Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia

Current risk stratification for thrombosis in essential thrombocythemia (ET) is two-tiered and considers low- and high-risk categories based on the respective absence or presence of either age >60 years or history of thrombosis.1 In the recent International Prognostic Score for Thrombosis in ET (IPSET-thrombosis), age and history of thrombosis were confirmed as independent risk factors for future thrombosis and the study also identified independent prothrombotic role for cardiovascular (CV) risk factors and JAK2V617F mutation.2 This model outperformed the two-tiered conventional risk stratification in predicting future vascular events and was not further affected by the recently discovered CALR mutation.3 In the current study, we re-analyzed the original IPSET-thrombosis data in 1019 patients with WHO-defined ET in whom JAK2 mutational status was available, to quantify the individual contributions of JAK2 mutations and CV risk factors in conventionally assigned low- and high-risk ET. After approval from their respective institutional review boards, seven centers from Italy, Austria and the United States, belonging to the International Working Group for myeloproliferative neoplasm (MPN) Research and Treatment (IWG-MRT), collectively submitted diagnostic and follow-up information on 1220 patients, locally diagnosed with ‘WHO-defined ET'.4 Among these, 1019 patients were selected in whom JAK2 mutational status was available. Objectively proven major arterial and venous events2 were reported as rates per 100 patient-years and the difference among groups was assessed by Mantel Cox log-rank test. The Kaplan–Meier product-limit method was used to estimate thrombosis-free survival curves, and the log-rank test was adopted to compare survival curves. At diagnosis, conventionally assigned low-risk and high-risk groups were significantly different in terms of the frequency of CV risk factors (P60 years but also display JAK2 mutations. In other words, the revised risk stratification scheme might include four categories: ‘very low risk' (no thrombosis history, age ⩽60 years and JAK2-unmutated); ‘low risk' (no thrombosis history, age ⩽60 years and JAK2-mutated); intermediate risk' (no thrombosis history, age >60 years and JAK2-unmutated) and high risk (thrombosis history or age >60 years with JAK2 mutation). Figures 1 c and ​anddd show the thrombosis-free survival probability of patients according to this revised risk stratification. Treatment recommendations for each one of the above-mentioned new risk categories should be examined in the context of prospective controlled studies. Until results from controlled studies become available, we would not insist on the use of aspirin in ‘very low risk' disease without CV risk factors while we advise once-daily aspirin in ‘very low risk' disease with CV risk factors. We believe that it is reasonable, but not mandated, to consider twice-daily aspirin in ‘low-risk' JAK2-mutated patients, especially in the presence of CV risk factors. Similarly, although we encourage the use of cytoreductive therapy in both ‘intermediate risk' and ‘high risk' disease, we would not insist in its use in ‘intermediate-risk' patients, who could be treated, instead, with twice-daily aspirin.