Efficacy and Safety of Once-Daily Oral Deferasirox (Exjade^®) during a Median of 2.7 Years of Treatment in Heavily Iron-Overloaded Patients with β-Thalassemia

Background: The ESCALATOR trial evaluated deferasirox (Exjade^®) in heavily iron-overloaded β-thalassemia patients (pts) previously treated with DFO and/or deferiprone. In the 1-year core study, 76% of pts required dose increases from 20 to 25/30 mg/kg/day at a median of 24 weeks, therefore the effect of deferasirox on liver iron concentration (LIC) and serum ferritin (SF) at 52 weeks may not reflect the effect of optimal dosing. An extension phase has assessed efficacy and safety after at least 1 additional year’s treatment at more optimal dose levels.

Methods: All pts initially received deferasirox 20 mg/kg/day (except three receiving 10 mg/kg/day). Deferasirox dose at the start of extension depended on the last dose received in the core trial. Dose adjustments, performed in steps of 5–10 mg/kg/day were based on SF levels and safety markers; dose increases above 30 mg/kg were permitted due to a protocol amendment in the extension phase. Efficacy was assessed yearly by LIC and monthly by SF. Adverse events (AEs) and lab parameters were monitored.

Results: 247 pts (166 pediatric [≥2–<16 years] and 81 adult [≥16 years]) entered the extension study; 93% completed this 1.7-year phase. Dose increases were performed in 137/245 pts (56%) in the extension study, with increases above 30 mg/kg/day in 112 pts. Dose increases were well tolerated; 7 pts required dose decreases due to AEs or abnormal lab values. Dose decreases and temporary treatment interruptions due to target ferritin level achievement (≤500 ng/mL × 2 consecutive occasions) occurred in 5 and 15 pts, respectively. Pts received deferasirox for a median of 139 weeks (2.7 years). Mean LIC decreased from 19.6±9.3 mg Fe/g dry weight (dw) at baseline to 16.7±12.1 mg Fe/g dw at 1 year and 12.0±10.7 mg Fe/g dw at end of study (EOS) (total change: −8.1 mg Fe/g dw; P<0.0001). Mean reduction in LIC from baseline to EOS was 8.9±11.7 and 7.9±8.7 mg Fe/g dw in adult and pediatric pts (both P<0.0001). At core baseline, 17 pts (6.9%) had LIC <7 mg Fe/g dw (5.8±0.9) and 230 had LIC ≥7 mg Fe/g dw (20.7±8.8). After 1 year’s treatment, LIC changed by −0.6±2.8 and −3.1±8.2, respectively (both P<0.0001); 24.7% (n=61) of pts reached an LIC <7 mg Fe/g dw. During the extension phase, LIC decreased by 0.7±2.0 and 6.9±8.7 in pts with extension baseline LIC <7 (n=61) and ≥7 mg Fe/g dw (n=186) (both P<0.0001). After a median of 2.7 years, 78/180 pts (43%) had LIC <7 mg Fe/g dw (3.9±1.7). Median SF decreased from 3395 (range: 914–25008) ng/mL at baseline to 3182 (146–15815) ng/mL at 1 year and 2051 (236–14085) ng/mL at EOS (overall decrease: 1140 [−13046–4985] ng/mL, P<0.0001). EOS change in SF for pediatric and adult pts was −1126 and −1611 ng/mL (both P<0.0001). Reasons for withdrawal from the extension study were: lost to follow-up (n=8, 3%), AEs (n=3, 1%), death (n=3 [cerebral hemorrhage, subarachnoid hemorrhage, respiratory failure], 1%), protocol violation (n=2, 1%), and consent withdrawal (n=1, <1%). High doses of deferasirox were well tolerated. Reports of drug related AEs were lower in the extension than core phase (22% vs 42%). No progressive changes in markers of renal or liver function markers were seen. At EOS, left ventricular ejection fraction increased from baseline (65.1±6.7%) by 2.3±8.6%, (P<0.0007).

Conclusions: With adequate dose adjustments for a median of 2.7 years, deferasirox provided a significant drop in LIC and SF in heavily iron-overloaded β-thalassemia pts previously unsuccessfully chelated. LIC was maintained in pts with baseline LIC <7 mg Fe/g dw and more pts were able to achieve LIC <7 mg Fe/g dw with a longer course of deferasirox therapy. Despite dose increases to ≥30 mg/kg/day in many pts during the extension phase, the safety of deferasirox was maintained and a low discontinuation rate observed.