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4 A Large-Scale Trial Testing the Intensity of Cytoreductive Therapy to Prevent Cardiovascular Events in Patients with Polycythemia Vera (CYTO-PV trial)Clinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: Plenary Scientific Session
Sunday, December 9, 2012: 3:05 PM
Hall B5, Level 1, Building B (Georgia World Congress Center)

Tiziano Barbui, MD1*, Monia Lunghi, M.D.2*, Alessia Tieghi, M.D.3*, Guido Finazzi, MD1*, Roberto Latagliata, MD4*, Valerio De Stefano, MD5*, Rossella Cacciola, M.D.6*, Caterina Musolino, MD7*, Marco Ruggeri, MD8, Emilio Usala9*, Giorgina Specchia10, Elisa Rumi, MD11*, Maria Luigia Randi12*, Alessandra Iurlo, M.D.13*, Alessandro M. Vannucchi, MD14, Davide Rapezzi15*, Anna Rita Scortechini, MD16*, Francesca Lunghi, MD17*, Maria Carmen Martorelli18*, Daniela Cilloni, MD19, Michele Nobile, MD20*, Sergio Siragusa, MD21, Simone Santini22*, Elena Elli23*, Giuseppe Visani24*, Giovanni Quarta, MD25*, Antonio Spadea26*, Rosa Maria Marfisi27*, Arianna Masciulli, BSc27* and Roberto Marchioli, MD27*

1USC Hematology, Ospedali Riuniti di Bergamo, Bergamo, Italy
2Division of Hematology, Department of Clinical and Experimental Medicine & IRCAD, Amedeo Avogadro University Hospital, Novara, Novara, Italy
3Hematology Unit, Arcispedale S.Maria Nuova
4Hematology, Sapienza University, Rome, Italy
5GIMEMA Italian Myeloma Network, Roma, Italy
6Biomedical Science, Section of Hematology, University of Catania, Catania, Italy
7Hematology Section, University of Messina, Messina, Italy
8S. Bortolo Hospital, Vicenza, Italy
9Hematology and Bone Marrow Transplantation Unit, Ospedale Oncologico Armando Businco, Cagliari, Italy
10Department of Hematology, University of Bari, Bari, Italy
11Department of Hematology Oncology, FFondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
12University of Padua, Italy
13Division of hematology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milano, Italy
14University of Florence, Florence, Italy
15A.O. S.Croce e Carle, Cuneo, Cuneo
16Hematology, OSPEDALI RIUNITI DI ANCONA, Ancona, Italy
17Haematology and Bone Marrow Transplantation Unit - EBMT cic 813, San Raffaele Scientific Institute, Milan, Italy
18Department of Onco-Hematology, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy
19Division of Internal Medicine & Hematology, University of Turin-San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
20Casa Sollievo della Sofferenza San Giovanni Rotondo
21Cattedra ed U.O. di Ematologia, Università degli Studi di Palermo, Palermo, Italy
22Ospedale di Prato
23Ospedale San Gerardo di Monza
24Division of Hematology, Pesaro, Italy
25Division of Hematology, Ospedale A. Perrino, Brindisi, Italy
26Hematology, IFO, Rome, Italy
27Istituto Mario Negri Sud, S. Maria Imbaro, Italy

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.

*signifies non-member of ASH