Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia

• Published in: Blood advances Vol. 6; no. 7; pp. 1969 - 1976
• Main Authors: Dekker, Linde, Calkoen, Friso G., Jiang, Yilin, Blok, Hilly, Veldkamp, Saskia R., De Koning, Coco, Spoon, Maike, Admiraal, Rick, Hoogerbrugge, Peter, Vormoor, Britta, Vormoor, H. Josef, Visscher, Henk, Bierings, Marc, Van Der Vlugt, Marieke, Van Tinteren, Harm, Nijstad, A. Laura, Huitema, Alwin D.R., Van Der Elst, Kim C.M., Pieters, Rob, Lindemans, Caroline A., Nierkens, Stefan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12-04-2022; American Society of Hematology
• Subjects: Antigens, CD19; Child; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive - methods; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy; Prospective Studies; Recurrence; Retrospective Studies; Vidarabine - analogs & derivatives; Young Adult
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2021006700

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.
•A cumulative fludarabine AUCT0−∞ ≥14 mg*h/L correlates with improved LFS after CD19 CAR T-cell infusion.•Clinical outcome in patients receiving CD19 CAR T cells might be improved by optimizing fludarabine exposure in the lymphodepleting regimen.
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