Comparative Adverse Event Reporting of Asparaginase-Containing Induction Regimens in Pediatric Acute Lymphoblastic Leukemia Using the United States Food and Drug Administration Adverse Event Reporting System.
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Background Asparaginase (ASP) is a key component of pediatric acute lymphoblastic leukemia (ALL) therapy, but its use is limited by concerns about hypersensitivity, hepatic dysfunction, pancreatitis, thrombosis, and other toxicities. Comparative information on adverse event (AE) reporting signals for ASP-containing versus ASP-free induction regimens differing only by ASP inclusion remains limited in real-world pharmacovigilance data. Objectives To compare AE reporting patterns between ASP-containing and ASP-free regimen pairs in pediatric ALL and to characterize regimen-specific reporting signals across major AE categories. Methods Pediatric ALL reports submitted to the United States Food and Drug Administration Adverse Event Reporting System (FAERS) from 2004 to 2025 were identified using ALL indication terms. As FAERS does not reliably encode treatment phase, we operationally restricted the analysis to induction-oriented reports by requiring both a corticosteroid and vincristine as the backbone regimen, limiting concomitant drugs to a predefined set of induction agents, and excluding reports containing drugs typically used in consolidation, maintenance, targeted therapy, or immunotherapy. Comparisons were restricted to paired regimens in which ASP inclusion was the defining difference within the same induction-oriented backbone. AEs were grouped into 10 predefined categories. Reporting odds ratios (RORs), adjusted RORs (aRORs), and, when necessary, modified RORs were estimated using logistic regression, adjusting for age, sex, and continent when feasible. Findings were interpreted as spontaneous reporting signals rather than incidence estimates, and greater emphasis was placed on AE categories for which both the unadjusted ROR and adjusted ROR showed concordant statistically significant associations. Results Among pediatric ALL reports meeting the induction-oriented criteria, five regimen pairs met the predefined case-count threshold for comparative analysis, comprising 740 reports in total. AE reporting patterns differed across regimen pairs and AE categories, reflecting regimen‑specific disproportionality in FAERS data. Increased reporting signals were observed for infections, nervous system disorders, pancreatitis, and gastrointestinal disorders in selected ASP-containing regimens, whereas lower reporting signals were observed for hepatobiliary and hematologic disorders in other regimen pairs. Overall, the direction and magnitude of the signals differed across AE categories and induction backbones. Conclusions In pediatric ALL induction therapy, ASP-containing regimens showed regimen-specific AE reporting signals in FAERS rather than evidence of true incidence differences or causal effects. These patterns may reflect the influence of accompanying chemotherapy components as well as reporting bias, including notoriety bias, whereby well-recognized ASP toxicities may be more likely to be attributed and reported. As FAERS is a spontaneous reporting system, these findings are hypothesis-generating and support prospective studies to clarify the safety profile of ASP across distinct induction regimens.