Deferasirox (Exjade®, ICL670) Is Effective and Tolerable in β-Thalassemia Patients with High Iron Burden and History of Inadequate Chelation Therapy.

Unless effectively controlled, transfusional iron overload results in progressive organ dysfunction and early death. Despite available chelation therapies, iron overload is often suboptimally treated as compliance can be poor. Previous studies with the once-daily, oral chelator deferasirox demonstrated a clear dose response, with higher doses required in pts with high iron burdens and transfusion rates. This study evaluated the safety/efficacy of deferasirox in pts with high iron burden due to inadequate prior chelation.

All pts had β-thalassemia, LIC ≥2 mg Fe/g dw and serum ferritin (SF) levels ≥500 ng/mL. Entry criteria included contraindications/unsatisfactory therapeutic response to, or unacceptable toxicity/non-compliance with, previous therapy. Pts received a starting dose of 20 mg/kg/day: based on results of another large study (Cappellini, Blood 2006), the protocol was amended mid-study to allow dose adjustment based on monthly SF trends. Safety and efficacy were assessed monthly, primarily by evaluating the incidence and type of AEs and by measuring laboratory parameters. LIC was measured at baseline and study end. Compliance was assessed monthly by pill counts.

1-year data are presented from 128 pts: 103 children (2–15 years), 25 adults (≥16 years); 121 had previously received DFO, six L1 and one DFO/L1 combination. The median exposure to deferasirox was 51.7 wks (range 6.4–56.0). Although many pts were previously poorly compliant, overall compliance to deferasirox was 98.9 ± 3.6% (range 79.3–115.1). Overall median dose was 22 mg/kg/day (range 12–26.9) and was similar in adults and children. Mean baseline LIC was 18.5 ± 8.5 in children and 19.5 ± 9.7 mg Fe/g dw in adults, decreasing by 2.3 ± 6.4 and 4.4 ± 4.1 mg Fe/g dw, respectively at 1 year. SF values at baseline were 4378 ± 2361 and 3639 ± 2261 ng/mL in children and adults, falling by 158.3 ± 1272.7 and 782.9 ± 703.2 ng/mL, respectively. Baseline LIC and SF values were significantly correlated. The mean iron excretion:intake ratio exceeded 1 in both pediatric (1.05) and adult (1.53) pts. Per the protocol amendment, dose was escalated to 25 or 30 mg/kg/day (median 38 wks) in 89 pts who were not achieving the target reduction in iron burden.

All pediatric and 22 adult pts completed (overall 96.9%). The most common drug-related AEs were transient, mild/moderate vomiting (n=6, 4.7%), nausea (n=5, 3.9%), headache and skin rash (both n=4, 3.1%). Two deaths, unrelated to study medication, were reported. No clinically significant changes in median levels of renal or liver function markers were observed. There was no drug-induced agranulocytosis, neutropenia or arthralgia. Physical/sexual development proceeded normally in children.

Deferasirox, initiated at 20 mg/kg/day, was generally well tolerated with high compliance and led to an overall maintenance or reduction in iron burden in this difficult-to-treat population. Due to high iron burden in these pts, dose escalation to 25 or 30 mg/kg was required to reduce iron levels. This highlights the importance of timely dose adjustments to achieve therapeutic goals. The impact of the higher dose on reduction of iron burden is being evaluated in the ongoing extension trial.