Relationship between additional mutations at diagnosis and treatment response in patients with essential thrombocythemia.

Patients with essential thrombocythemia (ET) have a chronic evolution with a risk of hematological transformation associated with a dismal outcome. Since patients with resistance or intolerance have an adverse prognosis, it is important to identify which patient will respond to first-line treatment. We therefore aim to describe the association between additional mutations and response to first-line treatment in patients with ET. In this retrospective study, we analyzed the molecular landscape of 121 ET patients first-line treated with hydroxyurea (n=86) or pegylated interferon (n=35). Patients undergoing peg-IFN therapy were younger and had higher proportion of low and very low risk of thrombosis recurrence. Sixty-two patients (51%) had ≥1 additional mutations at diagnosis. The most frequent additional mutations involved TET2 (15.7%) DNMT3A (10.7%), non-W515-MPL (6.6%), ASXL1 (4.13%), and splicing factors SRSF2 and SF3B1 (6.6%) genes. At 12-months of treatment, 75 (62%) patients achieved complete response (CR), 37 (31%) partial response, and 7 (6%) no response. The presence of at least one additional mutation at diagnosis was associated with not achieving CR (HR: 0.66;p=0.045), whereas treatment with interferon was associated with higher CR (HR: 2.01;p=0.002). The number of additional mutations at diagnosis was associated with hematologic progressions (p<0.0001). None of the patients receiving peg-IFN therapy progressed to myelofibrosis, while 16/86 patients (19%) treated with HU developed secondary myelofibrosis. In conclusion, our results suggest that the presence of at least one additional mutation at diagnosis is associated with failure to achieve CR and is also associated with an increased risk of hematologic evolution.