Identifying an Optimal Fludarabine Exposure for Improved Outcomes after CD19 CAR T cell therapy for Aggressive B-NHL.

Fludarabine is one of the most common agents given for lymphodepletion before CD19 CAR 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*h/L), optimal (18-20 mg*h/L), and high (>20 mg*h/L) AUC groups for analyses. The 6-month cumulative incidences of relapse/progression (relapse/POD) by AUC group were 54% (45-62%), 28% (15-44%), and 30% (14-47%), respectively. One-year PFS rates at were 39% (31-48%), 66% (52-84%), and 46% (30-70%), and OS rates were 58% (50-67%), 77% (64-92%), and 66% (50-87%), respectively. In multivariable analyses compared to low AUC, an optimal AUC was associated with the highest PFS (HR 0.52; 0.3-0.91, p=0.02) and lowest risk of relapse/POD (HR 0.46; 0.25-0.84, p=0.01) without an increased risk of any-grade CRS (HR 1.1; 0.7-1.6, p=0.8) or ICANS (HR 1.36; 0.83-2.3, p=0.2). A high AUC was associated with the greatest risk of any-grade ICANS (HR 1.9; 1.1-3.2, p=0.02). While the main cause of death in all groups was relapse/POD, non-relapse-related deaths, including 3 deaths due to 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.