Effect of Deferasirox (Exjade®) on Labile Plasma Iron Levels in Heavily Iron-Overloaded Patients with Transfusion-Dependent Anemias Enrolled in the Large-Scale, Prospective 1-Year EPIC Trial
Authors: Porter John B , Cappellini Maria Domenica , El-Beshlawy Amal , Kattamis Antonis , Seymour John F , Lee Jong Wook , Nick Hanspeter , Habr Dany , Domokos Gabor , Hmissi Abdel , Taher Ali 
Published: October 2019

Abstract
Background: Labile plasma iron (LPI) is a toxic, directly chelatable form of non-transferrin- bound iron that is produced continually in conditions of iron overload and, due to rapid uptake into hepatocytes, myocardium and endocrine tissues, leads to secondary expansion of the cellular iron pool. The sustained presence of an iron chelator in the plasma may help avoid accumulation of LPI, thereby minimizing iron-related morbidity and mortality. This analysis evaluates the effect of deferasirox on LPI levels in patients (pts) with transfusion-dependent anemias enrolled in the large-scale, prospective, 1-yr multicenter EPIC trial.
Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusion episodes or >100 mL/kg of RBCs) and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw). Deferasirox starting dose was determined based on blood transfusion frequency. Dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) were based on SF trends and safety markers. Blood samples to measure LPI and assess the deferasirox pharmacokinetic profile were taken pre-administration and 2 hrs post administration at baseline and wks 12, 28 and 52.
Results: LPI data are available from 1602 pts (825 M, 777 F; mean 30.4±23.0 yrs). Underlying anemias were: β-thalassemia (n=1029), myelodysplastic syndromes (MDS; n=305), aplastic anemia (AA; n=104), sickle cell disease (SCD; n=79), rare anemias (mostly hemolytic in nature) (n=42), and other conditions associated with anemias requiring transfusion (n=43). Mean LPI, pre and post deferasirox administration, at baseline and wks 12, 28 and 52 are shown in Table 1.
Table 1. Mean LPI, pre and post deferasirox administration, at baseline and after repeat doses
Baseline Week 12 Week 28 Week 52 Pre Post Pre Post Pre Post Pre Post NOTE: Data are mean LPI±SD (μmol/L); normal levels are 0–0.40 μmol/L All pts 0.89 ±1.84 0.33 ±1.59 0.30 ±0.90 0.11 ±0.56 0.27 ±0.87 0.11 ±0.62 0.47 ±1.35 0.30 ±1.33 β-thalassemia 1.25 ±2.34 0.58 ±2.10 0.40 ±1.07 0.15 ±0.67 0.34 ±0.94 0.13 ±0.72 0.60 ±1.55 0.39 ±1.52 MDS 0.53 ±0.63 0.02 ±0.11 0.08 ±0.28 0.02 ±0.10 0.15 ±0.88 0.03 ±0.18 0.14 ±0.32 0.02 ±0.07 AA 0.23 ±0.34 0.01 ±0.02 0.08 ±0.20 0.01 ±0.04 0.06 ±0.20 0.01 ±0.03 0.04 ±0.10 0.03 ±0.10 SCD 0.11 ±0.54 0.04 ±0.29 0.09 ±0.42 0.06 ±0.31 0.11 ±0.28 0.14 ±0.46 0.10 ±0.21 0.07 ±0.19 Rare anemias 0.50 ±0.55 0.01 ±0.04 0.05 ±0.13 0.01 ±0.03 0.06 ±0.18 0.01 ±0.03 0.29 ±0.52 0.02 ±0.03
Overall mean deferasirox dose during the 1-yr treatment period was 22.4±6.0 mg/kg/day (β-thalassemia, MDS, AA, SCD and rare anemias: 24.3±5.5, 19.3±5.7, 17.8±4.7, 20.2±3.8 and 18.6±5.6 mg/kg/day, respectively). At each time point, peak LPI levels observed just before deferasirox dosing were decreased compared with baseline and were mostly within the normal range from week 12 onwards in each underlying anemia. A small rebound at 52 wks was seen in the thalassemia sub-group: this could be associated with decreased compliance or other reasons, to be investigated further. In all pts, mean steady-state plasma concentration (ie pre-administration value) of deferasirox at wks 12, 28 and 52 was 32.9, 35.9 and 39.4 μmol/L, respectively. At each time point this was approximately half of the concentration value observed at 2 hrs post administration (84.4, 89.3 and 97.0 μmol/L, respectively).
Conclusions: The results from this 1-yr study confirm the ability of once-daily deferasirox to provide sustained reduction in toxic LPI levels across various transfusion-dependent anemias, supporting previous data in pts with β-thalassemia. This is likely due to trough levels of deferasirox being within the therapeutic range, thereby preventing LPI levels rebounding between doses. Deferasirox therapy may therefore reduce unregulated tissue iron loading and prevent further end-organ damage in these pts.