Clonal Hematopoiesis as a Molecular Risk Factor for Doxorubicin-Induced Cardiotoxicity: A Proof-of-Concept Study.

Abstract

The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC). We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA. After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m²; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; <i>P</i> = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; <i>P</i> = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; <i>P</i> = .0495) were associated with DIC. This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.