The impact of thrombosis on probabilities of death and disease progression in polycythemia vera: a multistate transition analysis of 1,545 patients
Tiziano Barbui, Alessandra Carobbio, Jüergen Thiele, Naseema Gangat, Elisa Rumi, Alessandro Rambaldi, Alessandro M. Vannucchi, Ayalew Tefferi, IWG-MRT group, Georg Jeryczynski, Leonhard Müllauer, Rakhee Vaidya, Nanna Sulai, Animesh Pardanani, Dirk R. Larson, Mario Cazzola, Ilaria Carola Casetti, Guido Finazzi, Lisa Pieri, Heinz Gisslinger, Bettina Gisslinger, Francesco Rodeghiero, Marco Ruggeri, Maria Luigia Randi, Irene Bertozzi, Francesco Passamonti
Abstract
We applied a parametric Markov five-state model, on a well-characterized international cohort of 1,545 patients with polycythemia vera (PV; median age 61 years; females 51%), in order to examine the impact of incident thrombosis on the trajectory of death or disease progression. At a median follow-up of 6.9 years, 347 (23%) deaths, 50 (3%) blast phase (BP), and 138 (9%) fibrotic (post-PV MF) transformations were recorded. Incident thrombosis occurred at a rate of 2.62% pt/yr (arterial 1.59% and venous 1.05%). The probability of death, in the first 10 years, for 280 (18%) patients who developed thrombosis during follow-up was 40%, which was two-fold higher than that seen in the absence of thrombosis or any other transition state (20%; p < 0.01); the adverse impact from thrombosis was more apparent for arterial (HR 1.74; p < 0.01) vs venous thrombosis (p=NS) and was independent of other fixed (i.e., age, prior venous thrombosis, leukocytosis) or time-dependent (i.e., progression to BP or MF) risk variables. The transition probability to post-PV MF increased over time, in a linear fashion, with a rate of 5% capped at 5 and 10 years, in patients with or without incident thrombosis, respectively. The impact of thrombosis on transition probability to death or post-PV MF tapered off beyond 10 years and appeared to reverse direction of impact on MF evolution at the 12-year time point. These observations suggest thrombosis in PV to be a marker of aggressive disease biology or a disease-associated inflammatory state that is consequential to both thrombosis and disease progression.