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Results of a retrospective study suggest that patients with low-risk essential thrombocythemia (ET) may benefit from a genotype-based approach to
antiplatelet therapy.
The study showed that, overall, neither CALR-mutated nor JAK2V617F-positive patients derived a significant benefit from treatment with low-dose aspirin.
JAK2V617F-positive patients had a somewhat lower risk of thrombosis while on the therapy than during observation.
But CALR-mutated patients had a significantly increased risk of major bleeding and no decrease in the risk of thrombosis while on antiplatelet therapy.
Carlos Besses, MD, PhD, of Hospital del Mar in Barcelona, Spain, and his colleagues reported these results in haematologica.
The researchers evaluated 433 patients with low-risk ET—271 with CALR mutations and 162 with JAK2V617F. In all, 353 patients received low-dose aspirin (81-100 mg/day), but the treatment was withdrawn in 50 patients (permanently in 46 of them).
Two hundred and thirty-one patients received cytoreductive therapy, including hydroxyurea (n=143), anagrelide (n=66), interferon (n=18), and busulfan (n=4).
The projected time from diagnosis to the start of cytoreductive therapy was significantly shorter in patients with CALR-mutated ET than in JAK2V617F-positive patients—a median of 5.0 years and 9.8 years, respectively (P=0.002). The most common reason for cytoreduction in CALR-mutated patients was extreme thrombocytosis.
Thrombosis
After 2215 person-years of follow-up free from cytoreduction, there were 25 arterial or venous thrombotic events.
Fourteen thrombotic events occurred while patients were receiving low-dose aspirin, and 11 occurred while patients were under observation only. The incidence rates were 10.7 and 12.1 events x 1000 person-years, respectively (P=0.7).
Among CALR-mutated patients, there were more thrombotic events during antiplatelet therapy than during observation—9.7 and 6.9 events x 1000 person-years, respectively (P=0.6).
Among JAK2V617F-positive patients, there were fewer thrombotic events during antiplatelet therapy than during observation, but the difference was not significant—11.6 and 21.1 events x 1000 person-years, respectively (P=0.3).
Coexistence of the JAK2V617F mutation and cardiovascular risk factors increased the risk of thrombosis, even after the researchers adjusted for treatment with low-dose aspirin. The incidence rate ratio (IRR) was 9.8 (P=0.02).
Bleeding
After 2215 person-years of follow-up free from cytoreduction, there were 17 major bleeding episodes.
Thirteen occurred while patients were on antiplatelet therapy, and 4 occurred while patients were on observation. The incidence rates were 9.9 and 4.6 events x 1000 person-years, respectively (P=0.2).
There was no significant difference in major bleeding episodes between the treatment groups for JAK2V617F-positive patients.
But CALR-mutated patients had a significantly higher rate of major bleeding while on antiplatelet therapy than on observation—12.9 and 1.8 events per 1000 person-years, respectively (P=0.03).
In CALR-mutated patients, antiplatelet therapy was associated with a tendency toward an increased risk of bleeding (IRR: 6.9, P=0.06), but extreme thrombocytosis was not (IRR: 2.7, P=0.1).
In JAK2V617F-positive patients, extreme thrombocytosis was associated with an increased risk of bleeding (IRR: 9.8, P=0.002), but antiplatelet therapy was not (IRR: 0.9, P=0.9).
Potential treatment recommendations
The researchers said this retrospective study suggests a genotype-based approach to antiplatelet therapy may be effective for patients with low-risk ET. However, this needs to be confirmed in prospective trials.
The failure of antiplatelet therapy to prevent thrombosis in CALR-mutated patients and their increased need for cytoreductive therapy suggest these patients require a different approach from that used in JAK2V617F-positive patients.
The researchers said the data suggest that patients with CALR-mutated ET who have a low risk of thrombosis and no symptoms should simply be observed. And CALR-mutated patients with symptoms or marked thrombocytosis should receive cytoreductive therapy, as it poses a lower risk of bleeding than antiplatelet therapy.
Patients with JAK2V617F-positive ET should receive antiplatelet therapy rather than undergoing observation, as antiplatelet therapy may reduce the risk of thrombosis in these patients and does not pose an increased risk of bleeding.
However, in JAK2V617F-positive patients with concomitant cardiovascular risk factors and/or leukocytosis, antiplatelet therapy may not be sufficient. These patients might be candidates for cytoreductive therapy, especially if they have marked thrombocytosis.
