Safety and efficacy of combined chelation therapy with deferasirox and deferoxamine in a gerbil model of iron overload

Abstract

Introduction: Combined therapy with deferoxamine (DFO) and deferasirox (DFX) may be performed empirically when DFX monotherapy fails. Given the lack of published data on this therapy, the study goal was to assess the safety and efficacy of combined DFO/DFX therapy in a gerbil model.

Methods: Thirty-two female Mongolian gerbils 8-10 weeks old were divided into 4 groups (sham chelated, DFO, DFX, DFO/DFX). Each received 10 weekly injections of 200 mg/kg iron dextran prior to initiation of 12 weeks of chelation. Experimental endpoints were heart and liver weights, iron concentration and histology.

Results: In the heart, there was no significant difference among the treatment groups for wet-to-dry ratio, iron concentration and iron content. DFX-treated animals exhibited lower organ weights relative to sham-chelated animals (less iron-mediated hypertrophy). DFO-treated organs did not differ from sham-chelated organs in any aspects. DFX significantly cleared hepatic iron. No additive effects were observed in the organs of DFO/DFX-treated animals.

Conclusions: Combined DFO/DFX therapy produced no detectable additive effect above DFX monotherapy in either the liver or heart, suggesting competition with spontaneous iron elimination mechanisms for chelatable iron. Combined therapy was well tolerated, but its efficacy could not be proven due to limitations in the animal model.

Fig. 1

Representative histological examination of the heart and liver following 12 weeks of chelation therapy. Specimens were stained with H&E (a – c, e, f) and Perl’s Prussian blue iron stain (d, g, h). Increased appearance of dense fibers (a) and mild levels of nuclear hypertrophy (b) were observed in all cardiac samples. Misshapen nuclei were present in some of the combined therapy-treated specimens (c). Cardiac iron was mainly found in the interstitium (d). Accumulation and distribution of iron in the heart was very similar for all samples. Signs of focal area of inflammation were present in particular in DFO and control livers (e). Pallor was increasingly observed in ICL and combined treated livers (f). Whereas DFO did not significantly remove hepatic iron (g), ICL and combined treatment cleared hepatocytes from iron (h). ×100 (a), ×200 (e, g, h), ×400 (b–d, f).