Abstract
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n="131" of 152), 12-month os of 75.1% (95% confidence interval [ci], 67.6% to 82.6%), and 12-month cir of 36.4% (95% ci, 27.5% to 45.2%). optimal fludarabine exposure was determined as auc ≥13.8 mg × h l. in multivariable analyses, patients with auc><13.8 mg × h l had a 2.5-fold higher cir (hazard ratio [hr], 2.45; 95% ci, 1.34-4.48; p=".005)" and twofold higher risk of relapse or loss of bca (hr, 1.96; 95% ci, 1.19-3.23; p=".01)" compared with those with optimal fludarabine exposure. high preinfusion disease burden was also associated with increased risk of relapse (hr, 2.66; 95% ci, 1.45-4.87; p=".001)" and death (hr, 4.77; 95% ci, 2.10-10.9; p>< .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy. Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
