Efficacy and Safety of Deferasirox (Exjade®) in Preventing Cardiac Iron Overload in β-Thalassemia Patients with Normal Baseline Cardiac Iron: Results from the Cardiac Substudy of the EPIC Trial
Authors: Pennell Dudley , Sutcharitchan Pranee , El-Beshlawy Amal , Aydinok Yesim , Taher Ali , Smith Gillian , Habr Dany , Kriemler-Krahn Ulrike , Hmissi Abdel , Porter John B 
Published: October 2019

Abstract
Background: Myocardial siderosis is a leading cause of cardiac morbidity in patients (pts) with β-thalassemia undergoing regular blood transfusion therapy. Myocardial and liver siderosis do not correlate in cross-sectional studies, hence the importance of monitoring both cardiac and liver iron in heavily transfused β-thalassemia pts. Iron chelation therapy has an important role in preventing the accumulation of cardiac iron. Deferasirox (Exjade®) is a once-daily, oral iron chelator with efficacy in removing cardiac iron in preclinical and small clinical studies. This subgroup analysis from the cardiac substudy of the EPIC trial, the largest prospective, multicenter clinical trial evaluating the effects of iron chelation therapy, assesses the longitudinal effect of deferasirox over 1 year in preventing myocardial siderosis (maintaining T2* values >20 ms) in non-cardiac iron overloaded pts with β-thalassemia and normal cardiac function.
Methods: Pts with β-thalassemia (≥10 years) and with normal myocardial iron levels (magnetic resonance [MR] myocardial T2* of ≥20ms) were included in the prevention arm of the cardiac substudy. Other inclusion criteria were: serum ferritin (SF) >2500 ng/mL; MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw); left ventricular ejection fraction (LVEF) ≥56%; and a lifetime minimum of 50 previous packed red blood cell transfusions. Deferasirox was initiated at 30 mg/kg/day with subsequent dose adjustments of 5–10 mg/kg/day based on changes in SF, month-6 myocardial T2*, and safety parameters. Change from baseline in myocardial iron at 1 year was the primary endpoint. Changes in cardiac function, SF and LIC were also evaluated.
Results: We enrolled 78 pts into the cardiac prevention arm (35 male and 43 female; mean age, 20.2±7.5 years). The geometric mean (± coefficient of variation) myocardial T2* was 32.0 ms ±25.6%. Mean baseline (±SD) LVEF was 67.7±4.7%, LIC 28.8±10.2 mg Fe/g dw, and median SF 4712 ng/mL. Transfusion requirements were 133.7 mL/kg in the year prior to enrollment. Previous chelation therapy had been received by 76 pts (deferoxamine [DFO], 69.2%; combination DFO/deferiprone, 28.2%). Mean deferasirox dose over 1 year was 27.6±6.0 mg/kg/day. After 12 months of therapy, the geometric mean myocardial T2* was 32.5 ms ±25.1% (ratio of geometric mean = 1.02; P=ns) and LVEF increased to 69.6% (P<0.0001). None of the pts from this cohort with cardiac T2* >20 ms at baseline had a value below 20 ms at 12 mths. Median SF was significantly reduced from baseline at 12 months by 1048 ng/mL (P<0.0001), representing a 20% relative reduction. LIC was also significantly reduced from baseline by 7.2 mg Fe/g dw (P<0.0001; 30% reduction). One year of treatment was completed by 75 pts (96.2%); three pts (3.8%) discontinued because of AEs (n=2) or for other reasons (n=1). The most common investigator-assessed drug-related AEs were mild (78%) in severity and included diarrhea (n=8, 10%), rash (n=7, 9%), nausea (n=4, 5%) and urticaria (n=4, 5%). One pt (1.3%) had an increase in serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. No pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits. No pts died and no drug-related serious AEs were reported in this cohort.
Conclusions: In β-thalassemia pts with normal myocardial iron levels at baseline, deferasirox treatment over 1 year maintained myocardial iron levels whilst significantly reducing body iron burden measured by SF and LIC. LVEF increased significantly. Deferasirox was well tolerated with a clinically manageable safety profile.