Efficacy and Safety of Deferasirox (Exjade^®) in Patients with Transfusion- Dependent Anemias: 1-Year Results from the Large, Prospective, Multicenter EPIC Study

Background: Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. In registration trials, the starting dose was based on baseline liver iron concentration (LIC). The prospective multicenter EPIC trial, the largest ever conducted for an iron chelator, included patients (pts) with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. One-year results are presented.

Methods: Pts (aged ≥2 yrs) had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg of RBCs) and R2 MRI-confirmed LIC of >2 mg Fe/g dry weight (dw). Deferasirox starting dose was 20 mg/kg/d for pts receiving 2–4 blood units/mth. An initial dose of 10 or 30mg/kg/d was considered for pts receiving less or more frequent blood transfusions, respectively. Protocol-specified dose adjustments of 5–10 mg/kg/d (range 0–40 mg/kg/d) were done every 3 months based on SF trends and safety markers. Primary efficacy endpoint was SF change from baseline (BL) at 1 year.

Results: 1744 pts (901 M, 843 F; mean age 30.6±23.3 yrs) were enrolled; 33.1% (n=577) aged <16 yrs. Underlying anemias were: β-thalassemia (n=1115), myelodysplastic syndromes (n=341), sickle cell disease (n=80), aplastic anemia (n=116) and other conditions associated with anemia (n=92). Pts received a mean of 17.8 transfusions and 159 mL/kg of blood in the previous year. 77% had received prior chelation therapy: deferoxamine (DFO; 58.6%), deferiprone (1.6%), DFO/deferiprone combination (16.7%) or other (0.3%). 1555 pts (89%) started on ≤20 mg/kg/d and 187 (11%) on >20 mg/kg/d. 39% of pts had dose increases at a median of 24 weeks after treatment initiation (range 2–53). Overall, median SF was significantly decreased from BL by 264 ng/mL after 1 year (P<0.0001) at an average actual received dose of 22.2±5.9 mg/kg/d. SF changes based on average dose the pts received throughout the course of the study are presented in Table 1. The extent of reduction in SF was reflective of dosage adjustments over the study.

Table 1. Median change from BL in SF (ng/mL) and mean iron intake (mg/kg/day) by average actual dose

1389 pts (79.6%) completed 1 year; reasons for discontinuation were adverse events (AEs; n=153; 8.8%), consent withdrawal (n=77; 4.4%), unsatisfactory therapeutic effect (n=20; 1.1%) and various other reasons (n=62; 3.6%); there were 31 (1.8%) drug related SAEs and 42 deaths, none assessed by investigators as treatment related. The most common drug-related (investigator-assessed) AEs were diarrhea (n=251; 14.4%), rash (n=174; 10.0%), nausea (n=135; 7.7%) and abdominal pain (n=97; 5.6%). 175 pts (10.0%) had serum creatinine value >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. 13 (0.7%) had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in 11 pts.

Conclusions: This large study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated with a safety profile consistent with data from previous clinical trials.