Simple SummaryTyrosine kinase inhibitors (TKI), such as imatinib, nilotinib, and dasatinib, are the first-line treatment of choice for patients with chronic myeloid leukemia (CML). However, patients may develop serious cardiovascular events (CVE) with their use. Cardiotoxicity is an important issue given the associated mortality of CVE and the long-term nature of TKI treatment. This study aimed to investigate the association of the presence of somatic myeloid mutations (including those with a reported role in clonal hematopoiesis) at diagnosis and the development of CVE for 102 patients on TKI treatment. The presence of a somatic myeloid mutation was a significant risk factor for CVE on any TKI and shortened the CV event-free survival for patients receiving first-line imatinib treatment. Our work shows that the low risk of CVE, traditionally associated with first-line imatinib, was increased by the presence of myeloid mutations as well as older age. Our findings may help inform first-line TKI choice.AbstractFor chronic myeloid leukemia (CML) patients with a known risk of cardiovascular events (CVE), imatinib is often recommended for first-line tyrosine kinase inhibitor (TKI) treatment rather than a second-generation TKI (2G-TKI) such as nilotinib or dasatinib. To date, very few studies have evaluated the genetic predisposition associated with CVE development on TKI treatment. In this retrospective study of 102 CML patients, 26 CVEs were reported during an average follow-up of over 10 years. Next-generation sequencing identified pathogenic/likely pathogenic mutations in genes associated with myeloid malignancies in 24.5% of the diagnostic samples analyzed. Patients with a recorded CVE had more myeloid mutations (0.48 vs. 0.14,p= 0.019) and were older (65.1 vs. 55.7 years,p= 0.016). Age ≥ 60 years and receiving a 2G-TKI in first-line were CVE risk factors. The presence of a pathogenic somatic myeloid mutation was an independent risk factor for CVE on any TKI (HR 2.79,p= 0.01), and significantly shortened the CV event-free survival of patients who received first-line imatinib (by 70 months,p= 0.011). Indeed, 62% of patients on imatinib with mutations had a CVE vs. the 19% on imatinib with a mutation and no CVE. In conclusion, myeloid mutations detectable at diagnosis increase CVE risk, particularly for patients on imatinib, and might be considered for first-line TKI choice.