Absence of detectable cardiotoxicity with L-Annamycin despite high cumulative anthracycline exposure

Background

Anthracyclines are among the most widely used chemotherapeutic agents, but their use is limited by dose-dependent cardiotoxicity and lifetime cumulative dose restrictions. L-Annamycin is a next-generation, modified anthracycline being evaluated in acute myeloid leukemia (AML) and soft tissue sarcoma. It is designed to eliminate cardiotoxicity and overcome multidrug resistance while preserving anti-tumor efficacy.

Purpose

To evaluate the cardiac safety of L-Annamycin using pooled clinical trial data with comprehensive cardiac monitoring and independent cardio-oncology review.

Methods

Cardiac safety was evaluated across sponsor- and investigator-initiated clinical trials of L-Annamycin and included pre- and post-treatment serial 12-lead ECGs, cardiac biomarker (troponin I and T) concentrations, as well as transthoracic echocardiography with centralized global longitudinal strain (GLS) analysis. All available cardiac data were independently reviewed by a cardio-oncology laboratory.

Results

An independent cardio-oncology review was conducted for 90 patients who were treated with L-Annamycin across five completed clinical trials. Among those, 78 had source-data verified pre- and post-treatment ejection fraction measurements. The median cumulative dose for this subset of patients was 660 mg/m2 (95% CI, 645-690; range 210-2,970). Analysis of the change in ejection fraction from baseline to final assessment revealed no statistically significant difference (mean difference, −0.12%; 95% CI, −1.34 to 1.09; p=0.84). Linear regression analysis showed no correlation between total L-Annamycin dose and change in ejection fraction (p= 0.12) or between age and change in ejection fraction (p=0.73) (Figure 1). Independent review of serial ECGs, serum troponin concentrations, and available GLS values also demonstrated no evidence of drug-induced cardiotoxicity.

Conclusion

L-Annamycin was not associated with detectable cardiotoxicity despite high cumulative anthracycline exposure. Although limited by sample size, these findings suggest a favorable cardiac

safety profile, even in those who significantly exceeded conventional lifetime anthracycline dose limits.

Figure 1: Scatterplots demonstrating the relationship between patient age (left) and cumulative L-Annamycin dose (right) with change in left ventricular ejection fraction from baseline to final assessment.Figure 1