Semi-Quantitative Assessment of Hemosiderin Distribution Accurately Reflects Reductions in Liver Iron Concentration Following Therapy with Deferasirox (Exjade®, ICL670) or Deferoxamine in Patients with Transfusion-Dependent Anemia.
Authors: Deugnier Yves , Turlin Bruno , Ropert Martine , Bejaoui Mohamed , Athanassiou-Metaxa Miranda , Cario Holger , Vichinsky Elliott , Opitz Herbert , Ressayre-Djaffer Catherine , Rabault Bertrand , Ford John 
Published: April 2020

Introduction: Direct biochemical measurement of liver iron from biopsy is the reference standard for determining liver iron concentration (LIC) and therefore the efficacy of chelation therapy. Semi-quantitative assessment of liver iron using Prussian blue stained tissue sections has, however, also been shown to correlate with LIC in patients with non-transfusional hemosiderosis.

Aim: To determine the value of semi-quantitative liver iron measurement as an indicator of LIC in patients with transfusion-dependent anemia treated with reference standard therapy deferoxamine (DFO) or the investigational once-daily, oral iron chelator deferasirox. The differential involvement of hepatocytes and macrophages in the storage of excess iron was also assessed.

Methods: During the deferasirox registration studies, semi-quantitative determination of liver tissue iron score (TIS) was performed in all patients who underwent liver biopsy; these data were compared with other markers of iron overload such as LIC and serum ferritin. In Studies 0107 and 0108, 454 patients with β-thalassemia and 101 patients with β-thalassemia or rare anemias (MDS, DBA and others) underwent liver biopsy at the start of the study and again after 1 year of chelation therapy with deferasirox (Study 0107, n=224 and all patients of 0108) or DFO (Study 0107 only, n=230). Patients analyzed in Study 0108 had β-thalassemia (n=61) or rare anemias (n=40).

Results: There was a good correlation between semi-quantitative and quantitative liver iron measurements in all patient populations (R≥0.80, Pearson correlation coefficient). Baseline and change from baseline TIS and LIC are given in Table 1. These changes were dose-dependent, with the greatest decrease observed in patients treated with the highest deferasirox dose (30 mg/kg: TIS decreased from 34.3 ± 7.7 to 25.9 ± 11.2, n=107, in Study 0107; and from 35.3 ± 7.6 to 29.2 ± 10.3, n=78, in Study 0108). Further analyses demonstrated that both deferasirox and DFO were active in removing iron from different functional areas of liver tissue (hepatocytic, sinusoidal and portal areas).

Table 1. Overall TIS and LIC changes after 1 year of treatment Study 0107 Study 0108 DFO Deferasirox β-thalassemia Rare anemias (n=230) (n=224) (n=61) (n=40) *Mean ± SD TIS* - Baseline 24.0 ± 10.3 25.3 ± 11.2 29.9 ± 10.9 34.1 ± 9.2 - Change from baseline −2.4 ± 11.2 −3.5 ± 7.1 −4.8 ± 11.2 −6.2 ± 10.1 LIC, mg Fe/g dw* - Baseline 14.5 ± 9.6 15.7 ± 10.1 21.2 ± 10.9 22.8 ± 9.4 - Change from baseline −3.0 ± 8.8 −3.2 ± 5.7 −5.8 ± 9.1 −5.5 ± 7.5

Conclusions: Semi-quantitative iron assessment clearly correlates with quantitative iron measurement. The impact of iron chelation therapy on iron deposits was seen in all functional areas of the liver, with the highest decrease observed in patients treated with deferasirox.