Abstract
Background: The clinical outcome of transfusion-dependent TM patients with iron overload has been shown to depend on the dose and frequency of deferoxamine (DFO) use. However, the demanding regimen of slow subcutaneous infusions often leads to poor compliance. Deferasirox (Exjade®), a once-daily oral chelator, has potential compliance advantages. Doses of 20–30 mg/kg/day are non-inferior to DFO >35 mg/kg in TM patients with baseline liver iron concentration (LIC) >7 mg Fe/g dry weight (dw). This analysis reports efficacy and safety data from TM patients with iron overload who received DFO in a 1-year core trial (107), and then switched to deferasirox in an ongoing 4-year extension trial (107E).
Methods: TM patients with iron overload ≥2 years of age were randomized to DFO or deferasirox in study 107. Patients with LIC <7 or ≥7 mg Fe/g dw received DFO <25–<35 or 35-≥50 mg/kg, respectively, but some patients with baseline LIC <7 mg Fe/g dw remained on their higher pre-study DFO doses since these were efficacious. Patients completing the 1-year core trial had a repeat LIC assessment by biopsy or SQUID, and were continued on or switched to deferasirox during 107E for long term efficacy and safety evaluation. Deferasirox dose was based on the end of 1-year LIC, and adjusted according to trends in serum ferritin (SF) level. Efficacy and safety data were analyzed annually for patients receiving DFO in study 107 who switched to deferasirox in 107E, to determine long-term outcome.
Results: 259 patients, 129 children (2–<16 years) and 130 adults (≥16 years) are included. Average daily DFO dose during study 107 was 42.7±9.2 mg/kg; mean transfusional iron intake was 0.4±0.3 mg/kg/day (range 0.2–0.9). Baseline LIC was ≤7 and >7 mg Fe/g dw in 85 and 174 patients, respectively. Median SF change after 12 months of DFO was −264 ng/mL (baseline 2037 ng/mL). Patients crossed over to deferasirox and have received treatment for a median of 35.2 months. At month 42 of deferasirox, median SF had further decreased by −257 ng/mL (baseline 1843 ng/mL) in a dose-related manner (Figure 1).
Figure 1. Median SF during DFO and deferasirox treatment, by deferasirox dose group Figure 1. Median SF during DFO and deferasirox treatment, by deferasirox dose group
During DFO treatment the most common drug-related AEs were injection-site reaction (n=6, 2.3%) and pain (n=6, 2.3%); no drug-related AEs led to discontinuation. One patient had a serious drug-related AE. Three patients (1.2%) had an alanine aminotransferase (ALT) increase >10 × ULN on at least one visit, where baseline ALT values were normal, ≥1–<5 × ULN and ≥5–<10 × ULN. Irrespective of relationship to DFO, deafness, tinnitus and hypoacusis were reported in five, four and three patients, while five and one had lenticular opacities and maculopathy, respectively.
During year 1 of deferasirox treatment the most common drug-related AEs were rash (n=17, 6.6%), diarrhea (n=11, 4.2%) and nausea (n=7, 2.7%); the annual frequency of these drug-related AEs decreased to <1.5% thereafter. Five drug-related AEs led to discontinuation. Seven patients (2.7%) had a serious drug-related AE. In year 1, three patients (1.2%) had serum creatinine increases >33% above baseline and ULN on two consecutive visits, with a subsequent overall annual incidence of 2–3%. In year 1, four patients (1.5%) had an ALT increase >10×ULN on at least one visit (baseline values were ≥1–<5×ULN for three patients and ≥5–<10×ULN for the other), as did six patients in year 2 of deferasirox therapy; no ALT values >10×ULN were reported thereafter. Irrespective of relationship to deferasirox, hypoacusis, deafness and tinnitus were seen in four, two and one patients, respectively, and one had lenticular opacities.
Conclusions: TM patients who have previously received chelation therapy with DFO can maintain effective chelation when switched to deferasirox, as demonstrated by a continued and dose-dependent decrease in SF. Over long-term deferasirox treatment with increased dose, there was no increased risk of toxicity, no evidence of progressive renal or liver dysfunction and an annual decrease in drug-related AEs.
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