In Polycythemia Vera, 45 Is the Number

An increased red blood cell mass distinguishes polycythemia vera (PV) from other myeloproliferative neoplasms (MPNs) and is associated with an increased risk of thrombosis and cardiovascular death. Elevation of the platelet and white blood cell count are shared features between PV and other MPNs; while an association between the degree of thrombocytosis and thrombosis has not been established, an emerging body of data suggests a link between leukocytosis and an excess risk of thrombosis. Risk stratification and management of PV is primarily based on reducing thrombosis, the complication that imposes the greatest morbid burden and risk of death. Data from prospective and retrospective trials of PV (and essential thrombocytosis) indicate that age > 60 or prior history of thrombosis identify individuals with a high risk of vascular complications; lower-risk patients exhibit neither risk factor.¹  Lower-dose aspirin (e.g., 81-100 mg daily) with phlebotomy is the cornerstone of therapy for low-risk patients, and cytoreductive therapy with hydroxyurea is added to this regimen in high-risk individuals. While current guidelines recommend that phlebotomy be undertaken to maintain a hematocrit < 45 percent (and by inference, a target goal of < 42% in women), post-hoc analyses of studies from the Polycythemia Vera Study Group and the European Collaboration on Low-Dose Aspirin in Polcythemia Vera (ECLAP) have not reinforced this hematocrit threshold; for example, thrombosis rates were not increased in the hematocrit range of 45 to 50 percent.^2,3 

Dr. Roberto Marchioli and investigators from the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) Collaborative Group conducted a multicenter, randomized trial of PV patients in order to test the hypothesis that a hematocrit target of < 45 percent confers a lower rate of cardiovascular death and major thrombosis than a target of 45 to 50 percent. Stratification of 365 patients was partly based on age (< 65 years or ≥ 65 years) and on absence or presence of a history of thrombosis. Baseline patient characteristics were well-matched. Individuals were randomized to treatment with phlebotomy and hydroxyurea, with intensity of therapy geared toward maintaining a target hematocrit < 45 percent (low-hematocrit group) versus 45 to 50 percent (high-hematocrit group). With a median follow-up of 31 months, the primary composite endpoint of death from cardiovascular causes or major thrombotic events occurred in five out of 182 patients (2.7%) in the low-hematocrit group and in 18 out of 183 patients (9.8%) in the high-hematocrit group (hazard ratio 3.91, P=0.007). Total cardiovascular events occurred in 4.4 percent of patients in the low-hematocrit group and 10.9 percent of those in the high-hematocrit group (hazard ratio 2.69, P=0.02). There was no significant difference in adverse events, including bleeding, or in evolution to myelofibrosis and myelodysplastic syndrome, or leukemia. In the low- and high-hematocrit groups, the median hematocrit level was maintained at 44.4 percent and 47.5 percent, respectively, and 75 percent of patients in each arm maintained the hematocrit in the assigned target range. While the platelet count was not significantly different between treatment arms, the leukocyte count was significantly higher in the high-hematocrit group.