosis, venous thromboembolism, major hemorrhage, transformation to AML, MDS, PET-MF or death from any of these causes - showed no difference between the arms (p=0.6). There were no significant differences in the frequency of adverse events including non-hematological cancers. Quality of life data were recorded annually for five years using the EORTC QLQ-C30 questionnaire (v2), with no significant differences in summary scores in any year


In ET patients aged 40-59 who lack high-risk factors pre-emptive addition of hydroxycarbamide to aspirin did not reduce the risk of vascular events or myelofibrotic or leukemic transformation. These results indicate that intermediate-risk ET patients should be treated with aspirin alone until another clinical indication for cytoreduction arises. Moreover patients receiving hydroxycarbamide showed no increase in leukemic transformation or other malignancies, supporting the concept that hydroxycarbamide is a safe therapy for ET.


McMullin: Italfarmaco S.p.A.: Consultancy; Shire, Novartis: Honoraria, Speakers Bureau. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison: Shire: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI: Speakers Bureau.

Author notes


Asterisk with author names denotes non-ASH members.

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