Abstract LB327: Optimizing fludarabine exposure in pediatric CAR T-cell patients through an adaptive dosing approach

Abstract

Background B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer in children and young adults. While initial response rates are high (∼90%), 15-20% of patients relapse within 2 years, and outcomes for relapsed or refractory (r/r) disease are poor. CD19-directed CAR T-cell therapy offers a potential cure for r/r B-ALL, but relapse currently occurs in approximately 50% of patients. Lymphodepletion with fludarabine (Flu) and cyclophosphamide is essential for CAR T-cell expansion and efficacy, with recent data showing that Flu exposure strongly correlates with outcome. Cumulative area under the curve (cAUC) values <14 mg.h/L were associated with shorter leukemia-free survival (1.8 vs 12.9 months) and higher CD19⁺ relapse (100% vs 27.4%). Notably, 40% of patients achieved suboptimal exposures (Dekker et al 2022), suggesting that therapeutic drug monitoring (TDM) to individualize Flu exposure may be beneficial. Methods r/r B-ALL patients receiving CAR T-cell therapy were recruited to the NCCPG TDM 2018 clinical trial (ISRCTN10139334). Patients received 30 mg/m2/day Flu for 4 days and ≥4 plasma samples were taken per patient over the first 24 hours post Flu infusion for pharmacokinetic (PK) analysis. Plasma concentrations were analyzed by liquid chromatography-tandem mass spectrometry. PK analysis was conducted using a 3-compartment population PK model in InsightRX. Analysis was conducted in real time with dose adjustments implemented to target a cAUC within the therapeutic window of 16-20 mg.h/L. For a proportion of patients, further PK analysis was conducted on day 4 post dose adjustment. PK analysis was conducted with and without the inclusion of patient specific concentration-time data to assess the appropriateness of model-based dosing (MBD). Results To date, analysis has been conducted for 21 patients. Estimated cAUCs were variable (10.2-26 mg.h/L) with no trends between exposure and age or weight. 81% of patients (17/21) required dose adjustments to achieve exposures within the therapeutic window. Without dose adjustments, nine patients would have achieved exposures <16mg.h/L, putting them at risk of CAR-T failure, with eight patients achieving exposures >20mg.h/L, increasing risk of drug toxicity. Three patients underwent additional TDM to validate dose adjustments, with final cAUCs within 6% of target exposures. Model-predicted exposures were significantly different from exposure predictions incorporating concentration-time data, with exposures outside the therapeutic window predicted in 47% of patients using MBD alone. Conclusions Preliminary data indicate considerable interpatient variability in Flu exposure in r/r B-ALL patients receiving CAR T-cell therapy. BSA-based dosing and MBD approaches may be inadequate, demonstrating the need for adaptive dosing. TDM is feasible with Flu dosed across 4 days and leads to accurate target exposure attainment. Citation Format Emma Barlow, Su Han Lum, Geoff Shenton, Denise Bonney, Rachael Hough, Sophie Hambleton, Gareth Veal, Shelby Barnett. Optimizing fludarabine exposure in pediatric CAR T-cell patients through an adaptive dosing approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8_Suppl):Abstract nr LB327.

https://www.researchgate.net/publication/403941310_Abstract_LB327_Optimizing_fludarabine_exposure_in_pediatric_CAR_T-cell_patients_through_an_adaptive_dosing_approach