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Lookup NU author(s): Dr Frederik van DelftORCiD
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© The Author(s), under exclusive licence to Springer Nature Limited 2025.Relapsed and refractory disease in children with T-cell acute lymphoblastic leukemia (R/R T-ALL) remains a major clinical challenge. Outcomes for children who relapse or exhibit resistance to initial treatments are dismal, with survival rates frequently below 25% despite aggressive therapy. To minimize toxicities and improve outcomes, individualized precision medicine approaches targeting the underlying biology of R/R T-ALL are especially important, considering that T-ALL is characterized by genetic, epigenetic and posttranscriptional heterogeneity, and organ and niche specificities (e.g. the central nervous system), all of which underlie disease progression and therapy resistance. Here, we summarize the current understanding of the complexity of pediatric T-ALL biology and how such knowledge may be clinically leveraged, emphasizing the need for innovative therapeutic routes to improve outcomes for children with R/R T-ALL. Emerging approaches that hold promise or show palpable results include proteasome inhibitors, BCL-2 antagonists, and JAK (for JAK- and IL-7R-driven cases), ABL and SRC family tyrosine kinase (for LCK-activated cases), MEK or PI3K-mTOR inhibitors. MYC-targeting agents, DNA demethylating agents, histone deacetylase inhibitors, splicing modulators, or drugs exploring T-ALL metabolic vulnerabilities, are other examples for potential pharmacological intervention. Immunotherapies, particularly CAR T-cell products targeting CD7 and other markers, but also biologics (e.g. targeting CD38), are under development and increasing interest. These agents should be rationally integrated into precision medicine combination therapies informed by genetic, epigenetic, and posttranscriptional insights that will be essential to refine risk stratification and minimize the risk of resistance. Novel strategies leveraging artificial intelligence and machine learning could accelerate discovery and optimize treatment frameworks.
Author(s): Amaral P, Christie R, Gresham DOF, Lucas EJM, Xu LK, Behrmann L, Bond J, Degerman S, van Delft FW, Goossens S, Hagleitner M, Halsey C, Jones N, Lammens T, van Leeuwen FN, Mansour MR, Ntziachristos P, O'Connor D, Barata JT
Publication type: Review
Publication status: Published
Journal: Leukemia
Year: 2025
Pages: epub ahead of print
Online publication date: 14/08/2025
Acceptance date: 21/07/2025
ISSN (print): 0887-6924
ISSN (electronic): 1476-5551
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41375-025-02723-2
DOI: 10.1038/s41375-025-02723-2
