The optimal area under the curve (AUC) dose of fludarabine lymphodepletion prior to treatment of aggressive B-cell non-Hodgkin lymphoma (NHL) with CD19-targeted chimeric antigen receptor (CAR) T-cells was associated with lower risk of relapse and longer progression-free survival (PFS) compared with lower and higher doses, according to population pharmacokinetic model.
Researchers determined this optimal AUC dose for fludarabine was 18 to 20 mg*h/L, according to study results published in the journal Blood Advances.
In this retrospective, multicenter study, data from 199 adults with aggressive B-cell NHL from the Cell Therapy Consortium registry were analyzed stratified by fludarabine AUC. The AUC was categorized as low for <18 mg*h/L, optimal for 18 to 20 mg*h/L, and high for >20 mg*h/L.
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The cumulative incidence of relapse or progression at 6 months was lowest in the optimal AUC group at 28% (hazard ratio [HR], 0.46; 95% CI, 0.25-0.84; P =.01) compared with 30% in the high group and 54% in the low group. The median PFS was not reached in the optimal group, 12 months in the high group, and 3.6 months in the low group.
The optimal group also demonstrated the longest PFS ([HR, 0.52; 95% CI, 0.3-0.91; P =.02), with 66% at 1 year compared with 46% in the high group and 39% in the low group.
The 1-year overall survival (OS) was 77% with the optimal AUC compared with 66% with a high AUC and 58% with a low AUC. The median OS was not yet reached, 16 months, and 18 months in the optimal, high, and low groups, respectively.
The rates of cytokine release syndrome (CRS; HR, 1.1; 95% CI, 0.7-1.6; P =.8) and immune effector cell-associated neurotoxicity syndrome (ICANS; HR, 1.36; 95% CI, 0.82-2.3; P =.2) were similar between the optimal and low AUC groups. The rates of any-grade CRS were 78% and 79% in the optimal and low AUC groups, respectively. ICANS occurred among 56% and 44% of patients.
However, there was an increased risk for any-grade ICANS in the high AUC group (HR, 1.9; 95% CI, 1.1-3.2; P =.02), with 85% of patients in this group developing any-grade and 37% grade 3 or higher ICANS.
The greatest number of nonrelapse related death occurred in the high AUC at 11%, followed by 5% in the low AUC group and 3% in the optimal AUC group.
“Our data suggest that a more personalized fludarabine exposure is achievable using population pharmacokinetic-directed dosing, thus representing a novel and easily modifiable strategy to improve outcomes after CD19 CAR T cell therapy,” the authors concluded in their report.
Disclosures: This study was supported in part by a grant from Novartis Pharmaceuticals. One of the study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.
Reference
Scordo M, Flynn JR, Gonen M, et al. Identifying an optimal fludarabine exposure for improved outcomes after CD19 CAR T cell therapy for aggressive B-NHL. Blood Adv. Published online July 31, 2023. doi: bloodadvances.2023010302
