In Contemporary Patients with Polycythemia Vera, Rates of Thrombosis and Risk Factors Delineate a New Clinical Epidemiology

Abstract

Background Current risk stratification in Polycythemia Vera (PV), is designed to estimate the likelihood of thrombotic complications. In ECLAP large prospective study of 1638 PV cases diagnosed by Polycythemia Vera Study Group (PVSG) criteria, risk factors were age over 65 years and prior thrombotic events. After the JAK2V617F discovery, diagnosis has undergone substantial revision by the World Health Organization (WHO). Consequently, current risk factors determination should be described in patients diagnosed by the most recent recommendations and requires a large sample size with reliable and sufficiently long clinical course documentation. Accordingly, the current study includes 1545 patients with strictly WHO-defined PV diagnosed and followed-up in seven centers from Italy, Austria and the United States, belonging to the International Working Group for Myeloproliferative Neoplasm (MPN) Research and Treatment (IWG-MRT). Objective and design 1) Describe the rate of thrombosis in this population; 2) Report the sites and frequency of recurrences after a first arterial or venous event; 3) Identify separately risk factors for arterial versus venous thrombosis and develop practically useful prognostic models. Results 1. Presenting features The characteristics of the cohort recruited reflected well the heterogeneity of epidemiologic and clinical features that are found in the routine clinical practice of PV. Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) and 114 (7.4%) patients, respectively. The frequencies of arterial and venous thrombosis were lower than those recorded in the ECLAP4 (27% and 11% respectively) but comparable to those reported in the recent Cyto-PV2 (arterial 17%, venous 12%) studies. The discrepancy might be partly related to earlier diagnosis in the post-ECLAP JAK2mutation era. 2. Thrombotic events after diagnosis Median follow-up was 6.9 years and treatment included aspirin (84%) and cytoreductive agents (73%), in addition to phlebotomy. Post-diagnosis total major thrombosis rate was 2.62% pt/yr, lower than reported in the ECLAP trial (4.4% pt/yr) but comparable to the Cyto-PV study (2.7% pt/yr) where management of cardiovascular risk factors was more intensive than in ECLAP. Arterial or venous thrombosis occurred in 184 (12%, rate: 1.59 % pts/yr) and 137 (9%, rate: 1.05 % pts/yr) patients, respectively. In addition, prior arterial events were associated in 75% of cases with subsequent arterial events and in the remaining 25% with venous thrombosis including splanchnic vein events. Moreover, patients with prior venous events had recurrences in venous district in 61% of cases and in the arterial district in 39%. 3. Risk factors for arterial versus venous thrombosis and prognostic models In multivariable analysis, arterial thrombosis was predicted by previous arterial event (HR 1.7, 95% CI 1.2-2.4), and hypertension (HR 1.6, 95% CI 1.2-2.2) while predictors of venous events were previous venous thrombosis (HR 2.6, 95% CI 1.5-4.4), and age ≥ 65 years (HR 1.7, 95% CI 1.2-2.5). We used the above-mentioned risk factors in order to develop prognostic models allowing to identify patients at different probability to develop arterial or venous thrombosis. For arterial thrombosis, the absence of previous arterial thrombosis and hypertension defined lower-risk (rate 1.27 % pts/yr) while the presence of one or both identified higher-risk patients (rate 2.04 % pts/yr). Previous venous event and/or age ≥ 65 years identified patients at higher risk of venous (rate 1.62 % pts/yr) thrombosis and, if absent, patients at lower risk (rate 0.78 % pts/yr). Conclusion The overall rate of thrombosis was half than in ECLAP and should be considered in future clinical trials. Of note, patients with a prior venous thrombosis had a more frequent subsequent recurrence in the venous district but a proportion of them (40%) had also arterial events; conversely, recurrences after previous arterial event were also registered in the leg and non-leg veins in 30 % of cases, indicating that in PV, venous and arterial thrombosis may share some common pathogenetic mechanisms. These findings may have practical implications and suggests antiplatelet therapy and anticoagulant therapy as the favorite choice to prevent arterial and venous thrombosis, respectively, but also suggests studies of antithrombotic drug combination. Disclosures No relevant conflicts of interest to declare.

Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk‐stratification, and management

“…Most recently, mutant CALR (vs JAK2 ) was associated with lower incidence of thrombotic events without necessarily affecting the international prognostic scoring system for thrombosis in ET . In PV, arterial and venous thromboses were the main risk factors for recurrent arterial or venous vascular events, respectively . In addition, history of hypertension predicted arterial thrombosis and advanced age venous thrombosis …”

Patterns of presentation and thrombosis outcome in patients with polycythemia vera strictly defined by WHO‐criteria and stratified by calendar period of diagnosis

“…In a recent article, we documented a change of clinical epidemiology in WHO‐defined as compared with PVSG‐diagnosed PV . In this study of 1,545 cases of WHO‐defined PV, we show significant differences in presenting HB/HCT levels, age, and thrombosis risk among patients diagnosed before or after 2005.…”

“…After approval from their respective institutional review boards, seven centers from Italy, Austria, and the United States, belonging to the International Working Group for MPN Research and Treatment (IWG‐MRT), collectively submitted diagnostic and follow‐up information on 1,818 patients, locally diagnosed with “WHO‐defined PV” . The two principle investigators (AT and TB) reviewed all submitted cases and, based on diagnostic accuracy and eligibility criteria, selected 1,545 patients for further analysis . Patients' diagnosis ranged between 1971 and 2011.…”

“…However, after the JAK2 mutation discovery and the 2008‐WHO diagnostic criteria that combine genetic, laboratory and morphological features contemporary patients represent a more homogeneous population with possible more specific clinico‐hematologic characteristics that might influence patterns of presentation and clinical outcomes . This notion is supported by the results of a recent study in 1,545 WHO‐PV patients in whom the thrombosis incidence was inferior to that registered in the PVSG‐defined PV cohort of ECLAP study . What is not yet known is whether clinical features at presentation and rates of thrombotic events were changing over time even in a homogeneous patient population diagnosed by the current WHO criteria .…”

“…What is not yet known is whether clinical features at presentation and rates of thrombotic events were changing over time even in a homogeneous patient population diagnosed by the current WHO criteria . Using a data base of 1,545 routinely diagnosed practice patients , we have compared the clinical epidemiology in patients diagnosed before and after 2005, when JAK2 V617 mutation analysis was introduced in the diagnostic work‐up of PV. The aim was to provide estimates of major vascular events according to calendar period of diagnosis in contemporary patients potentially eligible in clinical trials.…”