(172) Model-Informed Precision Dosing of Fludarabine for Adult CAR-T Lymphodepletion

Poster Abstract:

Background: Fludarabine with cyclophosphamide is the most commonly used regimen for lymphodepletion prior to CAR-T infusion. Each CAR-T product package insert has recommended dosing for fludarabine in this setting based on body surface area (BSA). However, BSA-based dosing of fludarabine has been shown to result in highly variable exposure in terms of cumulative area under the curve (AUC). Population pharmacokinetic models for fludarabine have been published and validated and can more accurately predict fludarabine exposure than BSA-based dosing. These models use body weight and renal function as covariates.

Fludarabine exposure has been associated with key outcomes after CAR-T. Several studies have shown an association between subtherapeutic fludarabine exposure and increased rates of relapse or progression or decreased progression-free survival (PFS). Additionally, there is evidence that excessive fludarabine exposure may increase risk of CAR-T toxicities, specifically neurotoxicity and cytokine-release syndrome (CRS). To date, axicabtagene ciloleucel (axi-cel) is the only adult CAR-T product to have an evidence-based therapeutic range for fludarabine cumulative AUC, which has been defined as 18-20 mg*hr/L.

Objectives: Identify any association between fludarabine exposure (in terms of cumulative AUC) and key efficacy and safety outcomes after CAR-T and determine targets for fludarabine exposure to allow for broader application of model-informed precision dosing of fludarabine in this setting.

Methods: This study is a retrospective analysis of all patients who have received CAR-T at our institution. All patients’ lymphodepleting chemotherapy regimens were assessed for fludarabine exposure in terms of cumulative AUC at the time of chemotherapy administration using a validated population pharmacokinetic model and precision-dosing software. Key efficacy and safety outcomes (relapse/progression, PFS, overall survival, CRS, and neurotoxicity) will be analyzed by chart review to a determine therapeutic fludarabine exposure range for each product.

Results: pending

Discussion/conclusions: pending

References (must also be included in final poster): 1. Scordo, Michael, et al. "Identifying an optimal fludarabine exposure for improved outcomes after axi-cel therapy for aggressive B-cell non-Hodgkin lymphoma." Blood Advances 7.18 (2023): 5579-5585.
2. Fabrizio, Vanessa A., et al. "Optimal fludarabine lymphodepletion is associated with improved outcomes after CAR T-cell therapy." Blood advances 6.7 (2022): 1961-1968.
3. Dekker, Linde, et al. "Fludarabine exposure predicts outcome after CD19 CAR T-cell therapy in children and young adults with acute leukemia." Blood Advances 6.7 (2022): 1969-1976.
4. Wagner, Charlotte B., et al. "Fludarabine Lymphodepletion Exposure Is Associated with Idecabtagene Vicleucel Toxicity in Relapsed and Refractory Multiple Myeloma Patients: Real-World Experience from the US Myeloma Immunotherapy Consortium." Blood 142 (2023): 4880.
5. Langenhorst, Jurgen B., et al. "Population pharmacokinetics of fludarabine in children and adults during conditioning prior to allogeneic hematopoietic cell transplantation." Clinical pharmacokinetics 58 (2019): 627-637.