Abstract

Background: Steroid-resistant patients with Diamond-Blackfan anemia (DBA) require life-long transfusion therapy, which ultimately results in toxic iron overload. Efficacy and safety of a once-daily, oral iron chelator, deferasirox (Exjade®), in patients with DBA have been demonstrated in one trial in which patients were dosed based on liver iron concentration (LIC) at enrollment. More recently, patients with various transfusion dependant anemias have been enrolled as part of a large, prospective, multicenter trial, the EPIC study, to evaluate whether fixed starting doses of deferasirox, based on transfusion history and subsequent dose titration, can provide clinically acceptable chelation, as measured by serum ferritin (SF). Data for the DBA sub-group are presented.

Methods: Fourteen patients with transfusion-dependent DBA and SF levels of ≥1000 ng/mL, or <1000 ng/mL but with a history of multiple transfusions (>20 transfusions or 100 mL/kg of blood) and a R2 MRI confirmed LIC >2 mg Fe/g dry weight, were enrolled. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of 3-month SF trends and safety markers. SF was assessed every 4 weeks; the primary efficacy endpoint was change in SF from baseline at 52 weeks. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters.

Results: Male (n=7) and female (n=7) patients with DBA (mean age 17.3 years), had a median baseline SF of 2288.8 ng/mL, and received a mean of 185.0 mL/kg of blood in the year prior to enrollment. Most patients had received previous chelation therapy with deferoxamine (DFO; 71.4%); two patients (14.3%) had received combination DFO/deferiprone and two (14.3%) had received no prior chelation therapy. All patients completed 12 months of treatment with no discontinuation. At 12 months, a significant reduction in SF from baseline was observed in the total population at an average actual dose of 21.0±4.8 mg/kg/day (−789.5 ng/mL; 2288.8 ng/mL [baseline]; P=0.0121). A similar reduction was seen in patients receiving an average actual dose of deferasirox ≥20–<30 mg/kg/day (−1095.0 ng/mL; 2808.5 ng/mL [baseline]; 0.40 mg/kg/day [mean iron intake]; P=0.0015) and in five patients who received an average actual dose of deferasirox <20 mg/kg/day (−434.3 ng/mL; 1556.5 ng/mL [baseline]; 0.34 mg/kg/day [mean iron intake]; P=0.77). The most common drug-related AEs as assessed by investigators were diarrhea (n=3), nausea (n=3), upper abdominal pain (n=2), and rash (n=2), the majority of which were mild (>80%). There were no clinically relevant changes in markers of renal function. Two (14.3%) patients had an increase in alanine aminotransferase (ALT) that exceeded >10xULN (upper limit of normal) on two consecutive visits; all had elevated ALT levels at baseline.

Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent DBA patients with iron overload. Efficacy was demonstrated in patients receiving doses above and below 20 mg/kg/day, suggesting the need to individually titrate the dose according to the rate of iron intake from ongoing blood transfusions, as well as current iron burden and target SF levels. Deferasirox was well tolerated, with an AE profile similar to that observed in other patient groups.

Disclosures: Porter:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Membership on an entity’s Board of Directors or advisory committees. Forni:Novartis: Research Funding. Beris:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis: Employment. Domokos:Novartis: Employment. Hmissi:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

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