Impact of fludarabine dosage on outcomes in large B-cell lymphoma patients treated with CAR T-cell therapy: a retrospective study of the CTIWP of the EBMT

Lymphodepleting conditioning (LD) with fludarabine and cyclophosphamide is critical to ensure optimal expansion and persistence of CD19 CAR T-cells. We conducted a retrospective EBMT registry study to assess the impact of fludarabine dosing in LD on outcomes in large B-cell lymphoma (LBCL). Among 1498 patients treated between 2019 and 2023 with tisagenlecleucel (tisa-cel; n = 549) or axicabtagene ciloleucel (axi-cel; n = 949), we observed marked variability in fludarabine dosing for tisa-cel, whereas axi-cel was consistently administered at standard doses. In the tisa-cel cohort, higher fludarabine dosing (82.6-120 mg/m 2) was associated with inferior overall survival (HR 1.29; 95% CI, 1.02-1.64; p = 0.036) compared with standard-dose fludarabine (67.5-82.5 mg/m 2). We next compared three groups including axi-cel. Relapse incidence was higher after tisa-cel treatment and not improved using higher-dose fludarabine (standard dose tisa-cel: HR 1.69; 95% CI, 1.39-2.06; p < 0.001; high-dose tisa-cel: HR 1.45; 95% CI, 1.09-1.94; p = 0.012). Axi-cel achieved superior PFS and OS vs standard-dose tisa-cel: HR 1.21; 95% CI, 1.00-1.45; p = 0.049; vs high-dose tisa-cel (HR 1.57; 95% CI, 1.26-1.95; p < 0.001), albeit with more ICANS. In conclusion, in this large EBMT analysis, fludarabine dose escalation did not improve outcomes with tisa-cel in LBCL, while axi-cel was associated with superior efficacy.