JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis

Abstract

Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.

Fig. 1. Venous and arterial thrombosis-free survival for JAK2V617F positive PV patients from training cohort stratified by their JAK2V617F VAF (>50% vs ≤50%).

Kaplan–Meier curves representing venous thrombosis-free survival (A) and arterial thrombosis-free survival (B) including a total of 576 PV patients. The number of patients at risk for each time point is shown below the graph. Tick marks indicate censored data.

Fig. 2. Venous thrombosis-free survival for low and high-risk JAK2V617F positive PV patients from training and validation cohorts stratified by their JAK2V167F VAF (>50% vs ≤50%).

Kaplan–Meier curves representing venous thrombosis-free survival for training cohort considering those at low risk (A) and high risk (B) at diagnosis. The same analysis on validation cohort patients at low-risk (C) and high-risk (D). The number of patients at risk for each time point is shown below the graph. Tick marks indicate censored data.

Fig. 3. Venous and arterial thrombosis-free survival for JAK2V617F positive PV patients from validation cohort stratified by their JAK2V617F VAF (>50% vs ≤50%).

Kaplan–Meier curves representing venous thrombosis-free survival (A) and arterial thrombosis-free survival (B) including a total of 289 PV patients. The number of patients at risk for each time point is shown below the graph. Tick marks indicate censored data.