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Lookup NU author(s): Dr Britta Vormoor
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2022 by The American Society of Hematology. 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 AUCT021 $14 mg*h/L, and underexposure was defined as an AUCT021 ,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 AUCT021 $14 mg*h/L (12.9 months; P, .001; and 27.4%; P 5 .0001, respectively). Furthermore, the duration of B-cell aplasia within 6 months was shorter in the underexposed group (77.3% vs 37.3%; P 5 .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.
Author(s): Dekker L, Calkoen FG, Jiang Y, Blok H, Veldkamp SR, De Koning C, Spoon M, Admiraal R, Hoogerbrugge P, Vormoor B, Vormoor HJ, Visscher H, Bierings M, Van Der Vlugt M, Van Tinteren H, Nijstad AL, Huitema ADR, Van Der Elst KCM, Pieters R, Lindemans CA, Nierkens S
Publication type: Article
Publication status: Published
Journal: Blood Advances
Year: 2022
Volume: 6
Issue: 7
Pages: 1969-1976
Print publication date: 12/04/2022
Online publication date: 08/02/2022
Acceptance date: 03/02/2022
Date deposited: 05/05/2022
ISSN (print): 2473-9529
ISSN (electronic): 2473-9537
Publisher: American Society of Hematology
URL: https://doi.org/10.1182/bloodadvances.2021006700
DOI: 10.1182/bloodadvances.2021006700
PubMed id: 35134115
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