Real-World Experience of Asciminib Treatment and Its Clinical Outcomes Including Cardiovascular (CV) Event-Free, Failure-Free Survival Associated with CV Comorbidity and Framingham CV Risk Score in Patients with Chronic Myeloid Leukemia

Introduction Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for chronic myeloid leukemia (CML). However, a significant limitation of long-term TKI use comes mainly from the risk of cardiovascular (CV) events (CVEs) mainly related to 2nd generation TKI (2G-TKI). Asciminib (ASC), a novel TKI with a distinctive mechanism of action targeting the ABL myristoyl pocket, has shown superior efficacy and excellent tolerability in clinical trials. A real-world data suggest that ASC may not elevate the risk of CVEs (Khadadah, 2023), even in patients (pts) with pre-existing CV risk factors or a history of CVEs such as myocardial infarction (MI), coronary artery disease (CAD), or stroke. The analysis considering the CV risk factors would help to clarify the implication of ASC on CVE risk. The present study attempted to assess the CV risk profiles of the pts, including their baseline Framingham Risk Scores (FRS), and to analyze its effect on the risk of CVEs during ASC treatment. Patients and method A total of 54 CML pts who were treated with ASC were reviewed retrospectively. ASC was started at 40mg twice daily or 80mg once daily in the case of non-T315I mutated CML (n=50) and at a higher dose for T315I mutated CML pts (n=4). Prior to ASC's start, the CV risk profile was captured, including past history of CVE, lipid profile, blood pressure, HbA1c level, body mass index, creatinine and GFR, and smoking/alcohol history. The pts were monitored for vital signs and blood work, including blood sugar, every visit. The CVE was captured prospectively during their clinic follow-up. The CVEs were defined as 1) acute coronary syndrome and hospitalization for unstable angina; 2) myocardial infarction; 3) angina pectoris or coronary artery disease (CAD) confirmed by angiography or the need for revascularization; 4) heart failure event; 5) symptomatic peripheral arterial occlusive disease proved anatomically or stroke; and 6) death related to CV or cerebrovascular accident. CVE-free, event free survival (CVEFS) was defined from ASC start date to the date of CVE episode, discontinuation of ASC due to intolerance, failure by ELN2020 criteria or death of any cause. Incidence of CVE was calculated considering competing events including discontinuation of ASC due to intolerance, failure by ELN2020 criteria or death of any cause. Result Out of overall 54 pts, 31 (57%) pts were male with a median age of 62. Thirty-six (66%) pts had Hypertension; 11(20%), diabetes mellitus (DM); 31 (57%), dyslipidemia; 16 (30%), history of smoking, 23 (44%), obesity; and 19 (35 %) had a previous history of CV or cerebrovascular events. According to the baseline FRS, the pts were divided into low (n=11, 26%), moderate (n=10, 20%) or high FRS group (n=27, 54%). The median follow-up duration was 18 months, with a total of 85 person-year exposure to ASC. ASC was used as a third-line therapy in 30 patients (56%), as a fourth-line or later therapy in 18 patients (33%), and as an early-line therapy in 6 patients (11%). The reason for using ASC was intolerance to the previous line of therapy (n=35, 65%), followed by treatment failure (n=11, 20%) or others (n=9, 15%). The proportion of pts who achieved MR2, MR3 and MR4 at last follow-up was 84.3% (n=43/51), 66.7% (n=34/51), 35.3% (n=18/51), respectively. The failure-free survival rate was 80.5% (61.2-90.9%), while the OS rate of 93.5% (75.9-98.4%) at 18 months. During the follow-up of ASC treatment, we observed only 1 patient with a CVE who experienced stroke and stopped ASC therapy after this event. Accordingly, the incidence of CVE was calculated as 2.4% at 18 months (0.2-11.2%). Out of 85 person-years of ASC exposure, 1 CVE case was observed, thus resulting in 1.17 CVE per 100 person-year. Four patients died during the treatment, 2 (50%) were related to disease progression and 2 (50%) due to other malignancy progression, no case related to ASC toxicity observed. The 18 months' CVEFS rate was 70.7% (52.7-82.9%) and there is no association of CVEFS with the FRS group (p=0.382). We have analyzed the risk factors for CVEFS including the clinical factors for CV comorbidity and FRS. The only clinical factor identified to be significant was presence of DM (HR, 3.589 [1.112, 11.59], p=0.03). Conclusion Based on the present real-world experience study, ASC can be used safely without any alarming signals for increased risk of CVE, and can provide comparable treatment outcomes regardless of CV comorbidities risk based on the FRS.

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