An analysis of diagnostic metabolomic profiles associated with hepatotoxicity during childhood ALL induction therapy
Year: 2025
Type: article
Study design: Observational Study
Abstract: ABSTRACT: Hepatotoxicity is a well-documented complication of induction chemotherapy for acute lymphoblastic leukemia (ALL), but our understanding of its biological mechanisms is limited. We identified 314 patients with ALL (aged 1-19 years) treated at Texas Children's Hospital (2008-2019) with diagnostic bone marrow plasma available for metabolomic profiling: 234 for discovery and 80 for replication. Hepatotoxicity during induction was defined as follows: (1) transaminitis: grade ≥3 aspartate aminotransferase or alanine aminotransferase or (2) conjugated hyperbilirubinemia: conjugated bilirubin (c.bili) >3 mg/dL. Untargeted profiling detected 519 metabolites. Adjusted odds ratios (aORs) for each metabolite were calculated with logistic regression, accounting for sex, age, body mass index, race/ethnicity, and treatment intensity. The population was 56% Latino, 57% male, 92% B-ALL, 25% overweight/obese, and 57% National Cancer Institute standard-risk at a median age of 5 years. Transaminitis was observed in 34% of the discovery and 24% of the replication cohort. Seven instances of c.bili >3 mg/dL were observed in the discovery cohort, with none in the replication cohort. Furthermore, 12 metabolites were associated with transaminitis (P < .05) in the discovery cohort, including 2 that replicated (P < .05): 1,2-dipalmitoyl-glycerophosphocholine (GPC) (aOR combined = 1.88 [95% confidence interval [CI], 1.26-2.79], P = .002) and 1-(1-enyl-palmitoyl)-2-palmitoleoyl-GPC (aOR combined = 1.56 [95% CI: 1.17-2.09], P = .003). In the discovery cohort, 34 metabolites were associated with c.bili >3 mg/dL, including the top association of 1,2-dipalmitoyl-GPC (aOR = 5.76 [95% CI: 2.20-23.16], P = .002). We observed and replicated associations between phosphatidylcholine metabolites at ALL diagnosis and hepatotoxicity during induction therapy, suggesting a potential role for lipid dysregulation in the development of hepatotoxicity.
Source: Blood Advances
Authors: Emily J. Mason, Anna M. Crain, Michael E. Scheurer, Philip J. Lupo, Karen R. Rabin, Olga A. Taylor, Marley Roberts, John P. Woodhouse, Ashley Chavana, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, M. Monica Gramatges, Joanna S. Yi, Sandi L. Pruitt, M. Brooke Bernhardt, Hong Zhu, Steven D. Mittelman, Van Huynh, Etan Orgel, Jeremy M. Schraw, Austin L. Brown
Institutions: Baylor College of Medicine, Texas Children's Hospital, Emory University, University of California, San Francisco, The University of Texas Southwestern Medical Center, Cook Children's Medical Center, Children's Hospital of San Antonio, Harold C. Simmons Comprehensive Cancer Center, St. Jude Children's Research Hospital, University of Virginia, University of California, Los Angeles, Children's Hospital of Orange County, Children's Hospital of Los Angeles
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funder: National Cancer Institute
Awards: G4215928989, G465472366
OpenAlex ID: W4413316286