Age-adjusted dosing of fludarabine for lymphodepletion in CAR T-cell therapy: a clinical trial simulation study.

Fludarabine (FLU) is used for lymphodepletion and improves the persistence and expansion of chimeric antigen receptor (CAR) T cells in vivo. Higher FLU systemic exposure is associated with lower relapse risk and improved leukemia-free survival in pediatric patients with acute lymphoblastic leukemia treated with CD19 CAR T-cell therapy. FLU pharmacokinetics (PKs) is age dependent, with increased clearance in younger children. Here, we used modeling and simulation, including clinical trial simulations, to define age-adjusted FLU dosage regimens that may maintain effective FLU exposures and improve outcomes. The FLU PK and pharmacodynamic relationships with overall survival (OS) and cumulative incidence of relapse (CIR) were derived from published pediatric populations. Four FLU dosages were considered for the simulations: 75 or 120 mg/m2 cumulative fixed dose, age-adjusted dosing, and doses based on therapeutic drug monitoring (TDM). The target FLU cumulative area under the curve range was defined as 13.8 to 25 mg × h/L. Clinical trial simulations showed that across the pediatric age range, the number of individuals in the target range increased from a median of 22% to 61% with fixed dosages, to 72% with age-adjusted dosing and 94% with TDM. Clinical trial simulations also showed that age-adjusted or TDM dosing could increase the median number of individuals with OS at 24 months by 67% and decrease the median number of individuals with CIR at 12 months by 72%, compared with fixed dosages. In conclusion, these simulation studies support using FLU age-adjusted or TDM dosing to increase the number of individuals achieving exposure within the targeted range and, therefore, improve clinical outcomes.