Individualized Fludarabine Dosing for Predictable Immune Reconstitution and Increased Survival Chances after Allogeneic Hematopoietic Cell Transplantation (2018)

Background: Busulfan (Bu) combined with Fludarabine (Flu) and ATG is a frequently used conditioning regimen in allogeneic hematopoietic cell transplantation (HCT). For Bu and ATG (Thymoglobuline), optimal exposures in relation to survival have recently been described for paediatric and adult patients. For Flu these data are sparse. We therefore aimed to associate Flu exposure to various outcomes after HCT, including immune reconstitution (IR) and viral reactivation (VR). Methods: We retrospectively analyzed patients transplanted between 2010 and 2016 at the UMC Utrecht (pediatric and adult program), conditioned with myeloablatively targeted Bu (cumulative exposure 90 mg⋅h/L), Flu 160 mg/m2 and ATG (from day −9: 8-10 mg/kg). There were no limitations for age and indication. The optimal Flu exposure was derived through relating the individual estimate of cumulative Flu exposure to various outcomes: event-free survival (EFS), graft-failure (GF), relapse and non-relapse mortality (NRM). Relations were quantified in a parametric time-to-event (EFS) or cause-specific hazard model (NRM, relapse, GF). Subsequently, the effect of cumulative Flu exposure (categorical: under-, optimal- and over-exposed) was evaluated on IR (defined as reaching CD4+ T-cell levels >50/L twice) and VR (defined as CMV and EBV-reactivations >1000 cp/mL). Finally, exposures were simulated with 3 different dosing strategies to assess target exposure attainment: current dosing, dosing based on a Flu pharmacokinetic population model (pop-PK: weight and creatinine clearance based) and the first combined with therapeutic drug monitoring (TDM). Results: 197 patients (73 children, 124 adults: 129 malignant and 68 benign disorders) were included. Minimal event probability (1-EFS) was determined to be at a cumulative Flu exposure of 17.6 mg⋅h/L (optimum: 13-22 mg⋅h/L, P = .049, Figure 1A). The exposure event relation was driven by an increased relative hazard at high exposures for NRM (P < .001) and at low exposures for GF (P = .012) but no effect on relapse (P = .97, Figure 1B-D). Bu and ATG exposure did not significantly differ between Flu exposure groups. An increased incidence of VR (at day 100) was observed in patients exposed above the optimal range (25%) versus 6% within optimum (P = .0047), associated with lower probability on IR (at day 100; 32% versus 57% within optimum, P = .0023, adjusted P = .022). For VR however, age was found a significant confounder (age adjusted P = .13, Figure 2A). Current dosing of 160 mg/m2, dosing based on the pop-PK model, or based on TDM, resulted in 51%, 77% and 96% of patients, respectively, reaching the exposure target (Figure 3).Figure 2Comparing immunological event incidence in patients exposed at and above optimum. A) viral reactivations: dashed lines indicate cumulative incidence of CMV or EBV levels reaching 1000 copies/ml. Solid lines depict the corrected cumulative incidence as estimated by use of Fine-Gray models, which can be interpreted as the expected incidence given the same set of covariates B) immune reconstitution: dashed lines depict the cumulative incidence of reaching CD4+ T-cell levels above 50 × 106/l. Solid lines depict corrected incidence estimated similarly to viral reactivation. Unadjusted P-values are calculated by Gray's test and adjusted P-values by means of the likelihood ratio test, corrected for covariatesView Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Comparing dosing regimens by calculating the expected exposures in the studied population. Exposures were calculated using the individual pharmacokinetic parameters and only changing the dose. Doses were assumed to be evenly adminstered over 4 days in 1-hour infusions and were: 1) 160 mg/m2 for all patients 2) Individualized dosing based on the model, patient weight and serum-creatinine levels 3) Therapeutic drug monitoring with 40 mg/m2 for 1-day and using the 4 measured samples on that day to alter the subsequent doses in order to achieve the target exposureView Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: Cumulative exposure to Flu during the conditioning phase influenced outcomes following HCT. Individualizing drug exposure by different dosing and/or TDM may reduce Flu overexposure, resulting in better IR and subsequent higher survival chances.