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

Abstract

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.

Graphical abstract

Figure 1.

Simulated FLU AUC vs age. (A) FLU concentration vs time given 30 mg/m² per day for 4 days based on the population PKs from Langenhorst et al. Curve and blue shading: median and quartile range for a person aged 5 years; curve and gray shading: median and quartile range for a person aged 15 years. (B-D) Cumulative FLU AUC vs age for different FLU dosing regimens. (B) FLU 25 mg/m² per day for 3 days. (C) FLU 30 mg/m² per day for 4 days. (D) Age-adjusted FLU dose (37 mg/m² per day × 4 days for age <6 years; 33.75 mg/m² per day × 4 days for age ≥6 but <11 years; 30 mg/m² per day × 4 days for age ≥11 but <15 years; and 26.25 mg/m² per day × 4 days for age ≥15 years). Panels B-D: median (black curve), 25th to 75th percentiles (blue shaded region), and 5th to 95th percentiles (gray shaded region).

Figure 2.

Clinical trial simulation of the percentage of individuals with a FLU cumulative AUC in the target range with different dosing schemas. Simulated percentage of individuals (of a study sample size of 18) with a cumulative FLU AUC in the target range of AUC of ≥13.8 to ≤25 mg × h/L using 4 different FLU dosing regimens. R1, 25 mg/m² per day for 3 days; R2, 30 mg/m² per day for 4 days; R3, age-adjusted dosing; or R4, TDM-guided dosing. Horizontal line, median; box, 25th to 75th percentile; whiskers, quartile range.

Figure 3.

Clinical trial simulation of the percentage of individuals with either OS at 24 months or CIR at 12 months. Simulated percentage of individuals (of a study sample size of 18) with OS at 24 months (A) and CIR at 12 months (B) using 4 different FLU dosing regimens. R1, 25 mg/m² per day for 3 days; R2, 30 mg/m² per day for 4 days; R3, age-adjusted dosing; or R4, TDM-guided dosing. Horizontal line, median; box, 25th to 75th percentile; whiskers, quartile range.