Standard Fludarabine Dosing Results in Overexposure in Young Children Undergoing Hematopoietic Cell Transplantation
Authors: Möhlmann Julia , Ploeg, van der Lisanne , Langenhorst Jurgen , Bognar Tim , Elst, van der Kim , Bierings Marc , Huitema Alwin D.R. , Vries Schultink, de Aurelia , Lindemans Caroline 
Published: December 2024

Introduction
Fludarabine is an immune suppressive agent and is often used in the conditioning regimen prior to hematopoietic cell transplantation (HCT). The active metabolite inhibits DNA- as well as RNA-synthesis of CD4+ and CD8+ T-lymphocytes. There is a proven relationship between exposure to the dephosphorylated fludarabine (F-ara-A) in plasma and outcome after HCT, regarding treatment-related and non-relapse mortality, immune reconstitution, graft failure and fludarabine-induced neurotoxicity. In patients with a combined fludarabine-busulfan (FluBu) regimen, optimal outcomes after HCT were reached with a cumulative F-ara-A exposure of 20 (range 15 to 25) mg*h/L (Langenhorst, Blood Adv. 2019). Currently, fludarabine dosing is mostly based on body surface area (BSA), leading to extensive variability in exposure (Langenhorst, Clin Pharmacokinet. 2019). Infants and young children are underrepresented in the pharmacokinetic (PK) data published so far, despite an ongoing debate among pediatric transplant consortia on how infant regimens should be dose-adjusted. Therefore, the aim of this study was to retrospectively assess F-ara-A exposures in the very young population.
Methods
Previously obtained plasma samples (May 2010 - February 2024) from patients younger than 2 years of age or weighing 15 kg or less were analysed for F-ara-A concentrations using liquid chromatography - tandem mass spectrometry. Consent to use data and biobanked material was obtained according to the declaration of Helsinki and falls within the parental and patient informed consent given to institutional biobank protocols 11/063 and PMCLAB2024.502. Patients had received a conditioning regimen consisting of FluBu or a combination of clofarabine, fludarabine and busulfan (CloFluBu), with cumulative fludarabine dosages of 160 mg/m2 or 40 mg/m2, respectively. Cumulative exposure to fludarabine was assessed by extrapolation to T=192 hours after first infusion and expressed as the area under the concentration-time curve (AUC). The population PK estimates of a previously published three-compartment fludarabine population PK model were used for AUC calculations (Langenhorst, Clin Pharmacokinet. 2019). A cumulative F-ara-A exposure of 15 to 25 mg*h/L was considered as the optimal target window. Patients with the CloFluBu regimen were excluded for target achievement analysis, since no optimal target AUC is established for this dosing strategy, yet.
Results
Data of 66 eligible patients were available, with 752 samples divided over 164 concentration-time curves. In the 47 patients (71%) with the FluBu regimen, standard BSA-based dosing resulted in a median cumulative F-ara-A exposure of 22.5 (range 11.5 to 39.9) mg*h/L and a strong inverse correlation between exposure and BSA was observed. Overall, only 50% of patients had cumulative F-ara-A exposures inside the target range of 15 to 25 mg*h/L. All patients with overexposure were below the age of 1, while patients older than 1.5 years tended to subtherapeutic F-ara-A exposures. In children aged younger than 0.5 years and aged 0.5 to 1 years, 80% and 50% exceeded the target range, respectively. Moreover, 3 out of 4 patients with potential fludarabine-induced neurotoxicity had cumulative exposures &gt;24.5 mg*h/L. Of note, the median cumulative fludarabine AUC for the patients receiving the CloFluBu regimen was 5.2 (range 3.2 to 12.3) mg*h/L. The relative high exposures were mostly observed in children below 1 year of age, comparable to patients receiving the FluBu regimen.
Conclusions
The results of this study suggest that the current BSA-based dosing regimen is inappropriate in infants and young children, indicating the urge for an optimised dosing strategy to prevent complications after HCT in this population. Dose reductions in children below 1 year of age could improve achievement of a cumulative fludarabine AUC within the target range. Of note, the established optimal target should be evaluated for the young population, in addition to assessment of the fludarabine PK estimates with an improved population PK model.