CAR T-Cell Therapy in Pediatric Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia: Efficacy, Safety, Mechanisms of Failure, Long-Term Outcomes, and Next-Generation Strategies — A Comprehensive Review (2023–2026)

Background: CD19-directed chimeric antigen receptor (CAR) T-cell therapy has fundamentally transformed the treatment of relapsed/refractory (R/R) pediatric B-cell acute lymphoblastic leukaemia (B-ALL). Despite impressive initial response rates, relapse remains frequent, and long-term durability continues to be a major challenge.

Objectives: This review synthesises the current evidence — drawn from pivotal clinical trials, real-world registries, systematic reviews, and meta-analyses published between 2023 and 2026 — on four interconnected themes: (1) the clinical efficacy and early safety management of CD19-directed CAR T-cells; (2) the primary mechanisms of treatment failure; (3) long-term outcomes including the role of consolidate haematopoietic stem cell transplantation (HSCT); and (4) next-generation strategies including dual-targeted (CD19/CD22), humanised, and allogeneic constructs.

Methods: A structured narrative synthesis was conducted incorporating data from systematic reviews and meta-analyses (Navarro et al., 2026; Wu et al., 2023; Zinzi et al., 2023; Nguyen et al., 2023), pivotal randomised and observational trials (ELIANA, FELIX; Cappell & Kochenderfer, 2023; Saleh et al., 2023; Pasvolsky et al., 2023), real-world registry studies (Bader et al., 2023; Baguet et al., 2023), retrospective cohort analyses, and preclinical/early-phase studies covering next-generation constructs. A total of 90+ unique papers were considered across all review modules.

Results: CD19-directed CAR T-cells consistently achieve complete remission (CR) and MRD-negativity rates exceeding 80–86%, with 1-year overall survival (OS) of 72–77%. Grade ≥3 cytokine release syndrome (CRS) and neurotoxicity (ICANS) occur in 7–21% of patients and are substantially mitigated by early tocilizumab and corticosteroid intervention. Both CD19-negative antigen escape and CD19-positive persistence failures drive relapse. Consolidative allogeneic HSCT after MRD-negative CR improves 3-year OS to 58–76% versus <40% without transplant. Next-generation dual-targeted (CD19/CD22) constructs reduce antigen escape, while humanized scFv domains improve persistence; allogeneic products offer scalability but face persistence and immune-compatibility challenges.

Conclusions: Next-generation CAR T platforms are progressively addressing the key limitations of first-generation products, but significant research gaps remain — particularly regarding long-term durability, head-to-head comparisons, and biomarker-guided patient stratification.