Impact of ELN clinical signs and symptoms on the thrombotic risk in Polycythemia Vera patients treated with front-line hydroxyurea

The European LeukemiaNet recently proposed specific Clinical Signs and Symptoms (CSSs) that should be considered to trigger cytoreduction in patients with polycythemia vera (PV) at low risk (LR) according to conventional criteria (age<60 years and no previous thrombosis). To evaluate the impact of CSSs on the thrombotic risk across different risk categories, including LR, high risk by age only (HR-AGE) or previous thrombosis (HR-THRO), we conducted a multicenter cooperative study (NCT06134102) involving 739 PV patients treated with first-line hydroxyurea. CSSs, including persistent/progressive leukocytosis, extreme thrombocytosis, progressive splenomegaly, inadequate hematocrit control, relevant cardiovascular risk factors (CVRFs), and severe itching, were evaluated for association with thrombosis using incidence rate ratio (IRR) per 100 patient-years (%p-y) and thrombosis-free survival (TFS) adjusted for delayed entry. At hydroxyurea start, 443 patients (60.0%) had at least one CSS. In patients with and without CSSs, the IRR of thrombosis was 2.2 and 0.7 %p-y, respectively (p<0.001), and the TFS at 5 years was 88.7% and 96.1% (p<0.001). The prognostic impact of CSSs was confirmed in all risk categories, with worse TFS in HR-THRO patients with CSSs. In multivariate analysis including each CSS singularly, inadequate hematocrit control (HR: 2.32, 95% CI: 1.45 – 3.72, p<0.001); relevant CVRFs (HR: 2.87, 95% CI: 1.36 – 6.06, p=0.006); progressive splenomegaly (HR: 4.02, 95% CI: 1.18 – 13.65, p=0.03) and previous thrombosis (HR: 3.76, 95% CI: 2.32 – 6.10, p<0.001) remained significantly associated with thrombotic risk. CSSs identify an increased thrombotic risk phenotype in all conventionally defined risk categories, supporting their evaluation in clinical practice.