Cardiac safety of L-annamycin at high cumulative anthracycline exposure: Pooled analysis.

12025 Background: Anthracyclines are widely used chemotherapeutic agents but limited by dose-dependent cardiotoxicity and lifetime cumulative dose restrictions. L-Annamycin is a next-generation anthracycline designed to eliminate cardiotoxicity and overcome multidrug resistance. In a Phase 1b/2 study in patients with acute myeloid leukemia (AML), L-Annamycin administered in combination with cytarabine as second-line therapy achieved a 50% complete remission (CR) rate and a 60% composite CR (CRc) rate with a median overall survival of 12.39 months (95% CI, 2.07–13.96) in the intent-to-treat population. We evaluated the cardiac safety of L-Annamycin in multiple clinical trials to assess its ability to support sustained anthracycline exposure in patients with AML and soft tissue sarcoma. Methods: Cardiac safety was evaluated across sponsor- and investigator-initiated clinical trials of L-Annamycin. Assessments included serial 12-lead electrocardiograms (ECGs), cardiac biomarkers (troponin I and T), and transthoracic echocardiography with centralized evaluation of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS), where available. Cardiac data were reviewed independently by a reviewer in the Division of Cardiovascular Medicine at the Cleveland Clinic. Changes in LVEF from baseline to final assessment were analyzed in relation to cumulative L-Annamycin dose and patient age. Results: An independent cardiac safety review was conducted for 90 patients who were treated with L-Annamycin across five completed clinical trials; 78 of these patients now have source-verified pre- and post-treatment left ventricular ejection fraction (LVEF) assessments. The median cumulative L-Annamycin dose among these patients was 660 mg/m² (95% CI, 645–690; range, 210–2,970 mg/m²), with most of the cumulative doses exceeding conventional lifetime anthracycline limits. Analysis of the change in LVEF from baseline to final assessment demonstrated no statistically significant difference (mean difference, −0.12%; 95% CI, −1.34 to 1.09; p = 0.84). Linear regression analysis documented no correlation between cumulative L-Annamycin dose and change in LVEF (p = 0.12), nor between patient age and change in LVEF (p = 0.73). Independent review of serial ECGs, cardiac biomarkers, cardiac adverse events, and available global longitudinal strain measurements also demonstrated no evidence of drug-induced cardiotoxicity. Conclusions: L-Annamycin was not associated with any detectable cardiotoxicity despite high cumulative anthracycline exposure. These findings suggest that L-Annamycin represents a next-generation anthracycline capable of delivering effective anthracycline therapy without traditional cumulative dose limitations, thus further supporting its ongoing pivotal Phase 2b/3 trial in AML patients.