Non-driver mutations in patients with <Emphasis Type="Italic">JAK2</Emphasis>V617F-mutated polycythemia vera or essential thrombocythemia with long-term molecular follow-up

JAK2V617F monitoring and NGS of non-driver genes was performed in 100 patients with polycythemia vera (PV) or essential thrombocythemia (ET) with long molecular follow-up. Patients who did not progress to myelofibrosis (MF) or acute myeloid leukemia (AML) after more than 10 years (n?=?50) showed a low frequency of mutations at first sample (18%) and an incidence rate of 1.7 new mutations?×?100 person-years. Mutations were detected at first sample in 83% of PV/ET patients who later progressed to AML (n?=?12) with these patients having a rate of 25.6 mutations?×?100 person-years. Presence of mutations at diagnosis was the unique risk factor for acquiring a new genetic event (HR 2.7, 95% CI 1.1–6.8, p?=?0.03) after correction for age, PV diagnosis, and total duration of hydroxyurea (HU) exposure. Patients with additional mutation at first sample showed a higher probability of developing cytopenia under HU therapy and a higher risk of AML (HR 12.2, 95% CI 2.6–57.1, p?=?0.001) with mutations in ASXL1 (p?<?0.0001), TP53 (p?=?0.01), SRSF2 (p?<?0.0001), IDH1/2 (p?<?0.0001), and RUNX1 (p?<?0.0001) being associated with a higher probability of AML. Myelofibrotic transformation was more frequent in patients with additional mutations, especially in SF3B1 (p?=?0.02) and IDH1/2 (p?<?0.0001) although a persistently high or a progressive increase of the JAK2V617F allele burden while receiving cytoreduction was the strongest predictor of MF transformation (HR 10.8, 95% CI 2.4–49.1, p?=?0.002). In conclusion, NGS may be useful to identify a minority of PV and ET patients with high genetic instability and increased risk of AML transformation.