Deferasirox (Exjade^®) Treatment in Pediatric β-Thalassemia Patients with High Iron Burden: 2.8 Years Results from ESCALATOR Trial

Background: As iron overload can cause serious clinical sequelae in pediatric patients with β-thalassemia, it is important to assess the long-term efficacy and safety profile of any iron chelator used in children. The ESCALATOR study evaluated deferasirox (Exjade^®) in β-thalassemia patients, during a 1-year core trial and an extension trial of at least 1 year’s duration. This analysis evaluates the efficacy and safety of deferasirox in a subgroup of pediatric patients enrolled in the ESCALATOR trial.

Methods: β-thalassemia patients included in this analysis were aged 2–<16 years with a liver iron concentration (LIC) of ≥2 mg Fe/g dw and serum ferritin (SF) ≥500 ng/mL. All had been previously unsuccessfully chelated with mono- or combination therapy with deferoxamine (DFO) and/or deferiprone. Initial deferasirox dose was 20 mg/kg/day, except in three patients who started on 10 mg/kg/day. Dose adjustments were performed in steps of 5–10 mg/kg/day based on SF levels and safety markers; due to a protocol amendment affecting most patients in the extension phase, dose increases above 30 mg/kg were permitted (dose range: 0–40 mg/kg/day). Efficacy was assessed yearly by LIC and monthly by SF. Safety was evaluated by monitoring adverse events (AEs) and laboratory parameters.

Results: In total, 166 pediatric patients entered, and 158 (95%) completed, the extension study; 149 (89.8%), 1 (0.6%) and 16 (9.6%) patients had received prior chelation with DFO, deferiprone and DFO/deferiprone combination, respectively. The median duration of exposure to deferasirox was 144 weeks (2.8 years). 101/166 patients (61%) had dose increases in the extension study; dose was increased above 30 mg/kg/day in most patients (n=75). Dose decreases due to AEs or abnormal lab values were required in only 4 (2%) patients. Three (2%) and 10 (6%) patients, respectively, had dose decreases and temporary treatment interruptions because target ferritin level (≤500 ng/mL ×2 consecutive occasions) had been achieved. At EOS, the final deferasirox dose exceeded 30 mg/kg/day in 114 patients (69%). Data for mean LIC and median SF at baseline, 1 year and end of study are presented in Table 1.

Table 1. LIC and SF at baseline, 1 year following treatment initiation and end of study.

Of eight discontinuations during the extension study, six patients were lost to follow-up, one was due to AEs and one patient died due to respiratory failure, considered by the investigator to be non-treatment related. Despite dose increases and longer exposure in the extension phase, there was no increase in drug-related AEs in the extension compared with the core phase. There were no significant changes in markers of liver or renal function during the extension phase. Mean left ventricular ejection fraction increased significantly from 65.3% at core baseline to 69.4% at study end (P<0.00001).

Conclusions: Following a median of 2.8 years, adequate dose adjustments with deferasirox significantly reduced LIC and SF in heavily iron-overloaded children who were previously unsuccessfully chelated. Doses ≥30 mg/kg/day were achieved in 69% of patients in the extension phase and deferasirox was generally well tolerated, with no increase in drug-related AEs compared with the 1-year assessment, and a low discontinuation rate.