Mapping the Safety Profile of Histone Deacetylase Inhibitors in Children with Cancer

Epigenetic alterations, including aberrant DNA hypermethylation and histone modifications, contribute to oncogenesis by disrupting normal gene expression programs. Unlike genetic mutations, these changes are potentially reversible, providing a strong biological rationale for the development of histone deacetylase inhibitors (HDACi) for therapy. Several HDACi are currently under investigation, either as monotherapy or in combination with other anticancer agents. A comprehensive understanding of toxicity is essential to appropriately balance risks and benefits, particularly because HDACi are most frequently evaluated within combination regimens. To date, no epigenetic agents have received regulatory approval for pediatric malignancies, and clinical development in this population remains at an early stage. The aim of this study was to systematically characterize the toxicity profiles associated with HDACi administration in pediatric patients with cancer, including both solid tumors and hematologic malignancies. To this end, we conducted a systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Toxicity profiles were extracted from twelve studies investigating six HDACi: panobinostat, vorinostat, entinostat, pracinostat, valproic acid, and depsipeptide. Eleven studies were Phase I or Phase I/II clinical trials, and one was a retrospective study. Patients with solid central nervous system tumors represented the most frequently studied population. Overall, treatment-related toxicities were predominantly mild, with few severe (grade 4) adverse events, mainly within the hematologic category. According to the Common Terminology Criteria for Adverse Events grading system, hematologic toxicities were the most common adverse events across all HDACi, particularly thrombocytopenia, followed by mild gastrointestinal and metabolic toxicities. Cardiac, neurological, respiratory, and systemic toxicities were generally mild, less frequent, and considered treatment-related. Dose and route of administration influenced both the frequency and severity of toxicities. Pan-HDAC inhibitors were associated with the highest rates of toxicity.

HDACi-related toxicities were moderate and manageable in pediatric patients. Differences in toxicity were observed among treatments, with higher doses linked to increased toxicity. These findings support further clinical trial development of HDACi in pediatric malignancies. However, Phase I design, small patient numbers, and heterogeneity in age, weight, and disease characteristics are major limitations in accurately assessing HDACi-induced toxicity.