ATLANTA – It took a randomized clinical trial to show that current treatment recommendations for polycythemia vera are right on target, investigators from Italy reported at the annual meeting of the American Society of Hematology.
Patients with JAK2-positive polycythemia vera who were randomized to an intensive hematocrit management strategy (target below 45%) had a fourfold lower risk of death, major cardiovascular complications, or major thrombotic events than patients treated to a target of 45% to 50%, reported Dr. Tiziano Barbui, professor of hematology at the Ospedali Riuniti di Bergamo, Italy.
When superficial vein thrombosis, a secondary endpoint, was added into the primary endpoint (a composite of cardiovascular deaths and thrombosis), the death rate for the less-than-45% target was 4.4%, compared with 10.9% in the 45%-50% group, Dr. Barbui said.
"We confirm that hematocrit less than 45% should be the target of therapy in polycythemia vera," Dr. Barbui said.
The findings were also published online in the New England Journal of Medicine (2012 Dec. 8 [doi: 10.1056/NEJMoa1208500]).
Polycythemia vera is a rare neoplasm in which there is overproliferation of bone marrow progenitor cells, leading in turn to overproduction of erythroid cells and increased red cell mass. Patients are at significantly elevated risk for cardiovascular complications and death from thrombosis and bleeding, as well as from hematologic transformation into acute leukemia or overt myelofibrosis.
It is typically treated with phlebotomy, cytoreductive drugs, or both.
The incidence of polycythemia vera is about 2-3 per 100,000, presenting most commonly in individuals aged 50-70 years, Dr. Barbui said, and is slightly higher among Jews of eastern European descent.
Optimal Approach Was Uncertain
Dr. Barbui and his colleagues undertook the study because of the uncertainty of the science behind the recommendations, which were based on studies showing proportional increases in thrombotic events among patients with higher hematocrit levels and platelet counts. But there was also concern that more intensive therapy needed to reach the hematocrit target could come at the cost of poor tolerability and adverse events, Dr. Barbui said.
The study enrolled 365 patients with a polycythemia vera diagnosis according to World Health Organization 2008 criteria, and assigned them to either a less-than-45% hematocrit target or the 45%-50% range. Treatment was at the investigators’ discretion, although they were encouraged to give hydroxyurea to high-risk patients (those over age 65 or with a history of thrombosis).
The trial was closed earlier than planned, in February 2012, because of competition for patients from clinical trials of JAK-2 inhibitors.
Dr. Barbui presented data from an intention-to-treat analysis.
At a median follow-up of 31 months, 2.8% of patients in the less-than-45% group had experienced one or more of the events in the composite primary endpoint (stroke, acute coronary syndrome, transient ischemic attack, pulmonary embolism, abdominal thrombosis, deep vein thrombosis, or peripheral arterial thrombosis), compared with 9.8% of those in the 45-50% group. The hazard ratio for the primary endpoint with the less intensive targeting strategy was 3.91 (P = .005).
The HR for total cardiovascular events (with superficial vein thrombosis thrown in for good measure) was 2.69 (P = .012).
Gender Disparity Noted
In an editorial accompanying the NEJM article, Dr. Jerry L. Spivak of the hematology/oncology division at Johns Hopkins University in Baltimore noted that women normally have a lower red-cell mass and hematocrit than men, putting women with polycythemia vera at risk for intra-abdominal venous thrombosis, even when their hematocrit appears to be normal.
"Therefore the hematocrit target described by [the investigators] is adequate for men but inadequate for women, who on the basis of other studies should have a target hematocrit of less than 42%," he wrote.
Dr. Barbui and Dr. Spivak reported no relevant conflicts of interest.