CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND: Idecabtagene vicleucel (ide-cel) is a BCMA-directed CAR-T associated with high response rates in relapsed/refractory multiple myeloma (RRMM), yet responses are not durable and most patients experience toxicities. Fludarabine (Flu) is a key component of lymphodepletion but exhibits significant pharmacokinetic (PK) variability. OBJECTIVE: Given Flu exposure (AUC) predicts outcomes after CD19-directed CAR-T, we hypothesized it would predict outcomes after ide-cel. Our objective was to determine the association between fludarabine AUC and clinical outcomes after standard-of-care (SOC) ide-cel. STUDY DESIGN: RRMM patients receiving ide-cel from 10 US Multiple Myeloma Immunotherapy Consortium centers were retrospectively analyzed. A population PK approach using cumulative Flu dose and PK covariates, eGFR and body weight (BW), was used to predict Flu AUC and C max and these were tested in univariable and multivariable analysis. RESULTS: 285 patients were analyzed, and the median predicted Flu AUC was 19.01 (11.23-41.47) mg * h/L. We observed an association between Flu AUC and Day 90 ORR (OR 2.11; 95% CI 0.99-4.68; P = .057). Flu AUC was significantly associated with grade 1 CRS (P = .013), and grade 1 ICANS (P = .032), which was consistent with the observed increase in tocilizumab and corticosteroid use in these patients. Flu AUC was also associated with day 60 grade 3/4 thrombocytopenia (P = .03). A non-statistical but clinically significant increase in the odds of occurrence of day 90 grade 3/4 neutropenia (P = .058) and infection (P = .017) was also observed. CONCLUSION: Predicted Flu exposure is an independent predictor of CAR-T toxicities in this real-world ide-cel-treated population. Validation of these findings with prospective therapeutic drug monitoring is needed to gain further insight into how personalized Flu dosing can mitigate these toxicities after ide-cel.