Practice-Relevant Revision of Ipset-Thrombosis Based on 1019 Patients with WHO-Defined Essential Thrombocythemia

Background

In the recent International Prognostic Score for Thrombosis in essential thrombocythemia (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 (Barbui et al. Blood 2012).

Methods

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, in order 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.

Results

After a median follow-up of 6.8 and 5.0 years in conventionally-assigned low- and high-risk patients, respectively, the overall annual rate of total thrombosis (108 events) in  conventionally-assigned  low- and high-risk patients was 1.11%-pt/y (CI 0.81-1.52) and 2.46%-pt/y (CI 1.94-3.11) respectively (p=0.001), and the difference was mainly due to a higher frequency of arterial thrombosis in high-risk patients (p<0.001).The influence of JAK2 mutational status and CV-risk factors on the rate of thrombosis in conventionally assigned low- and high-risk groups is presented in the table.

	Additional risk factors	N (%)	Event	Rate % pts/yr (95% CI)	P-value	P-value	P-value trend
Low risk		506 (50)	39	1.11 (0.81-1.52)
	None	200 (40)	7	0.44 (0.21-0.92)	ref
	Cardiovascular risk factor	36 (7)	3	1.05 (0.34-3.25)	0.220	0.227
	JAK2V617F	213 (43)	21	1.59 (1.04-2.44)	0.001	0.217
	Both	52 (10)	8	2.57 (1.29-5.15)	<0.001	ref	<0.001
High risk		513 (50)	69	2.46 (1.94-3.11)
	None	111 (22)	10	1.44 (0.78-2.68)	ref
	Cardiovascular risk factor	44 (9)	4	1.64 (0.62-4.37)	0.909	0.067
	JAK2V617F	222 (43)	30	2.36 (1.65-3.38)	0.168	0.082
	Both	136 (27)	25	4.17 (2.82-6.17)	0.011	ref	0.005

The number of major arterial and venous thrombosis  was reported as rates per 100 patient-years and the difference among groups was assessed by Mantel Cox log-rank test

i)              Conventionally-assigned low-risk group. Amongst 506 patients, 200 (40%) displayed neither JAK2 mutation nor CV risk factors and their annual rate of thrombosis was 0.44%, as opposed to 1.05%  in the presence of CV risk factors (P=NS), 1.59% in the presence of JAK2 mutation (p=0.001) and 2.57% in the presence of both CV risk factors and JAK2 mutation (P<0.001). There was no significant difference when low-risk patients with both JAK2 mutation and CV risk factors were compared with either those with CV risk factors only (p=0.227) or those with JAK2 mutation only (p=0.217).

ii)             Conventionally assigned high-risk group: The absence or presence of one or both of the aforementioned additional risk factors for thrombosis were documented in 111 (22%), 44 (9%), 222 (43%) and 136 (27%) patients, respectively, with corresponding annual rates of thrombosis at 1.44%, 1.64%, 2.36% and 4.17% (Table). High-risk patients with both risk factors had a significantly higher risk of thrombosis compared to their counterparts with the absence of JAK2 mutations and CV risk factors (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 thrombosis risk in patients where high-risk status was defined by age alone (p=0.05).

Conclusions

The current study suggests the possibility of considering four risk categories in ET: “very low risk” group (age ≤60 years and without thrombosis history, JAK2 mutations or CV risk factors); “low risk” (age ≤60 years and without thrombosis history but with JAK2 mutations or CV risk factors); “intermediate risk” (age>60 years but without thrombosis history or JAK2 mutations); and “high risk” (thrombosis history at any age or JAK2-mutated patients who are older than 60 years of age). Treatment recommendations for each one of the above-mentioned new risk categories should be examined in the context of prospective controlled studies.