Efficacy and Safety of Deferasirox (Exjade®) with up to 4.5 Years of Treatment in Patients with Thalassemia Major: A Pooled Analysis
Authors: Cappellini Maria Domenica , Galanello Renzo , Piga Antonio , Cohen Alan , Kattamis Antonis , Aydinok Yesim , Williamson Paul , Rojkjaer Lisa , Porter John B 
Published: April 2020

Abstract
Background: Assessing the long-term efficacy and safety of iron chelation therapy is important given that patients with β-thalassemia require lifelong treatment. The efficacy and safety of deferasirox (Exjade®), a once-daily, oral iron chelator was established in patients with β-thalassemia in four 1-year core trials. Initial doses were assigned by baseline liver iron concentration and a clear dose response was observed. Subsequent data highlighted that a number of factors need to be considered when adjusting deferasirox dose, including iron burden and transfusional iron intake. Dose adjustments were permitted in the extension phases to the 1-year core trials, to ensure that optimal dosing was achievable. This analysis evaluates efficacy and safety during up to 4.5 years of deferasirox treatment in adult and pediatric patients with β-thalassemia.
Methods: Following 1 year’s treatment with deferasirox in the four core studies, iron overloaded patients with β-thalassemia were enrolled in 4-year extension trials (105E–108E) evaluating the long-term efficacy and safety of deferasirox. Deferasirox doses in the extension trials were initially based on end-of-core liver iron concentration (LIC) and were subsequently adjusted according to serum ferritin (SF) levels. Efficacy was monitored by monthly SF levels; safety was assessed by the incidence and type of adverse events (AEs) and changes in laboratory parameters.
Results: In total, 472 patients with β-thalassemia are included in this analysis. Patients received deferasirox for a median period of 55 months (4.6 years) at an overall mean ± SD daily dose of 22.1 ± 6.4 mg/kg. Mean iron intake over the entire treatment period was 0.4 ± 0.1 mg/kg/day. Median SF was 2319 ng/mL at baseline; change from baseline in SF was 158 ng/mL at 12 months, during which time the mean daily dose was ~19.5 mg/kg/day. Following 1-year’s treatment, dose adjustments were permitted and by 54 months (4.5 years) median SF had decreased significantly from baseline by 931 ng/mL (P&lt;0.0001; Wilcoxon signed rank test). Mean deferasirox dose had increased to 25.2 mg/kg/day by month 54 (Figure 1).
Figure 1. Mean dose and median serum ferritin during deferasirox treatment Figure 1. Mean dose and median serum ferritin during deferasirox treatment
Over the treatment period, 159 patients discontinued because of: consent withdrawal due mainly to the commercial availability of deferasirox (n=52, 11.0%), AEs (n=50, 10.6%), unsatisfactory therapeutic effect (n=39, 8.3%), and other reasons (n=13, 2.8%). Five deaths occurred (one in the core and four in the extension phases), all of which were considered by the Program Safety Board as unrelated to deferasirox. Overall, the most common drug-related (investigator-assessed) AEs were abdominal pain (n=62, 13.1%), nausea (n=55, 11.7%), diarrhea (n=40, 8.5%), vomiting (n=32, 6.8%) and rash (n=23, 4.9%); the annual frequency of these AEs decreased from year to year, ranging from 0–2.3% in years 2 to 5. The types of drug-related AEs in the extension trials were similar in nature to those in the core trials. The most common drug-related AEs that led to discontinuation were increased transaminases (n=7), glycosuria and proteinuria (n=3 for both). Thirty-four patients (7.2%) had an increase in serum creatinine &gt;33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases or increase in the annual frequency from year to year. Twenty-nine (6.1%) patients had an increase in alanine aminotransferase &gt;10 × ULN on at least one visit; baseline levels were already &gt;ULN in 18 patients.
Conclusions: Over 4.5 years’ treatment, deferasirox provided a dose-dependent reduction in SF in patients with β-thalassemia. Deferasirox was generally well tolerated with the frequency of investigator-reported AEs decreasing over long-term treatment. There were no changes in liver or renal function that differed significantly from the 1-year core trials and there was no evidence of progressive liver/renal dysfunction.