Fludarabine Pharmacokinetics in Nonmyeloablative Hematopoietic Cell Transplantation (HCT): Association with Engraftment and Neurotoxicty.
Authors: Jacobson Pamala A. , Rogosheske John , Green Kathleen , Brunstein Claudio , Barker Juliet , Miller Jeff , Wagner John , McGlave Philip , Tan Ye , Weisdorf Daniel 
Published: April 2020

Abstract
Chemotherapy related complications and risk of graft vs host disease limit HCT to younger patients with good clinical status and organ function. Non-myeloablative (NMA) transplant is now being widely used to extend access to HCT for patients not fit for conventional allografting. However, the incidence of engraftment and toxicity of this procedure can vary. Most NMA preparative therapies include fludarabine, a purine analog antimetabolite infrequently associated with neurotoxicity. In vivo, fludarabine undergoes rapid dephosphorylation to the active compound, F-ara-A which is 40 % renally eliminated and accumulates in renal dysfunction. Given that patients receiving a NMA HCT are often older or have poor renal function we hypothesized that variability in toxicities and clinical outcomes may be related to differences in exposure to F-ara-A. We evaluated the pharmacokinetics of F-ara-A in 29 subjects receiving a fludarabine based NMA HCT and the relationship between pharmacokinetics, engraftment and neurotoxicity. All received fludarabine 40 mg/m2/day IV x 5 days (infused over 1 hour) on days −6 to −2 in combination with cyclophosphamide 50 mg/kg/day IV on day −6 and TBI 200cGy single fraction day −1. Sampling was performed with the 1st and 5th dose of fludarabine. F-ara-A plasma concentrations were measured by HPLC. Patients underwent weekly neurotoxicity evaluation. The median age and weight of subjects was 54.8 years (range, 36–69) years and 79 kg (range, 54.6–134), respectively. Diagnoses were leukemia (n=13), lymphoma (n=7), myelodysplastic syndrome (n=5) and other (n=4). Subjects were transplanted with peripheral blood stem cells from related donors (n=10) and unrelated donor umbilical cord blood (n=19). Median CrCl and total bilirubin on admission was 100 ml/min (range, 49–190) and 0.5 mg/dL (range, 0.2–1.2), respectively. Median F-ara-A area under the curve (AUC0-∞) was 5261 ng hr/mL (range, 2935–7762), half life 9.6 hr (range, 3.1–26.6), clearance 14.5 L/hr (range, 9.4–25.6) and Cmax 851 ng/mL (range, 409–1146). F-ara-A plasma concentrations were slightly higher with dose 5. Correlation (r2) between AUC and age, weight, CrCl, SCr and total bilirubin were all ≤0.1. F-ara-A concentrations were detectable, 13.8 ng/mL (range, 5.7–38.2), on day 0 in all patients. Twenty five (cumulative incidence 89%, 95% CI: 77–100%) patients engrafted at a median of day 7. While neutrophil engraftment occurred in 100% with an AUC &gt;5261 ng hr/mL (n=14), the incidence was 80% (95% CI 60–100%) for those with an AUC &lt;5261 ng hr/mL (n=15)(p=.83). Engraftment was 100% in patients with an F-Ara-A concentration on day transplant ≥14 ng/mL (n=13) and 79% (95% CI 58–100%) if &lt;14 ng/mL (n=16)(p=.45). The patient with the highest AUC (7762) and a Cmax of 1050 ng/mL died of probable fludarabine-related neurotoxicity on day 47. In summary, F-ara-A accumulates slightly between dose 1 and 5 and was detectable in all patients on the day of stem cell infusion. There was a weak correlation between F-ara-A exposure and renal and hepatic function within the ranges studied. The patient with the highest AUC died from severe neurotoxicity.