Arterial Versus Venous Events in Essential Thrombocythemia and Their Impact on Overall and Thrombosis Free Survival

Background:

Current risk stratification for thrombosis in essential thrombocythemia (ET) utilizes age >60 years, history of thrombosis, JAK2V617F mutation and cardiovascular risk factors (Barbui, Blood 2012;26:5128). Thrombosis history is also predictive of inferior overall survival (OS) in ET (Passamonti, Blood 2012;6:1197). However, whether or not the prognostic impact of thrombosis in ET is contributed by arterial versus venous thrombosis is unclear.

Methods:

More than 45,000 patient charts with “thrombocytosis” were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Details of type of thrombotic events were obtained by careful review of the medical record. A subset of patients was molecularly annotated for the JAK2, CALR and MPLmutations. OS was calculated from time of initial diagnosis to the time of last follow-up or death. Thrombosis-free survival (TFS) was calculated from the time of diagnosis of ET to the time of development of thrombosis or last follow up or death, in patients censored for thrombosis. Conventional statistics was utilized for all analyses.

Results:

1. Patient characteristics: A total of 610 patients met the above-stipulated criteria (median age 57 years; 61% females). 76 patients (12%) had thrombosis documented either prior to or at diagnosis of which 50 patients (66%) experienced arterial events. 302 patients were screened for JAK2/CALR/MPL mutations with a frequency of 53.5%, 31%, and 3%  respectively, while12.5% were “triple-negative”.

2. Impact of thrombosis history on OS: At a median follow-up of 8.9 years (range: 0-43.6 years), 185 (30%) deaths were documented. The median OS for the entire cohort was 20 years. On univariate survival analysis, the predictors of inferior OS included: age ≥60 years (p<0.001), leukocyte count ≥11 x 10(9) (p<0.001), male sex (p=0.0002), thrombosis before or at diagnosis (p=0.01), and presence of the JAK2V617F mutation (p=0.03). All but JAK2V617F (p=0.64) remained significant on multivariable analysis. When arterial and venous events were considered separately, in univariate analysis, only arterial (p<0.001) but not venous (p=0.387) thrombotic events retained significance. The significant prognostic contribution, to survival, of arterial thrombosis history was sustained (p=0.02) during multivariable analysis, that included age ≥ 60 years (p=<0.001), leukocyte count ≥11 x 10(9) (p=0.001), and male sex (p=0.001) on OS.

3. Impact of thrombosis history on TFS:  A total of 84 (14%) patients experienced thrombotic events during follow-up amongst which 60 (71%) experienced arterial thrombosis. On univariate analysis the predictors of inferior TFS included: age ≥ 60 years (p=0.016), leukocyte count ≥11 x 10(9) (p=0.001), thrombosis before or at diagnosis (p<0.001), and presence of the JAK2V617F mutation (p=0.002). On multivariable analysis, thrombosis before or at diagnosis (p<0.001), along with leukocyte count ≥11 x 10(9) (p=0.03), and presence of the JAK2V617F mutation (p=0.01) remained significant; the significance of age ≥60 years became borderline (p=0.07). When arterial and venous thrombosis were analyzed separately, only arterial (p<0.001), but not venous (p=0.48), thrombosis history was significantly associated with inferior TFS. The factors that predicted worse outcome with TFS included arterial thrombosis at or before diagnosis (p<0.001), leukocyte count ≥11 x 10(9) (p=0.03) and presence of the JAK2V617F mutation (p=0.01); the significance of age ≥60 years became borderline (p=0.13).

Conclusions:  The prognostic impact of thrombosis in ET, in terms of both overall and thrombosis-free survival, might be attributed to only arterial but not venous thrombotic events. The current study also confirms the independent prothrombotic role of JAK2V617F mutation in ET and suggests an additional role for leukocytosis.