Iron Chelation with Deferasirox Suppresses the Appearance of Labile Plasma Iron During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

During conditioning chemotherapy prior to allogeneic haematopoietic stem cell transplantation (HSCT), non-transferrin-bound iron and its chelatable form, labile plasma iron (LPI), regularly appear in the blood of patients at high levels of transferrin saturation (TfS). As these free iron species potentially favor infection and mediate transplantation-associated toxicities, chelation therapy could be an approach to improve outcome after transplantation. However, data addressing iron chelation in the immediate peritransplantation period are sparse. In this study, we investigated the influence of iron chelation with deferasirox during conditioning chemotherapy on the appearance of LPI, the incidence of infection and toxicities, and the tolerability of this treatment in the peritransplantation period. We conducted this single-center prospective observational study in 25 adults with iron overload (serum ferritin >1000 µg/L) undergoing allogeneic HSCT after myeloablative busulfan-based conditioning chemotherapy. Patients received iron chelation with deferasirox (14 mg/kg) from the start of conditioning until day 3 post-transplantation. Iron parameters, including LPI, were obtained at the chelator's trough level daily until day 0 and then on days 4, 7, and 14. Data on infection (bacteremia or invasive fungal disease) and toxicity, as well as the tolerability of deferasirox, were collected until the end of the follow-up period on day 28. Data were analyzed descriptively. TfS levels exceeded 70% in median on 6 days (range, 4 to 10 days) and in 63.6% (range, 36.4% to 90.9%) of the samples per patient, although in 19 of 25 patients (76%), no elevated LPI values were detected during the intake of deferasirox despite high TfS levels. Only 6 patients (24%) showed mildly increased LPI values (≤0.5 units) during the intake of deferasirox, 3 of whom had presented with elevated LPI values before the start of conditioning. Deferasirox was well tolerated, and no aggravation of toxicities was observed. Infection occurred in 5 patients (20%), including 3 of the 6 patients with elevated LPI values despite chelation therapy. In the present study, we demonstrate that iron chelation with deferasirox safely suppresses the appearance of LPI and might decrease the incidence of infection, whereas the impact on transplantation-associated toxicities remains to be elucidated.

Iron Chelation With Deferasirox Increases Busulfan AUC During Conditioning Chemotherapy Prior to Allogeneic Stem Cell Transplantation.

The negative effects of iron overload caused by repetitive blood transfusions and iron release during cytotoxic chemotherapy might be ameliorated by early treatment with an iron chelator. However, in the setting of allogeneic hematopoietic stem cell transplantation (HSCT), chelation therapy is often postponed until the late post-transplantation period because of potential drug interactions. Therefore we systematically investigated the influence of iron chelation with deferasirox on the pharmacokinetics of intravenous busulfan in adult patients in the context of routine therapeutic drug monitoring (TDM) before HSCT. We conducted a single-center, prospective, observational study in 25 adult patients with planned allogeneic HSCT after myeloablative, busulfan-based, TDM-guided conditioning chemotherapy. Busulfan was administered intravenously over 3 hours with an initial dose of 3.2 mg/kg once daily (based on adjusted ideal body weight [AIBW] in overweight patients). Four consecutive dosages were planned to achieve a cumulative area under the curve (AUC) of 80 mg · h/L. Patients received deferasirox for transfusional iron overload as per approval from the start of conditioning until day 3 after transplantation. Model-based calculation of the busulfan AUC was carried out by means of Bayesian prediction based on a population pharmacokinetic model after the first or second dose of busulfan, and dose adjustments were performed accordingly. Calculated median cumulative AUC before dose adjustment was 93.7 mg · h/L (65.1-151.4 mg · h/L), which was considerably above the target AUC of 80 mg · h/L ± 10%. Median dose adjustment was -17.1% (-50.0% to 18.2%), and patients ultimately received busulfan with a median cumulative dose of 10.60 mg/kg (6.38 - 15.62) mg/kg. A busulfan dose reduction was necessary in 19 patients (76%) whereas a dose increase was only needed in 1 patient. After dose adjustment the median AUC was 79.7 mg/L · h (62.5 - 84.2 mg/L · h). Median busulfan clearance was 0.134 L/h/kg (0.084 - 0.203 L/h/kg), which is significantly lower than the average clearance of 0.2 L/h/kg reported in the literature, whereas volume of distribution was not altered. We were able to demonstrate, that TDM is the key point to facilitate a safe co-administration of both medications, because the intake of deferasirox leads to a considerable increase in the busulfan AUC of about 35% to 40%. The reason for the increase in busulfan AUC is a reduction in busulfan clearance by about one third; therefore a lower initial dose of busulfan followed by TDM could be considered in patients with comedication with deferasirox.