A Large-Scale Trial Testing the Intensity of Cytoreductive Therapy to Prevent Cardiovascular Events in Patients with Polycythemia Vera (CYTO-PV trial)
Authors: Barbui Tiziano , Lunghi Monia , Tieghi Alessia , Finazzi Guido , Latagliata Roberto , De Stefano Valerio , Cacciola Rossella , Musolino Caterina , Ruggeri Marco , Usala Emilio , Specchia Giorgina , Rumi Elisa , Randi Maria Luigia , Iurlo Alessandra , Vannucchi Alessandro M. , Rapezzi Davide , Scortechini Anna Rita , Lunghi Francesca , Martorelli Maria Carmen , Cilloni Daniela , Nobile Michele , Siragusa Sergio , Santini Simone , Elli Elena , Visani Giuseppe , Quarta Giovanni , Spadea Antonio , Marfisi Rosa Maria , Masciulli Arianna , Marchioli Roberto 
Published: October 2019

Abstract
Abstract 4

Introduction
Current treatment recommendations in polycythemia vera (PV) have emphasized to maintain the hematocrit (HCT) values <0.45 based on hemorrheological notions, results of a few small observational retrospective studies and consensus of experts. However, post-hoc analysis of two large randomized clinical trials (namely PVSG-1 and ECLAP) failed to show a different incidence of major thrombosis when HCT levels were kept in the range between 0.40 and 0.50. So far, no randomized clinical trial has provided evidence-based data assessing the usefulness of tight HCT control in reducing thrombosis. Thus, uncertainty of the optimal HCT target exists in clinical practice.

Aim
In a large scale randomized clinical trial (Cyto-PV) we prospectively determined the efficacy and safety of maintaining the recommended HCT target versus HCT levels in the range of 0.45–0.50 to prevent thrombotic events in PV patients.

Methods
Patients were eligible if they met WHO-2008 diagnostic criteria for PV. Both cases with newly diagnosed disease and previous treatment were centrally randomized to Arm A (HCT <0.45) ) or to Arm B (HCT 0.45–0.50). The composite primary end points from randomization were major thrombosis (stroke, acute coronary syndrome, transient ischemic cerebral attack, peripheral arterial thrombosis, pulmonary embolism, abdominal thrombosis, deep vein thrombosis), and cardiovascular death. Secondary end points were the incidences of hematological transformation to myelofibrosis and acute leukemia. From February 2008 to May 2012, 21 Italian hematological centers enrolled 365 patients. The trial was closed in May 2012 because the research network had reached its maximal recruitment potential and the effect of the two treatment strategies were evaluated as to efficacy and safety.

Results
Arm A and Arm B included 182 and 183 patients respectively. At randomization, there were no significant differences between the two groups with respect to age, gender, years from diagnosis to recruitment, previous history of major thrombosis, bleeding, concomitant cardiovascular risk factors, and hematological presentation. Treatments were equally distributed with regard to phlebotomy, antiplatelet drugs, warfarin and hydroxyurea or their combination. After randomization, median HCT levels in arm A and Arm B during follow-up (median 31.0 months) were 0.44 and 0.48 respectively. A quarter of patients of arm A and Arm B failed to maintain the assigned HCT levels during the study period. Noticeable was that leukocyte levels remained higher in arm B than Arm A while no difference was revealed concerning the platelet count. Additionally, no difference in the safety profile was recognizable. As compared with arm B, the more intensive treatment aimed at maintaining the HCT <45% reduced the risk of the primary combined endpoint ( 1.1% versus 4.4% /patients per year; HR =3.90, p=0.007). Seven patients developed overt myelofibrosis (6 in Arm A and 1 in Arm B; p=0.10). There was no difference concerning frequencies of acute leukemia that occurred in 3 and 1 patients of Arm A and B respectively.

Conclusion
In this randomized clinical trial, the incidence of major cardiovascular events was 4 fold higher in patients who maintained HCT levels >0.45. Therefore, an HCT level <0.45 is significantly associated with a prevention of thrombotic complications and is confirmed to be the target of therapy in PV.

Disclosures:
No relevant conflicts of interest to declare.