Oral Deferasirox (Exjade®, ICL670) Is Effective, with a Clinically Manageable Safety Profile, in Pediatric β-Thalassemia Patients with High Iron Burden.

Background: The ESCALATOR study evaluated once-daily deferasirox in β-thal pts unsuccessfully chelated with DFO and/or deferiprone (L1). Phase II/III studies have shown that deferasirox 20–30 mg/kg/d maintains/reduces iron burden, depending on transfusional iron intake. However, PK evaluation indicated that exposure to deferasirox was lower in children than adults. To examine the relationship between dose and efficacy in heavily transfused children, a subanalysis of ESCALATOR pts (2–<16 years) was performed.

Methods: ESCALATOR was a prospective, open-label, 1-year study. Enrolled pts had β-thal and transfusional iron overload (LIC ≥2 mg/g dw, serum ferritin [SF] ≥500 ng/mL), and had been unsuccessfully treated with prior mono- or combination therapy with DFO and/or L1. Pts began treatment with deferasirox 20 mg/kg/d, except 3 who started on 10 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as LIC reduction of ≥3 mg/g if baseline LIC was ≥10 mg/g, or final LIC of 1–7 mg/g if baseline LIC was 2–<10 mg/g. Secondary endpoints included absolute reduction in LIC and safety; SF was assessed as a surrogate marker for LIC.

Results: Of 252 pts, 167 were children. In the year before study start, 150 received DFO, 1 L1 and 16 DFO + L1. Median (range) deferasirox dose was 22.6 (12–30) mg/kg/d. Overall, 130 children received dose adjustments to ≥25 mg/kg/d. Median (range) time to dose increase was 31 (8–48) wks. Treatment success rate was 56.9% (95% CI 49.5, 64.4). Mean (SD) baseline LIC and SF levels were 17.1 (8.5) mg/g and 3938 (2262) ng/mL, respectively.

The most common drug-related AEs were mild/moderate skin rash (n=16) and vomiting (n=15). No deaths were reported. 46 pts with normal baseline creatinine values experienced increases >33% on ≥2 consecutive visits; values also exceeded ULN in 4 pts. Increases in ALT to >5 × ULN on ≥2 consecutive visits were noted in 21 children; baseline values were high in 16/21 pts. Mean (SD) LVEF increased by 2.5% (8.2). Physical and sexual development progressed normally. At EOS, most pts reported greater satisfaction, convenience and less time lost compared with prior therapy. In total, 94.6% of pts preferred deferasirox.

Conclusions: These data suggest that with appropriate dosing, deferasirox can effectively control iron burden with a clinically manageable safety profile in heavily iron-overloaded children who were previously unsuccessfully chelated. Dose increases to ≥25 mg/kg/d were required to reach target reductions in iron burden, with no safety concerns. This highlights the importance of timely dose adjustments to achieve therapeutic goals. Pts preferred deferasirox to previous chelation therapy, which may improve long-term compliance.