Study Confirms Treatment Target in Patients With Polycythemia Vera

Tiziano Barbui, MD

To prevent potentially fatal cardiovascular complications in patients with polycythemia vera (PV), hematocrit values should be maintained at levels below 45%, a clinical trial has found. Patients with the rare form of blood cancer whose hematocrit levels hover between 45% and 50% have a four-fold higher incidence of thrombotic complications, according to the results of a study presented during the 54th Annual Meeting of the American Society of Hematology.

The randomized trial was the first ever to confirm the 45% threshold, a common recommendation in managing PV that previously was supported solely by hemorheology and retrospective studies and consensus of experts, explained Tiziano Barbui, MD, professor of Hematology and scientific director of the Research Foundation at Ospedali Riuniti di Bergamo, in Italy.

A post-hoc analysis of two previous large, randomized clinical trials did not show a significant increase in major thrombosis when a hematocrit value of 45% to 50% was maintained, Barbui said.

“There are some data showing that this recommendation is not so solid, and when you are uncertain, you need to do a clinical trial,” Barbui said. “It was also necessary because if you adopt an intensive therapy to reach the target, this could result in poor tolerance and treatment toxicity.”

PV affects two or three of every 100,000 people, with a higher incidence among some Jewish people of European descent, Barbui said. The disorder, which involves the production of too many red blood cells, typically presents when patients are between 50 and 70 years of age.

Known as the Cytoreductive Therapy in Polycythemia Vera—or Cyto-PV—trial and conducted at 21 centers in Italy, the study tested the efficacy and safety of keeping hematocrit values below 45%, compared with maintaining them at levels between 45% and 50%, in 365 patients with PV. The endpoint was the incidence of major thrombosis or cardiovascular death. Secondary endpoints included total cardiovascular events (the primary endpoint plus superficial vein thrombosis), as well as the incidence of hematological transformation to myelofibrosis and acute leukemia.

In a follow-up at 31 months, one group’s hematocrit was measured at a median level of 44%, while the other group had a median level of 48%, the authors wrote. Hematocrit was controlled with phlebotomy or hydroxyurea, or a combination of both, and most patients also took low-dose aspirin. Treatments were more intensive in the <45% arm.

At follow-up, investigators found that five of 182 patients (2.8%) in the low-hematocrit group had experienced major cardiovascular events or thrombosis, compared with 18 of 183 patients (9.8%)—including four who died&mdash;in the highhematocrit group (hazard ratio [HR] in the highhematocrit group = 3.91; P = .005). That translated into an incidence of death from cardiovascular causes or thrombosis of 1.1 per 100 person-years in the low-hematocrit group, and 4.4 per 100 person-years in the high-hematocrit group, Barbui reported.

OncLive TV Exclusive

Dr. Tiziano Barbui on Hematocrit Levels in Polycythemia Vera

The secondary endpoint of total cardiovascular events occurred in eight patients (4.4%) in the low-hematocrit group and 20 patients (10.9%) in the high-hematocrit group (HR = 2.69; P = .012).

On the other hand, “slight, nonsignificant increases in rates of hematologic progression and solid cancer were observed in the low-hematocrit group,” the authors wrote. “However, the followup period was too short to make inference about transformation rates into myelofibrosis, myelodysplasia, or leukemia in the two study groups.”

Looking at time to primary endpoint, Barbui said, the study found that “the probability of thrombosis-free survival for patients in the low-hematocrit arm approaches 95% or more; contrarily, thrombosis-free survival was 80% in the high-hematocrit arm, and this difference is highly significant.” He said the percentages were nearly identical when it came to the secondary endpoint of total cardiovascular events.

There were no differences in the safety profile between arms.

The authors concluded that a hematocrit level below 45% “is significantly associated with a prevention of thrombotic complications, and is confirmed to be the target of therapy in PV.”

While an initial goal was to enroll 1000 patients in Cyto-PV, the study was closed once it included 365 patients due to a progressive decline in enrollment. The decline occurred, in part, because of competition with clinical trials of JAK2 inhibitors, which may be able to lower hematocrit levels in PV patients without phlebotomy, Barbui said.

Despite the low enrollment, the study’s results are valid, he said.

“Doctors should convince these patients that, if they want to reduce the incidence of major thrombotic events that could be the cause of death or disability, they should take this hematocrit as the target of their therapies,” Barbui said.

Barbui T, Lunghi M, Tieghi A, et al. A large-scale trial testing the intensity of cytoreductive therapy to prevent cardiovascular events in patients with polycythemia vera (CYTO-PV trial). Blood. (ASH Annual Meeting Abstracts). 2012;120(21): abstr 4.