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First Department of Paediatrics
University of Athens
“Aghia Sophia” Children’s Hospital
Thivon and Levadias
Conventional management of patients with thalassaemia major (TM) with regular red blood cell transfusions and systematic iron chelation has led to a dramatic improvement in quality of life and survival. Transfusions eliminate the complications of anaemia and promote normal development, but they also lead to severe iron overload. The efficacy of chronic use of the iron chelator deferoxamine (Desferal®, DFO) in preventing iron-induced organ damage and reducing morbidity and mortality in transfusion-dependent patients is well documented.(1–3) The main limitation of DFO is its administration by slow subcutaneous infusion 8–12 hours/day, five to seven times per week. The orally active chelators have dramatically changed the treatment of thalassaemia.
Deferiprone (L1, DFP, Ferriprox®), a three times daily oral chelator, is approved in the European Union as secondline treatment in patients with TM for whom DFO is contraindicated, inadequate or unacceptable.(4) DFP is a bidentate (ie, three molecules of DFP bind one atom of iron), lipophilic molecule with low molecular weight that readily enters cells. It has a low chelating efficiency of around 4% and a good dose-to-iron excretion relationship. Iron is primarily excreted through the urine. Although recent studies have suggested a better cardioprotective effect than with DFO, wide use of DFP has been halted because of concerns for lower efficacy compared with DFO, especially regarding hepatic iron overload, and because of severe toxicity, namely agranulocytosis, which occurs at a rate of around 0.5%.(5)
Combining DFP and DFO has an additive and frequently synergistic effect in iron excretion. Long-term combined therapy of DFP and DFO results in significant decrease in total-body, hepatic and cardiac iron overload and in an improvement in cardiac function. Combined therapy may be associated with higher incidence of agranulocytosis and may be related longitudinally to decreasing compliance to DFO.(6)
As of March 2006, the novel, once-daily, oral chelator deferasirox (Exjade(®), ICL670) is approved in 12 countries (including Switzerland and the USA) as a firstline treatment for chronic transfusional iron overload in adult and paediatric patients aged ≥2 years.(7) Deferasirox was selected among 700 iron-chelating products and entered a rigorous development programme in 1998. It is a tridentate molecule (ie, two molecules bind one atom of iron; see Figure 1) with high and specific affinity for trivalent iron. It is orally bioavailable and has a long half-life of 8–16 hours allowing once-daily dosing. Deferasirox has shown stable chelating efficiency (22–33%) across different doses and linear dose-dependent effects on iron excretion, which is accomplished primarily through the biliary tract.(8)
Clinical efficacy of deferasirox
The efficacy of deferasirox has been evaluated in a comprehensive clinical trial programme, which has enrolled more than 1,000 adult and paediatric patients with a wide range of transfusion-dependent anaemias such as β-thalassaemia, myelo‑dysplastic syndromes (MDS), sickle cell disease (SCD) and Diamond–Blackfan anaemia (DBA). A large-scale phase III trial, which enrolled 586 transfusion-dependent thalassaemic patients, compared the iron chelation efficacy (estimated by changes in liver iron concentration [LIC] and in serum ferritin levels) of deferasirox 5–30mg/kg/day to DFO at <25 to ≥50mg/kg/day.(7) This study concluded that deferasirox at doses of 20 and 30mg/kg/day was as effective as DFO at doses of 35 to ≥50mg/kg, establishing a 1:2 dose ratio. Deferasirox in children as young as 2 years of age (n=292) was as effective and tolerable as in adults, without affecting physical and sexual development.(9)
In transfusion-dependent patients, the iron binding capacity of transferrin is frequently exceeded and iron can then be found in the form of labile plasma iron (LPI). LPI is considered to be toxic, contributing to uncontrolled multiorgan iron loading. Preliminary data demonstrate that trough levels of a once-daily oral dose of deferasirox are sufficient to maintain suppression of LPI, suggesting that deferasirox is able to control levels of LPI over 24 hours.(10) The main cause of death in patients with thalassaemia is cardiac complications. Thus, adequate cardioprotection is a prerequisite in iron chelation. Preclinical studies on cardiomyocytes demonstrated that deferasirox could access subcellular compartments, chelate intracellular iron and reduce cellular oxidative stress. Animal studies have also shown that the efficiency of deferasirox in removing cardiac iron is similar to that of deferiprone.(11,12) Preliminary clinical data demonstrate that deferasirox is effective in removing cardiac iron, as measured by magnetic resonance imaging.(13)
Safety and tolerability of deferasirox
Deferasirox is generally well tolerated in patients with a wide range of transfusion-dependent anaemia. The most common adverse events are dose dependent, transient and of mild-to-moderate severity, with most of them resolving spontaneously. They include transient gastrointestinal disturbances (~26%) such as nausea, vomiting, diarrhoea and abdominal pain, as well as transient skin rash (~7%). Mild, dose-dependent nonprogressive increases in creatinine were observed in around 34% of patients. There were no cases of moderate/severe renal insufficiency and no patients permanently discontinued therapy due to creatinine increases.(9) Preliminary data from extension studies of up to five years are encouraging and no new adverse effects have been observed.
The availability of different chelators, which can be used either as monotherapy or in combination, allows iron chelation therapy to be tailored to meet the specific needs of the patient. Replacing the cumbersome daily subcutaneous infusions of deferoxamine by oral chelators is a major step in improving quality of life and compliance and, thus, achieving further improvement in complication-free survival.
Deferasirox, given once-daily, offers 24-hour chelation coverage, is able to reduce body iron and seems to have good access to cardiac iron.