Tisagenlecleucel

The impact of fludarabine pharmacokinetics (PK) on chimeric antigen receptor (CAR) T-cell outcomes is not fully elucidated. We hypothesized that in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), measured fludarabine exposure during lymphodepletion would correlate with CAR T-cell results. We conducted a prospective, single-center study including patients with R/R LBCL treated with commercial, CD19-targeted CAR T-cell products. Up to 7 plasma samples per patient were collected at predefined intervals during lymphodepletion. Fludarabine exposure (area under the curve [AUC]) was estimated using a population PK model. An iterative cubic spline approach identified optimal AUC exposure ranges specific to each CAR T-cell product. The primary end point was progression-free survival (PFS). Among 54 patients with a median follow-up of 24.5 months, the median fludarabine AUC was 18.12 mg·h/L (interquartile range, 14.56-20.55). Optimal exposure windows were 17.5 to 21.5 mg·h/L for axicabtagene ciloleucel (axi-cel) and 14.0 to 18.0 mg·h/L for tisagenlecleucel, with 24 patients (44%) inside these ranges. Median PFS after CAR T-cell infusion was not reached vs 13.3 months in the optimal vs other cohort (P = .03). In the multivariable analysis, optimal exposure remained independently associated with improved PFS (P = .03), together with axi-cel treatment (P = .03). CAR T-cell expansion and rates of any grade cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and hematotoxicity were similar between groups. In conclusion, the prospective measurement of fludarabine exposure identified an optimal AUC window associated with prolonged PFS in patients with R/R LBCL receiving CAR T-cell therapy. These findings support the integration of PK-guided fludarabine dosing to enhance therapeutic outcomes.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has markedly improved outcomes for patients with relapsed or refractory B-cell malignancies, although coagulopathy characterized by hypofibrinogenemia has increasingly been recognized as a complication after CAR T-cell therapy. Nevertheless, its contemporary real-world incidence, risk factors, and clinical impact remain incompletely defined. This study aimed to determine the real-world incidence, risk factors, and clinical impact of hypofibrinogenemia following CD19-directed CAR T-cell therapy for relapsed or refractory B-cell lymphoma. This retrospective cohort study included all consecutive adult patients (≥16 years) with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) who received tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), or axicabtagene ciloleucel (axi-cel) at Kyoto University Hospital between December 2019 and December 2024. We also evaluated detailed CRS severity according to modified CRS grading (m-CRS), in which grade 1 was subdivided into grade 1a (duration of CRS-related symptoms ≤5 days) and grade 1b (duration of CRS-related symptoms >5 days), as previously described; grade 1b CRS was defined as "prolonged CRS." A total of 111 patients (74 tisagenlecleucel [tisa-cel] [67%], 24 lisocabtagene maraleucel [liso-cel] [22%], and 13 axicabtagene ciloleucel [axi-cel] [12%]) were included. Hypofibrinogenemia (fibrinogen ≤150 mg/dL) was observed in 28 patients (25%) within 30 days after infusion (median onset, 10.5 days). FFP was administered to 15 patients (14%). Multivariable analysis revealed that grade ≥1b CRS (adjusted hazard ratio [aHR], 4.59; 95% confidence interval [CI], 1.89 to 11.14; P < .01), lower baseline fibrinogen levels (aHR, 1.07 per 10 mg/dL decrease; 95% CI, 1.02 to 1.14; P = .01), and axi-cel use (versus tisa-cel: aHR, 3.29; 95% CI, 1.38 to 7.83; P < .01) were independently associated with hypofibrinogenemia. In our cohort, no fatal bleeding events occurred. Hypofibrinogenemia was not associated with inferior overall survival or progression-free survival. Prolonged CRS (grade 1b) or grade ≥2 CRS, lower baseline fibrinogen, and use of axi-cel were independently associated with hypofibrinogenemia. Risk-adapted fibrinogen monitoring may help identify patients who could benefit from closer surveillance, and timely fibrinogen replacement may optimize supportive care. Further multicenter studies are warranted to validate these findings and clarify the clinical impact of hypofibrinogenemia, including hemorrhagic outcomes.