Arsenic Plasma Concentrations and Methylation Efficiency as Key Factors of Arsenic Trioxide-Related Cardiac Toxicity in Acute Promyelocytic Leukemia.

Abstract

Arsenic trioxide (ATO) is highly effective for acute promyelocytic leukemia (APL), but ATO-induced cardiac adverse events (CAEs) frequently cause treatment interruption or fatal outcomes, and real-world evidence linking arsenic species levels, methylation capacity, and CAE risk remains limited. In this study, we included 547 APL patients treated with ATO between 2014 and 2024 (4741 treatment cycles). Plasma concentrations of inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA) were measured in 374 patients using HPLC-HG-AFS. Primary (PMI = MMA/iAs) and secondary (SMI = DMA/MMA) methylation indices were calculated. Univariate and multivariate Cox regression identified independent CAE determinants, ROC analysis evaluated predictive values and cutoffs, and a risk nomogram was constructed. CAEs occurred in 297 patients (54.3%) and 554 treatment cycles (11.7%). Plasma arsenic distribution followed DMA, MMA > iAs, with PMI > SMI (all P < 0.05). Patients with CAEs had significantly higher DMA, iAs, total arsenic (tAs), and aberrant methylation profiles (all P < 0.05). Concomitant cardiotoxic drug use, DMA, tAs, SMI, DMA%, and MMA% were independent determinants. ROC analysis demonstrated good predictive performance for these markers (AUCs 0.708-0.869). The nomogram showed favorable discrimination (C-index = 0.823) and clinical net benefit. ECG abnormalities were the most common CAEs. ATO-induced cardiotoxicity is closely related to arsenic species concentration and methylation metabolism; importantly, impaired primary methylation (lower PMI, lower MMA%) appears to be the key bottleneck, with secondary methylation enhanced as a compensatory response (higher SMI, higher DMA%). Arsenic toxicokinetic and methylation markers effectively predict CAEs, supporting routine therapeutic drug monitoring in APL patients receiving ATO.