Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels

Abstract

Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels <1000 ng/mL.Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level <1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was <1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of <1000 ng/mL, irrespective of future SF levels.Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF<1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level <1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value <1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the <1000 and >1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown).Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels <1000 ng/mL and patients who did notPatients who achieved SF <1000 ng/mLPatients who did not achieve SF <1000 ng/mLn174300Male:female85:89145:155Mean age ± SD, years23.8 ± 16.723.5 ± 18.2<16, n (%)65 (37.4)123 (41.0)≥16, n (%)109 (62.6)177 (59.0)Enrolled from study 107:108120:54175:125Median exposure to deferasirox, months56.345.2Mean actual deferasirox dose, mg/kg/day20.322.9Median baseline SF, ng/mL17912883Drug-related AEs* (≥5% in either group), n (%)Nausea26 (14.9)38 (12.7)Diarrhea17 (9.8)42 (14.0)Vomiting14 (8.0)25 (8.3)Abdominal pain12 (6.9)32 (10.7)Upper abdominal pain6 (3.4)20 (6.7)Rash9 (5.2)16 (5.3)Audiological abnormalities7 (4.0)4 (1.3)Ophthalmological abnormalities4 (2.3)5 (1.7)Two consecutive SCr increases >33% above baseline and above ULN26 (14.9)36 (12.0)Increase in ALT >10×ULN on at least 1 visit12 (6.9)20 (6.7)Baseline levels elevated6 (3.4)16 (5.3)*Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferaseConclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels <1000 ng/mL was similar to that observed in patients who did not achieve SF levels <1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels <1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases >33% above baseline and ULN or with ALTs >10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.