High Exposure to Fludarabine in Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation Predicts for Impaired CD4 Reconstitution and Lower Survival Chances (2017)

Background: Fludarabine (Flu) is widely used in conditioning prior to allogeneic hematopoietic cell transplantation (HCT) in combination with busulfan (Bu). Whilst targeting Bu to optimal exposure has been shown to increase survival chances, to date there is no optimal exposure known for Flu. Therefore, patients of all ages receive a standardized dose of 160 mg/m2 over 4 days on the same days as Bu. As Flu has strong cytotoxic and immunosuppressive properties, this study aims to relate Flu exposures with CD4 T-cell reconstitution (IR) and overall survival (OS). Methods: In this retrospective single-center study, the circulating metabolite of Flu (F-ara-A) was quantified in samples acquired for routine Bu therapeutic drug monitoring (TDM, from 2010) using a validated liquid chromatography mass spectrometry method. With these data a pharmacokinetic (PK) model was developed and validated using non-linear mixed effects modelling (NONMEM 7.0). Next, AUC was determined as measure of exposure. For outcome analysis only patients undergoing their first HCT receiving fludarabine 160 mg/m2 and busulfan (targeted to 90 mg*h/l) over 4 days were included. Anti-thymocyte globuline (ATG) was given in the unrelated donor HCT (from day -9: 8 mg/kg in adults and 10 mg/kg in children). There were no limitations for age, cell source and indication. Main outcomes of interest were overall survival (OS) and IR over time. Statistical analyses included Kaplan-Meier estimates, cox proportional hazard models and linear mixed effect models. Results: For the construction and validation of the PK model 227 patients were included (109 adults, 118 children). For the outcome analyses 141 patients were included (adults; n = 83, children; n = 58) treated for a variety of malignant (n = 79) and non-malignant disorders (n = 58), with a median age of 33 years (range .23-74). The available ATG exposure (n = 82) after HCT was similar in both groups. For the main outcome of interest OS, Flu-exposure was found to be a predictor. Patients with the highest exposure (Figure 1, upper quartile) showed inferior 2-year OS (32%) compared to the 3 lowest quartiles (62%, P = .001). Also in multivariate analyses Flu-exposure remained a predictor (HR = 2.22, P = .03), while age and indication (malignant/non-malignant) lost significance (P = .61, P = .93, resp.) With the linear mixed effect model a significantly slower IR for patients with the highest Flu-exposure was found (P < .001, Figure 2). Independently, increasing age had an additional significant contribution to slower IR (P < .001).Figure 2CD4+ T-cell reconstitution after allo HCT in patients receiving busulfan (targeted to optimal exposure) and fludarabine (160mg/m2). Groups consist of patients in the highest quartile of F-ara-A AUC exposure (red) and the lower three quartiles (green).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: High exposure to Flu significantly impairs CD4+ T-cell reconstitution and reduces survival chances after HCT. This is the first step in the definition of a target exposure for Flu in this setting. Dose individualization and/or TDM-based corrections towards the Flu target may reduce overexposure and improve survival chances after HCT.