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

Linde Dekker, Friso G Calkoen, Yilin Jiang, Hilly Blok, Saskia R Veldkamp, Coco De Koning, Maike Spoon, Rick Admiraal, Peter Hoogerbrugge, Britta Vormoor, H Josef Vormoor, Henk Visscher, Marc Bierings, Marieke Van Der Vlugt, Harm Van Tinteren, A Laura Nijstad, Alwin D R Huitema, Kim C M Van Der Elst, Rob Pieters, Caroline A LindemansStefan Nierkens

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.
Originele taal-2Engels
Pagina's (van-tot)1969-1976
Aantal pagina's8
TijdschriftBlood advances
Volume6
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - 12 apr. 2022

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