Impact of prior exposure to erythropoiesis-stimulating agents (ESA) on thromboembolic events in patients with myelodysplastic syndromes receiving luspatercept: A real-world TriNetX-based study.

e18585 Background: Luspatercept demonstrated superior transfusion independence over ESAs in ESA-naive Myelodysplastic Syndromes(MDS). Thromboembolic events were observed with luspatercept in both BELIEVE and COMMANDS trials, particularly among patients with baseline comorbidities. ESAs are also independently associated with higher thromboembolic risk. Whether prior ESA exposure modifies the subsequent thromboembolic risk during luspatercept therapy in older morbid MDS patients remains unknown. We conducted a real-world analysis to determine whether prior ESA exposure compounds the risk of venous thromboembolism and arterial thrombosis after luspatercept initiation in MDS. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with MDS treated with luspatercept and no prior venous or arterial thromboembolism. Patients were stratified into prior ESA-exposed versus ESA-naive cohorts. Propensity score matching (1:1) was performed using demographics, comorbidities/risk factors, anticoagulation/antiplatelet use, and baseline hematologic parameters. Outcomes were assessed at 90 days and 1 year; venous thromboembolism was defined as deep vein thrombosis and/or pulmonary embolism, and arterial thrombosis as acute myocardial infarction or ischemic stroke. Results: A total of 2,149 luspatercept-treated MDS patients were identified, out of which 1218 had prior ESA exposure and 931 were ESA-naïve. After propensity matching, 801 patients remained in each cohort. The overall mean age was 76.6 years, with 55.1% of patients being male. At 90 days interval, venous thromboembolism events occurred in 3.0% of the prior-ESA cohort versus 2.4% of the ESA-naive cohort (RR 1.22, p=0.521). Arterial thrombosis (acute myocardial infarction or ischemic stroke) occurred in 4.3% vs 2.7% (RR 1.60, p=0.090). At 1 year, venous thromboembolism occurred in 4.6% vs 4.7% (RR 0.98, p=0.906), and arterial thrombosis occurred in 7.4% vs 7.2% (RR 1.03, p=0.924). None of the between-group differences were statistically significant at either 90 days or 1 year. Conclusions: These findings suggest that prior ESA therapy does not compound the thrombotic risk associated with luspatercept and support the thrombotic safety profile of luspatercept even in prior ESA-exposed patients and warrant further prospective validation. Thromboembolic outcomes by prior ESA exposure. Time window (post-index) Outcome Prior ESA (%) ESA-naive (%) Effect estimate p-value 90 days Venous thromboembolism (DVT/PE) 3.0 2.4 RR 1.22 0.521 90 days Arterial thrombosis (MI/ischemic stroke) 4.3 2.7 RR 1.60 0.090 1 year Venous thromboembolism (DVT/PE) 4.6 4.7 RR 0.98 0.906 1 year Arterial thrombosis (MI/ischemic stroke) 7.4 7.2 RR 1.03 0.924