For years, expert consensus has recommended phlebotomy and hydroxyurea as the standard first-line therapies for polycythemia vera (PV). Current guidelines advise the use of phlebotomy, hydroxyurea and low-dose aspirin in high-risk patients and phlebotomy and aspirin alone for low-risk patients. High-risk patients include those over the age of 60 or anyone with a history of thrombosis.
Concerns about the potential increase in leukemic transformation associated with hydroxyurea have led to some calls to consider only phlebotomy as first-line therapy. Clinical trials and retrospective analyses to date have not demonstrated that hydroxyurea reduces thrombosis or extends survival, according to a recent review in the New England Journal of Medicine. That review recommends phlebotomy to reduce hematocrit to less than 45% in men and less than 42% in women and use of aspirin for microvascular events such as ocular migraine, transient ischemic attacks and erythromelalgia, regardless of risk assessment.
A new prospective analysis of 1,042 patients with polycythemia vera who participated in the European Collaborative Low-dose Aspirin (ECLAP) trial compared overall survival, disease progression and cardiovascular events in patients who received only phlebotomy or hydroxyurea. Researchers followed patients for an average of 2.8 years. The 2 groups were well balanced for age, gender, time since diagnosis, thrombotic history, aspirin use and cardiovascular risk factors.
The low rate of cardiovascular events, transformation and death in low-risk patients receiving either treatment precluded drawing any significant comparisons. Among high-risk patients, however, the difference in outcomes was striking.
Figure: High power magnification showing blasts with large nuclei and prominent nucleoli
(Figure 1 from Development of Myelodysplastic Syndrome and Acute Myeloid Leukemia 15 Years
after Hydroxyurea Use in a Patient with Sickle Cell Anemia Published in Clinical Medicine
The study found that patients treated with phlebotomy alone had three times the mortality rate of those receiving hydroxurea (0.3 vs 0.1 per 100 per years, respectively). Phlebotomy alone patients also had twice the rate of total cardiovascular events compared to patients receiving hydroxurea alone (5.8 vs 3.0 per 100 person years, respectively) and more than 7 times the cardiovascular mortality rate (0.7% vs 5%).
The study provided clear data in favor of hydroxyurea in reducing the risk of hematologic transformation as well. In the hydroxyurea group, the rate of transformation of all types was just 0.1 per 100 person years, while in the phlebotomy group it was more than 10-fold higher at 1.1 per 100 per person years. Two patients in the phlebotomy group and one in the hydroxyurea group developed acute leukemia. Notably, PV in 8 patients in the phlebotomy group transformed to myelofibrosis, whereas none in the hydroxyurea group did.
Fewer patients in the phlebotomy group reached the target hematocrit of less than 45% at 1 year (31% vs 52%) or at later follow up points.
Among high-risk PV patients, the researchers concluded the study demonstrated “an efficacy and safety profile of HU strongly suggestive of a positive role in reducing overall mortality, mainly associated with CV events and inferior rate of myelofibrosis evolution, in comparison with PHL treated patients.”