确定最佳氟达拉滨暴露量以改善侵袭性 B 细胞非霍奇金淋巴瘤患者接受 axi-cel 治疗后的结局

Fludarabine is one of the most common agents given for lymphodepletion before CD19 chimeric antigen receptor T cells, but its optimal therapeutic intensity is unknown. Using data from a multicenter consortium, we estimated fludarabine exposure (area under the curve [AUC]) using a population pharmacokinetic (PK) model in 199 adult patients with aggressive B-cell non-Hodgkin lymphomas who received commercial axicabtagene ciloleucel (Axi-cel).

We evaluated the association of estimated fludarabine AUC with key outcomes, aiming to find an AUC that optimized efficacy and tolerability.

We identified low (<18 mg × hour/L [mgh/L]), optimal (18-20 mgh/L), and high (>20 mgh/L) AUC groups for analyses; the 6-month cumulative incidences of relapse/progression of disease (relapse/POD) by AUC groups were 54% (45%-62%), 28% (15%-44%), and 30% (14%-47%), respectively; and the 1-year progression-free survival (PFS) rates were 39% (31%-48%), 66% (52%-84%), and 46% (30%-70%) and the overall survival (OS) rates were 58% (50%-67%), 77% (64%-92%), and 66% (50%-87%), respectively. In multivariable analyses compared with low AUC, an optimal AUC was associated with the highest PFS (hazard ratio [HR], 0.

52; 0. 3-0. 91; P = . 02) and lowest risk of relapse/POD (HR, 0. 46; 0. 25-0. 84; P = . 01) without an increased risk of any-grade cytokine release syndrome (HR, 1. 1; 0. 7-1. 6; P = . 8) or and immune effector cell-associated neurotoxicity syndrome (ICANS) (HR, 1. 36; 0. 83-2. 3; P = . 2). A high AUC was associated with the greatest risk of any-grade ICANS (HR, 1. 9; 1. 1-3. 2; P = . 02). Although the main cause of death in all groups was relapse/POD, nonrelapse-related deaths, including 3 deaths from ICANS, were more frequent in the high AUC group.

These findings suggest that PK-directed fludarabine dosing to achieve an optimal AUC may result in improved outcomes for patients receiving axi-cel.