Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

Abstract

The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.

Keywords: chelation therapy; deferasirox; deferiprone; deferoxamine; efficacy; iron absorption; iron overload; safety; thalassemia intermedia.

Figure 1

Structure of the chelating drugs. Notes: The chemical and physicochemical properties of chelating drugs influence their clinical activity, including their mode of action, organ targeting, efficacy, and toxicity. Deferiprone and deferoxamine are hydrophilic chelators that increase iron excretion and decrease iron absorption. Maltol, deferasirox, and 8-hydroxyquinoline are lipophilic chelators that form lipophilic metal complexes, and can cause an increase in iron and other metal absorption. Orally absorbed, nonmetal-bound deferasirox mobilizes excess iron, mainly from the liver, and causes an increase in iron excretion. The pharmacological effects of different drugs, eg, hydroxycarbamide (hydroxyurea) are affected by iron binding.

Figure 2

Iron-absorption and iron-overload mechanisms in non-transfusion-dependent thalassemias: the role of chelators and chelating drugs. Notes: Mechanism of iron absorption at the enterocyte using regulatory pathways of iron metabolism involving DMT1, hepcidin, ferroportin, and transferrin. Increased gastrointestinal iron absorption and iron overload is observed in non-transfusion-dependent thalassemias, due to ineffective erythropoiesis in the bone marrow (A). The level of increased iron absorption depends on the form and quantity of iron present in the diet and other factors, such as the presence of natural or synthetic iron chelators in the gastrointestinal tract. Iron-chelating drugs and other chelators have variable pharmacological effects on iron absorption, with lipophilic chelators causing an increase in iron absorption and hydrophilic chelators a decrease in iron absorption. Excess iron absorption causes iron overload and damage in the liver, the heart, and other organs. The liver is the main organ of excess iron deposition, whereas the heart is the most susceptible organ of iron toxicity, as a result of iron overload from increased iron absorption. Iron overload in both the liver (B) and the heart (C) in non-transfusion-dependent thalassemia are the main target sites of chelation therapy. Abbreviations: DMT1, divalent metal transporter 1; EDTA, ethylenediaminetetraacetic acid; DTPA, diethylenetriaminepentaacetic acid.