Impact of fludarabine exposure on CAR T-cell outcomes in patients with large B-cell lymphoma.

abstractThe impact of fludarabine pharmacokinetics (PK) on chimeric antigen receptor (CAR) T-cell outcomes is not fully elucidated. We hypothesized that in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), measured fludarabine exposure during lymphodepletion would correlate with CAR T-cell results. We conducted a prospective, single-center study including patients with R/R LBCL treated with commercial, CD19-targeted CAR T-cell products. Up to 7 plasma samples per patient were collected at predefined intervals during lymphodepletion. Fludarabine exposure (area under the curve [AUC]) was estimated using a population PK model. An iterative cubic spline approach identified optimal AUC exposure ranges specific to each CAR T-cell product. The primary end point was progression-free survival (PFS). Among 54 patients with a median follow-up of 24.5 months, the median fludarabine AUC was 18.12 mg·h/L (interquartile range, 14.56-20.55). Optimal exposure windows were 17.5 to 21.5 mg·h/L for axicabtagene ciloleucel (axi-cel) and 14.0 to 18.0 mg·h/L for tisagenlecleucel, with 24 patients (44%) inside these ranges. Median PFS after CAR T-cell infusion was not reached vs 13.3 months in the optimal vs other cohort (P = .03). In the multivariable analysis, optimal exposure remained independently associated with improved PFS (P = .03), together with axi-cel treatment (P = .03). CAR T-cell expansion and rates of any grade cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and hematotoxicity were similar between groups. In conclusion, the prospective measurement of fludarabine exposure identified an optimal AUC window associated with prolonged PFS in patients with R/R LBCL receiving CAR T-cell therapy. These findings support the integration of PK-guided fludarabine dosing to enhance therapeutic outcomes.