Refining prognostication of thrombosis in ET
Authors: Tiziano Barbui
Journal: American Journal of Hematology (2016)

The principal causes of morbidity and mortality in patients with essential thrombocythemia (ET) are thrombosis, bleeding, and progression to myelofibrosis (MF) or acute myelogenous leukemia (AML). There is concern that myelosuppressive therapy given to prevent vascular events can accelerate the rate of hematological transformation. Thus, the therapeutic dilemma in ET is how to prevent bleeding and thrombosis without increasing the risk of MF and AML. To tackle this dilemma, a risk-adapted treatment strategy is recommended. Conventional major risk factors for thrombotic events are increasing age and previous vascular episodes. Younger than 60 years and asymptomatic ET patients with platelet count below 1,500 × 109/L are considered at "low-risk" for thrombotic events and do not require myelosuppression. On the other hand, cytoreductive agents are recommended in patients above 60 years, or with a history of major thrombosis 1-3 Recent studies have raised the possibility of additional thrombotic risk factors in ET; these include cardiovascular risk factors (e.g., diabetes, hypertension, smoking), leukocytosis, the presence of JAK2V617F and its allele burden 4. However, the issue is still uncertain and is confounded by the lack of a broad-based multicenter study with large sample size and diagnostic accuracy 5. Lately, the International Prognostic Score for Thrombosis in ET (IPSET-thrombosis) confirmed age >60 years and history of thrombosis as independent risk factors for future thrombotic events among patients diagnosed according to the 2008 World Health Organization (WHO) diagnostic criteria for ET and also identified independent prothrombotic role for cardiovascular (CV) risk factors and JAK2V617F mutation 6. To each of these factors independently associated with thrombosis, an integer weight close to the corresponding hazard ratios (HR) resulting from the analysis was assigned and a new prognostic model was developed. Patients were categorized at "low, intermediate, and high risk" with rates of thrombosis of 1.03% patients/year (pts/yr) vs. 2.35% pts/yr vs. 3.56% pts/yr, respectively. 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 7. The applicability of the IPSET-thrombosis model in therapeutic decision making has been questioned 8 in particular in low risk patients in whom the residual annual rate of major arterial and venous thrombotic events was around 1%, a figure significantly higher than of non MPN general population calculated around 0.5% for arterial and 0.1% for venous thrombosis 9, 10. A re-analysis of the original IPSET-thrombosis data was conducted in 1,019 patients with ET, with the intent to quantify the individual contributions of JAK2 mutations and CV risk factors in conventionally assigned low and high risk ET, as well as in age- versus thrombosis-defined high risk status 11. A remarkably lower risk of thrombosis was found in low-risk JAK2-unmutated patients, especially if without CV risk factors (0.44% pts/yr vs. 1.05% pts/yr for those with CV risk factors) that clearly distinguishes them from conventionally assigned "low-risk" patients with JAK2 mutations, irrespective of the presence of CV risk factors. Therefore, it is reasonable to further risk-stratify conventionally assigned "low-risk" ET into "very low risk" and "low risk" categories 11, 12. Conventional high-risk patients with both risk factors had a significantly higher risk of thrombosis compared to their counterparts without JAK2 mutations and CV risk factors, that are classified as intermediate risk subgroup (P = 0.011). Additional analysis revealed limited enhancement of thrombosis risk by either JAK2 mutations or CV risk factors or both in patients whose high-risk status was defined by the presence of thrombosis history, regardless of age (P = ns). In contrast, the presence of JAK2 mutations, with or without CV risk factors, might have affected thrombotic risk in patients where high-risk status was defined by age alone (P = 0.05). In conclusion, the revised-IPSET thrombosis study delineates risk sub-groups whose current treatment approach might be modified accordingly (Fig. 1). Individual rates of thrombosis according to revised IPSET-thrombosis risk categories. These observations were validated by Mahnur et al. 13 in this issue of the journal. In an independent data set of 585 patients with WHO-defined ET followed-up at Mayo Clinic, these authors confirmed significant differences in thrombosis risk between "very low" and "low" (HR = 2.4, 95% CI = 1.1–5.3) and between "intermediate" and "high" (HR = 2.3, 95% CI = 1.1–5.2) risk patients. Furthermore, in multivariable analysis, they confirmed that only JAK2V617F (HR = 1.8, 95% CI = 1.07–2.94) and history of thrombosis (HR = 2.1, 95% CI = 1.20–3.58) were independently predictive of future thrombotic events. Therefore, the existence of a very low risk group of ET patients raises the issue whether aspirin should be indicated as primary prophylaxis in the subgroup of younger, asymptomatic cases, with the absence of CV and JAK2 mutation where its risk-benefit profile is of uncertain net value 14. On the contrary, the residual high rate of incident events in low risk JAK2 mutated patients with or without CV risk factors suggests inadequacy of current conventional therapy prophylaxis with once daily aspirin. Notably, there is demonstration of superior biological efficacy of twice-daily dosing to obtain a 24-hr optimal suppression of thromboxane-A2 synthesis in the presence of high platelet turnover as in patients with ET 15 and in this subgroup the risk-benefit profile of twice daily aspirin might be favorable. Therefore, according to this modified model based on the individual risk of thrombosis, a risk-based treatment algorithm has been proposed (Fig. 2) 12. Contemporary treatment algorithm in essential thrombocythemia. Another important finding highlighted in the Mahnur paper, regards the different prognostic weight exerted by age as compared to thrombosis history in conventionally defined high-risk group. They looked at the individual role of JAK2V617F and CV risk factors and demonstrated a trend toward significant effect of JAK2V617F in conventionally high-risk patients in whom high-risk disease status was defined by advanced age only. In contrast, there was no significant additional effect of either JAK2V617F or CV risk factors in conventionally high-risk patients in whom high-risk status was defined by thrombosis history. These findings corroborate the notion that JAK2 mutation and thrombosis history should be considered the two main prognostic factors for risk stratification of ET patients in clinical practice 12. Interestingly, additional data from the Mahnur paper is that around 15% of patients classified at low risk per the original IPSET-thrombosis were reclassified as intermediate risk and that a subset of IPSET-thrombosis at high risk were reclassified at low risk. This reclassification of the original IPSET-thrombosis underscores the value of this new classification and highlights an important impact in therapeutic decisions. In conclusion, the revised IPSET-thrombosis prognostic pattern represents a further improvement of risk classification of patients with ET, and after its validation, well designed prospective studies with the intent to reduce the still high residual rate of major thrombosis in this myeloproliferative neoplasm are warranted.