Introduction Tisagenlecleucel (tisa-cel), a CD19-directed CAR T-cell therapy, has transformed therapy in relapsed/refractory pediatric B-cell acute lymphoblastic leukemia. Over 80% of patients will achieve a complete remission after tisa-cel, however 40–50% of responders relapse within a year. Lymphodepleting chemotherapy with fludarabine (FLU) and cyclophosphamide (Cy) enhances CAR-T expansion and persistence, and previous studies have shown the importance of achieving minimum levels of FLU exposure to improve these outcomes. There is substantial interpatient variability in FLU pharmacokinetics (PK) with package insert body surface area dosing in pediatrics. A priori PK modeling allows for predicted FLU exposure estimates based on patient-specific variables. This study evaluated the relationship between model-predicted FLU area-under-the-curve (AUC, mg·hr/L) and clinical outcomes in pediatric patients receiving tisa-cel to identify optimal exposure targets.

Methods This retrospective single center cohort study included pediatric patients who received tisa-cel with standard lymphodepletion (FLU + Cy) between November 2017 and October 2024. FLU was administered for all patients at 30 mg/m²/day for 4 days. Individual AUCs for FLU were retrospectively calculated using a validated population PK model via Bayesian estimation (Brooks, 2022). Outcomes evaluated included 1-year overall survival (OS), relapse-free survival (RFS), and relapse-free, loss of B-cell aplasia (LBCA)-free survival. The cumulative incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were evaluated at Day 100. Disease burden immediately prior to lymphodepletion and infusion defined as High (>5%), Low (<5%), or Negative as measured by flow cytometry.

Recursive partitioning (RPART) was utilized to identify optimal AUC cutoffs for RFS. Survival outcomes and toxicity incidence were analyzed using Kaplan-Meier, cumulative incidence functions with competing risks, and Fine and Gray regression. Group comparisons used Wilcoxon rank-sum and chi-square tests.

Results 34 patients were included with a median age of 14.4 years (range 1.2–24.4) and median weight of 50.0 kg (range 9.8–97.3). RPART defined three FLU AUC groups: LOW (<18.5 mg·hr/L, n=8), OPTIMAL (18.5–21.7, n=11), and HIGH (≥21.7, n=15). There were no statistically significant differences in age, weight or disease burden across the FLU AUC groups.

RFS of the full study cohort at 1 year was 59% (95% CI:40–73%). RFS by AUC group was: LOW 25% (4–56%), OPTIMAL 81% (42–95%), and HIGH 60% (32–80%) (p=0.04). Low or negative disease burden was associated with higher RFS (69%, 46–84%) vs. high burden (36%, 13–63%) (p=0.01).

Full cohort 1-year OS was 78% (95% CI:60–89%). OS by AUC group was: LOW 57% (17–84%), OPTIMAL 100% (100–100%), and HIGH 73% (44–89%) (p=0.12). Patients with low disease burden had higher OS (90%, 66–97%) than those with high burden (55%, 23–78%) (p<0.01).

Relapse-free, LBCA-free survival at 1 year was 38% (95% CI:22–54%) overall, with a trend towards higher rates in patients in the OPTIMAL and HIGH cohorts: LOW 13% (1–42%), OPTIMAL 45% (17–71%), and HIGH 47% (21–69%) (p=0.20).

The cumulative incidence of relapse at 1 year was 39% (95% CI:22–55%). Relapse by AUC group was: LOW 75% (40–100%), OPTIMAL 19% (0–49%), and HIGH 33% (10–57%) (p=0.03). High disease burden was associated with higher relapse (55%, 25–84%) than low burden (31%, 12–50%) (p=0.04).

In multivariate analysis controlling for disease burden, hazard ratio for RFS in the OPTIMAL cohort was 0.16 (95% CI:0.03-0.83), HIGH 0.42 (0.13-1.34), relative to LOW at 1.00 (p=0.07). Hazard ratio for relapse in OPTIMAL was 0.15 (0.03-0.73), HIGH 0.29 (0.09-0.90), relative to LOW 1.00 (p=0.02).

The cumulative incidence of CRS was 62% (95% CI:44–80%). CRS did not differ by AUC group but was significantly higher in patients with high disease burden (91%, 61–100%) vs. low burden (48%, 27–68%) (p=0.01). The cumulative incidence of ICANS was 15% (3–26%), with no significant differences by AUC group or disease burden.

Conclusions Model-predicted FLU AUC appears to correlate with key clinical outcomes in pediatric patients receiving tisa-cel. These findings support the utility of model-informed target FLU AUCs to guide personalized lymphodepletion. Personalized lymphodepletion may offer a feasible and impactful approach to enhance the long-term efficacy of CAR T-cell therapy in children.

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2025
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