Fludarabine Exposure Is Associated with Increased Treatment Related Mortality after Nonmyeloablative Hematopoietic Cell Transplantation (HCT)

Fludarabine is a purine analog antimetabolite with antitumor and potent immunosuppressive activity. It is a prodrug that undergoes rapid dephosphorylation to the systemically circulating active compound, F-ara-A. Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of F-ara-A are poorly characterized in HCT recipients and exposure-response relationships remain undefined. Our objective of this study was to study the association between F-ara-A systemic exposures and engraftment, acute graft vs host disease (GVHD) and treatment related mortality (TRM). Eighty seven adult patients with a median age of 55 (range 20–69) years undergoing sibling peripheral blood or bone marrow (n=22) or unrelated cord blood (n=65) donor HCT were enrolled in this pharmacokinetic-pharmacodynamic study. Underlying diseases were ALL (n=6), AML (n=26), CML (n=1), myelodysplasia (n=14), NHL (n=17), Hodgkins (n=8) and other (n=15). Patients received a nonmyeloablative regimen of fludarabine 40 mg/m²/day intravenously (IV) as a single daily dose × 5 days on days -6 to -2 given over one hour (9 were dose reduced and received 30–35 mg/m²/day), cyclophosphamide 50 mg/kg/day IV day -6 and TBI 200cGy single fraction on day -1. Equine antithymocyte globulin 15 mg/kg every 12 hours from days -3 to -1 was administered to 40 subjects. Cyclosporine and mycophenolate mofetil were given beginning on day –3. Pharmacokinetic sampling was performed with the first dose of fludarabine at times 0, 1.6, 2, 3, 4, 6, 8, 12, 24 after the start of the infusion and quantified with HPLC. Median (range) F-ara-A area under the curve (AUC)0-∞ was 5,000 (2,000–11,5000) ng hr/mL, clearance (CL) 15.3 (6.2–36.6) L/hour, concentration 24 hours after the first dose 55 (17–166) ng/mL and concentration on day zero 16.0 (0.1–144.1) ng/mL. Median serum creatinine and creatinine clearance on the first day of fludarabine was 0.9 (0.4–1.5) mg/dL and 82.1 (49.5–153.2) ml/min, respectively. Median time to neutrophil recovery was day 11 (1–38) posttransplant. Graft failure occurred in 14 (16%) individuals. Acute GVHD II-IV and III-IV developed in 47 (54%) and 15 (17%), respectively. TRM occurred in 18 (21%) individuals by 6 months posttransplant. Primary causes of death were organ failure, infection, hemorrhage and ARDS. Higher F-ara-A exposure was associated with greater TRM. The cumulative incidence (95% CI) of TRM at 6 months for individuals with an F-ara-A AUC >6500 ng hr/mL was 50% (23–77) vs 15% (7–23) for AUC ≤ 6500 ng hr/mL (p=0.0005), CL ≤ 12.5 L/hr 45% (24–67%) vs for CL >12.5 L/hr 12% (4–20%)(p=0.0002), concentration at 24 hours >80 ng/mL 64% (33–94%) vs ≤ 80 ng/mL 15% (7–24%) (p<0.0001) and concentration on day zero >30 ng/mL 53% (28–78) vs ≤ 30 14% (5–22%) (p=0.0004). Sixteen percent of subjects had an F-ara-A AUC >6,500 ng hr/ml, 25% had an F-ara-A clearance <12.5 L/hr, 13% had a 24 hour concentration >80 ng/mL and 20% with a day zero concentration >30 ng/mL. The F-ara-A exposures remained significant towards TRM in multivariate analysis. There was no association between F-ara-A exposures and engraftment or acute GVHD. These data suggest that elevated F-ara-A concentrations are associated with a greater risk of TRM. Prospective testing of fludarabine dose modifications based on pharmacokinetics is needed and may protect patients from the toxicities of fludarabine overexposure.