Chelator Efficacy of Deferasirox and Deferoxamine Determined by SQUID Biosusceptometry.

Abstract

Chelation treatment of patients with iron overload from chronic blood (RBC) transfusion needs continuous monitoring of iron stores, iron influx rates from RBC, chelation dose rates, and compliance. Molar chelator efficacy depicts the combined effect from these variables. Treatment should always aim to maximize the efficacy of a certain chelator in an individual patient in order to reduce organ damage from iron toxicity. In a prospective trial on the oral chelator deferasirox, a total of 12 patients with b-thalassemia major have been followed by SQUID biomagnetic liver susceptometry in intervals of 6 to 12 months over a time period of up to 38 months under deferasirox. Patients were initially on deferoxamine (DFO, Desferal®) and then participated in an international multi-center trial randomized for s.c. DFO and the oral chelator deferasirox (DSX, Exjade®). Liver iron concentration LIC (μg/g-liver wet weight), liver volumes, RBC transfusion rates, chelation dose rates, and compliance from tablet counts were assessed. Total body iron stores were calculated from total liver iron taking into account that 70 – 90 % of the total body storage iron is accumulated in the liver. For each chelation interval, molar efficacies were calculated from the daily iron input rate due to RBC plus the change in total body iron per interval time (= mobilized iron rate), and the molar dose rate of DFO or DSX (Fischer et al: Ann N Y Acad Sci 2005; 1054: 350–7), equation 1.[Molarefficacy[ɛ]=mobilizedironrate/molarchelatordoserate]LIC values were in the range of 836 to 8404 with a median value of 2424 μg/g-liver, while ferritin levels were between 911 and 13609 μg/l with a median ratio of ferritin-to-LIC of 1.0 ((μg/l)/(μg/g)) (range: 0.4 to 3.2). The median molar dose rates for DFO and DSX were 3.2 and 1.6 mmol/d, respectively. For each patient, the molar efficacies for DFO and DSX were averaged. From these averaged values, a mean molar efficacy ± SD of 13.2 ± 3.4 % and 23.6 ± 10.3 % was found for DFO and DSX, respectively. Relative to DFO, in each patient an increase between 5.5 and 27.1 % was found for DSX (mean: 11.7 ± 7.3 %). Patients with a low efficacy on DFO also had a low molar efficacy on DSX and vice versa (e.g., 8.0 and 13.5 % versus 16.0 and 31.9 %). Compliance assessed from tablet count protocols was larger than 90% and did not change these data significantly. On a larger scale in highly compliant thalassemia patients, a molar efficacy of 17.6 ± 4.8 % was observed (Fischer et al: Brit J Haematol 2003; 121: 938–48). In comparison to that reference value, the molar efficacy of DFO for this patient group was decreased. The reported molar efficacy of 27.9 ± 13.8 % for DSX obtained from biopsy results (Porter et al: Blood 2005; 106(11): 755a) is only insignificantly higher than our value. In summary, we found deferasirox to be two times more efficient than deferoxamine on the same molar dose level, even for patients with a relatively low efficacy under both chelator treatment regimens.