Efficacy and Safety of Deferasirox (Exjade®) in Reducing Cardiac Iron in Patients with β-Thalassemia Major: Results from the Cardiac Substudy of the EPIC Trial
Authors: Pennell Dudley , Porter John B , Cappellini Maria Domenica , Li Chi-Kong , Aydinok Yesim , Lee Chan Lee , Kattamis Antonis , Smith Gillian , Habr Dany , Domokos Gabor , Hmissi Abdel , Taher Ali 
Published: October 2019

Abstract
Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis.
Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–<20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin (SF) >2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr.
Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was <10 ms in 47 (41%), and 10–20 ms in 67 (59%). Mean baseline LIC was 28.2±10.0 mg Fe/g dw, median SF 5235 ng/mL, and the mean amount of transfused blood in the previous yr 185 mL/kg. 68% of pts had received prior deferoxamine (DFO) and 32% DFO/deferiprone combination therapy. Mean actual deferasirox dose over 1 yr was 32.6 mg/kg/d. At 1 yr, the myocardial T2* improved significantly from a (geometric mean ± coefficient of variation) baseline of 11.2 ms ±40.5% to 12.9 ms ±49.5% (P<0.0001), representing an increase by a factor of 1.16 from baseline. Significant increases from 7.4 ms ±19.4% to 8.2 ms ±25.6% (P=0.0002) and from 14.6 ms ±20.9% to 17.4 ms ±31.2% (P<0.0001) were also noted in pts with baseline T2* <10 and 10–20 ms, respectively. Improvement in T2* (>4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P<0.0001 for both). Treatment was completed in 105 pts (92.1%) with 4 discontinuations due to AEs (3.5%) and 5 for other reasons (4.4%). No pts died during the study. Most investigator-assessed drug-related AEs (78.6%) were mild-to-moderate in severity; rash was the most common (n=15; 13.2%). Two drug-related serious AEs (one nephritis leading to acute renal failure and one renal tubular disorder) were reported which eventually resolved following drug discontinuation. In total, 5 pts (4.4%) 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. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts.
Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.