Presence of Myeloid Mutations in Patients with Chronic Myeloid Leukemia Increases Risk of Cardiovascular Event on Tyrosine Kinase Inhibitor Treatment

Abstract

For 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.

The Cardiovascular Event Risk Associated with Tyrosine Kinase Inhibitors and the Lipid Profile in Patients with Chronic Myeloid Leukemia

“…Taken together, our observations are consistent with prior reports [ 18 , 20 , 32 , 33 ] that suggest patients at risk of developing VAEs during TKI therapy might be identifiable at the time of diagnosis. Our results support the estimation of the cardiovascular risk at the time of diagnosis in order to choose the most appropriate first-line treatment to prevent the appearance of VAEs [ 32 ].…”

“…Nevertheless, consistent with prior reports, our analysis confirmed a higher incidence of VAEs in patients who were treated with nilotinib compared to those receiving other TKIs [ 15 , 16 , 18 , 26 ]. Specifically, a higher incidence of VAEs was observed for second-line nilotinib after first-line imatinib vs. first-line nilotinib (12.5% vs. 8.1%, respectively), and statistically significant differences in VAE were also observed when comparing nilotinib-naïve versus nilotinib-treated patients, and patients who received three lines of treatment with first-line imatinib versus first-line imatinib.…”

“…Subsequent clinical trials and retrospective studies have confirmed the risks of morbidity and mortality [ 3 , 6 , 15 , 16 , 17 ]. This is particularly important given that CML is typically diagnosed in older adults, with age as a CV risk factor for VAE [ 18 , 19 ]. Moreover, comorbidities such as arterial hypertension or diabetes mellitus are frequent among older patients.…”