氟达拉滨暴露预测急性白血病儿童和年轻成人 CD19 CAR-T 细胞治疗后的结局

The addition of fludarabine to cyclophosphamide as a lymphodepleting regimen prior to CD19 chimeric antigen receptor (CAR) T-cell therapy significantly improved outcomes in patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

Fludarabine exposure, previously shown to be highly variable when dosing is based on body surface area (BSA), is a predictor for survival in allogeneic hematopoietic cell transplantation (allo-HCT). Hence, we hypothesized that an optimal exposure of fludarabine might be of clinical importance in CD19 CAR T-cell treatment.

We examined the effect of cumulative fludarabine exposure during lymphodepletion, defined as concentration-time curve (AUC), on clinical outcome and lymphocyte kinetics. A retrospective analysis was conducted with data from 26 patients receiving tisagenlecleucel for r/r B-ALL. Exposure of fludarabine was shown to be a predictor for leukemia-free survival (LFS), B-cell aplasia, and CD19-positive relapse following CAR T-cell infusion.

Minimal event probability was observed at a cumulative fludarabine AUCT0- 14 mg*h/L, and underexposure was defined as an AUCT0- <14 mg*h/L. In the underexposed group, the median LFS was 1. 8 months, and the occurrence of CD19-positive relapse within 1 year was 100%, which was higher compared with the group with an AUCT0- 14 mg*h/L (12. 9 months; P < . 001; and 27. 4%; P = . 0001, respectively).

Furthermore, the duration of B-cell aplasia within 6 months was shorter in the underexposed group (77. 3% vs 37. 3%; P = . 009). These results suggest that optimizing fludarabine exposure may have a relevant impact on LFS following CAR T-cell therapy, which needs to be validated in a prospective clinical trial.