No Added Benefit When Hydroxyurea Is Combined With Aspirin in Middle-Aged Patients With Essential Thrombocythemia

Cytoreductive treatment with hydroxyurea has been shown to reduce the risk of thrombosis in patients with essential thrombocythemia (ET) and high-risk features, which include age >60 years or prior thrombosis or hemorrhage. But patients aged 40 to 59 years who lack high-risk features do not benefit from addition of hydroxyurea to aspirin, according to results of an open-label, randomized trial published in the Journal of Clinical Oncology. Compared with aspirin alone, the hydroxyurea/aspirin combination did not reduce rates of vascular events, leukemic transformation, or myelofibrotic transformation in patients with “intermediate-risk” ET.

Based on these results, the authors, led by Anna L. Godfrey, BMBCh, PhD MRCP, FRCPath, from Cambridge University Hospitals National Health Service (NHS) Foundation Trust, recommended that patients age 40 to 59 years without other clinical indications for treatment (such as previous thrombosis or hemorrhage) and with platelet counts <1,500×109/L should not receive cytoreductive therapy.

For this open-label, prospective, randomized study, the researchers recruited patients with newly diagnosed or previously treated ET from 140 hospitals across five countries and regions (Australia, France, New Zealand, Ireland, and the U.K.) over a 15-year enrollment period. All participants were between 40 to 59 years old and had intermediate-risk ET, defined by the investigators as:

  • no history of ischemia, thrombosis, or embolism
  • no hemorrhage caused by ET
  • no hypertension or diabetes requiring pharmacologic therapy
  • no history of extreme thrombocytosis (defined in this study as platelet counts 1,500×109/L)

This age group was selected based on previous research indicating that middle-aged patients have a slightly higher thrombotic risk than younger patients, the authors explained.

The 382 participants were randomly assigned 1:1 to receive either:

  • single-agent aspirin 75 mg/day (100 mg/day in Australia; n=176)
  • aspirin plus oral hydroxyurea 0.5 to 2 g/day (n=182)

In the hydroxyurea group, dosage was adjusted to maintain platelet counts within the range of 200 to 400×109/L.

At trial entry, the investigators collected peripheral blood samples from 259 patients for DNA extraction, which was subsequently screened for mutations in JAK2, CALR, or MPL. In 177 patients, a bone marrow trephine biopsy was performed at the start of the trial to confirm the diagnosis.

Patients were followed for a median of 73 months (range = 0-187 months), encompassing 2,373 total patient-years.

During follow-up, there were no significant differences between the aspirin monotherapy and hydroxyurea/aspirin groups in terms of the composite endpoint (time from randomization to thrombosis- or hemorrhage-related death or to a serious hemorrhage or thrombotic event). Investigators observed 11 events in each treatment group, for an odds ratio (OR) of 0.98 (95% CI 0.42-2.25; p=1.0). Incidence of the primary endpoint also did not differ based on the presence of JAK2, CALR, or MPL mutations, age at trial entry, sex, or blood counts at diagnosis (all p>0.05).

Rates of the secondary endpoint (including time to first arterial or venous thrombotic event or to the first serious hemorrhage; time to death; incidence of transformation to myelofibrosis, acute myeloid leukemia, myelodysplastic syndromes, or polycythemia vera; and patient-reported quality of life) are summarized in the TABLE.

The incidence rate of vascular events was low in both study groups, at 0.93 per 100 patient-years during follow-up, the authors reported, adding that “there remained no significant difference in this endpoint in a prespecified secondary analysis, in which patients were censored on reaching the age of 60 years, because most would start cytoreduction at this age if they were not already receiving it.”

Although more deaths were reported in the hydroxyurea arm compared with the aspirin-alone arm (10 and 7, respectively), there was no significant difference between the two groups in terms of overall survival (OR=1.4; 95% CI 0.54-3.61; p=0.5).

The rate of disease transformation during the 6-year follow-up period was low in both arms, and there was no difference between the groups for this endpoint (OR=0.79; 95% CI 0.24-2.58; p=0.7). However, a greater number of patients in the aspirin-alone arm were subsequently diagnosed with polycythemia vera, compared with the hydroxyurea arm (6 vs. 0; p=0.01). This finding was “in keeping with the nonspecific effect of hydroxyurea in constraining erythropoiesis,” the authors explained.

In addition, patients in each treatment group experienced similar rates and types of adverse events (most commonly minor hemorrhage and gastroenterologic symptoms) and reported similar quality-of-life scores throughout the study.

Although the researchers recruited patients from 140 hospitals, the sample size was still relatively small, representing a potential limitation of the analysis. An additional limitation was the long recruitment period of the study, during which diagnostic criteria for ET were refined by the World Health Organization.

The authors report financial relationships with Novartis, Amgen, Celgene, Roche, and Bristol-Myers Squibb (a manufacturer of hydroxyurea).


Godfrey AL, Campbell PJ, MacLean C, et al. Hydroxycarbamide plus aspirin versus aspirin alone in patients with essential thrombocythemia age 40 to 59 years without high-risk features. J Clin Oncol. 2018 August 28. [Epub ahead of print]