Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias

Abstract

The online version of this article has a Supplementary Appendix. BackgroundFollowing a clinical evaluation of deferasirox (Exjade ® ) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged ≥2 years) with transfusional hemosiderosis from various types of anemia. Design and MethodsThe recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. ResultsThe 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). ConclusionsAnalysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation

“…This is similar to the data reported by Vallejo et al 30 As expected, the most frequent deferasirox-related AEs in this trial were similar to what is already known. [22][23][24]27,45,46 In the EPIC (European Prospective Investigation into Cancer and Nutrition) trial for MDS, AEs were responsible for a discontinuation rate of 23%, many of which were renal or GI events (overall discontinuation rate 49%). 22,24 Further, deferasirox treatment is envisaged to be difficult after HSCT as GI, liver and skin AEs could mimic and/or exacerbate GvHD-associated abnormalities.…”

“…[22][23][24][25][26][27][28] However, data regarding the use of deferasirox after allogeneic HSCT are limited. 15,17,19,20 This prospective multicenter trial is, to the best of our knowledge, the largest trial evaluating the efficacy and safety of deferasirox after allogeneic HSCT.…”

Iron overload in myelodysplastic syndromes (MDS)

“…Iron chelation therapy in patients with transfusion-dependent MDS has been shown to be safe and effective [27,43,44]. Guidelines on ICT in MDS are often included in guidelines on MDS treatment in general.…”

Management of the Thalassemias

“…A study of the iron-chelating agent deferasirox based the initial dose on a calculated rate of transfusional iron loading and then adjusted the dose according to measurements of serum ferritin levels and safety markers over a 1-yr period (Cappellini et al 2010). As noted, the long-term efficacy and safety of this strategy are uncertain (Brittenham 2011).…”

“…The short-term effectiveness of deferasirox has been compared with deferoxamine in trials sponsored by Novartis Piga et al 2006;Vichinsky et al 2007;Porter et al 2008;Cappellini et al 2010). In the largest trial in which 586 children with thalassemia were randomly assigned to either agent, with dosing according to the baseline hepatic iron concentration , the primary end point was the percentage of patients with either a maintained or reduced hepatic iron concentration at 1 yr.…”