Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy in both adult and pediatric patients with transfusional iron overload. The clinical development program has demonstrated the efficacy of deferasirox for up to 4.5 years of treatment in patients with various underlying anemias, including β-thalassemia, myelodysplastic syndromes, sickle cell disease, aplastic anemia, and other rare anemias. In addition to reducing key indicators of total body iron levels (serum ferritin, liver iron concentration, and toxic labile plasma iron), deferasirox has also demonstrated the ability to remove cardiac iron and prevent future cardiac iron accumulation. Emerging long-term data confirm the tolerability profile of deferasirox, and data on patient compliance render deferasirox a suitable therapeutic option for patients with chronic conditions requiring ongoing iron chelation therapy. Data continue to accumulate in a wide range of patient groups, including those with non-transfusion-dependent anemias such as hereditary hemochromatosis.

Long-term red blood cell transfusion for the treatment of various chronic anemias inevitably leads to the accumulation of iron in the body. Several iron chelators have been developed, designed to mobilize tissue iron by forming complexes that are excreted in the feces and/or urine. Deferoxamine (Desferal®; DFO; Novartis Pharma, Basel, Switzerland) was developed more than 40 years ago and the wealth of clinical experience in iron-overloaded patients has established a role for iron chelators in the improvement of patient quality of life and overall survival [1,2]. However, due to its poor oral bioavailability and short plasma half-life, subcutaneous administration is required 5–7 days/week, often resulting in poor compliance [3]. Deferiprone (Ferriprox®; Apotex, Toronto, Ont., Canada) was the first oral iron chelator available in the European Union and a number of countries outside the USA and Canada for the second-line treatment of iron overload in adult patients with β-thalassemia in whom DFO therapy is contraindicated or inadequate (European Medicines Agency). Deferiprone has a short half-life (3– 4 h) and therefore requires three-times daily dosing. Deferasirox (Exjade®; Novartis Pharma) was developed as a once-daily oral iron chelator through a rational drug development program and represents a new class of tridentate iron chelators. Deferasirox is currently approved in many countries worldwide for the treatment of chronic iron overload due to blood transfusions in patients aged ≥2 years. The efficacy and safety of deferasirox has been evaluated in patients with β-thalassemia and also in a wide range of patients with other underlying anemias, including myelodysplastic syndromes (MDS), sickle cell disease (SCD), aplastic anemia (AA), Diamond-Blackfan anemia (DBA), and various other rare anemias [3,4,5,6,7,8,9,10,11].

The symptoms of β-thalassemia major occur as a result of complete or partial reduction in the production of the β-globin protein (due to mutations in the β-globin gene) that constitutes part of functional hemoglobin. This results in ineffective erythropoiesis and hemolysis causing severe life-threatening anemia, which normally presents in the 1st year of life and can be fatal during infancy or childhood if untreated. Red blood cell transfusions are the primary treatment approach and are often required from early childhood.

Deferasirox Therapy in Patients with β-Thalassemia Major

The pharmacokinetic profile of oral deferasirox was established in patients with β-thalassemia in two small, randomized, double-blind, placebo-controlled, dose-finding studies [3,4]. The pharmacokinetic profile, in particular the observed half-life for deferasirox (11–19 h), was supportive of a once-daily dosing regimen as deferasirox plasma levels were maintained within the therapeutic range over a 24-hour period providing continuous chelation coverage [4]. Deferasirox 20 mg/kg/day was also identified as an effective oral dose and shown to be generally well tolerated [3]. Furthermore, deferasirox 20–30 mg/kg/day was shown to be as effective in reducing liver iron concentration (LIC) as DFO at a dose of 40 mg/kg/day [10]. Additional analyses of these data demonstrated that ongoing transfusional iron loading affects the response to deferasirox and, together with serum ferritin trends, needs to be monitored on an ongoing basis and used to guide deferasirox dosing in order to achieve individual patient therapeutic goals of either maintenance or reduction in iron load (fig. 1) [8,12]. This approach was evaluated in the EPIC (Evaluation of Patients’ Iron Chelation) trial where the deferasirox dose was titrated every 3 months according to serum ferritin trends and safety markers [7]. Data from a large group (n = 937) of regularly transfused patients with β-thalassemia major showed that changes in serum ferritin were reflective of dose adjustments and mean iron intake during treatment. Patients who received an average actual dose ≥30 mg/kg/day had the greatest reduction in serum ferritin (–962 ng/ml; p < 0.0001 vs. baseline) and patients receiving <20 or ≥20–<30 mg/kg/day maintained their iron balance [13]. In a retrospective analysis including a large number of patients with β-thalassemia, doses >30 mg/kg/day were shown to safely reduce serum ferritin, which is important for heavily transfused patients who may require higher deferasirox doses to reduce body iron burden [14]. As well as affecting serum ferritin levels and LIC, deferasirox can also reduce levels of labile plasma iron (LPI) in patients with β-thalassemia major. LPI is a directly chelatable form of non-transferrin-bound iron readily taken up by cells and is able to participate in redox cycling reactions resulting in the formation of harmful reactive oxygen species [15,16]. Deferasirox doses ≥20 mg/kg/day provided sustained reduction in LPI levels and may therefore contribute to a reduction in unregulated tissue iron loading [17,18].

Fig. 1

Impact of transfusional iron intake and deferasirox dose on LIC. (This research was originally published by Cohen et al. [12 ]in Blood.)

Fig. 1

Impact of transfusional iron intake and deferasirox dose on LIC. (This research was originally published by Cohen et al. [12 ]in Blood.)

Close modal

Long-term data are critical for the evaluation of iron chelation therapy in patients with β-thalassemia due to the chronic nature of the disease. Median follow-up of patients treated with deferasirox has now been reported in extended phase trials for up to 4.5 years. Results have confirmed that the efficacy of deferasirox depends on both dose and transfusion [19,20] even in patients unsuccessfully chelated with DFO and/or deferiprone due to unacceptable toxicity, poor response to therapy or non-compliance with treatment regimens [21].

Tolerability and Management of Adverse Events in Patients with β-Thalassemia

The most common drug-related (investigator-assessed) adverse events (AEs) identified in β-thalassemia patients are abdominal pain, nausea, diarrhea, vomiting, and rash; however, the annual frequency of these AEs has generally been shown to decrease from year to year [20]. Such AEs are clinically manageable with regular patient monitoring as the many deferasirox clinical studies have provided information on their onset, severity, duration, and frequency. For diarrhea, patients should be advised to stay hydrated and take an anti-diarrheal for up to 2 days if required. Patients may also benefit from taking deferasirox in the evening rather than the morning or adding products such as Lactaid to their diet [22]. Mild-to-moderate skin rashes are likely to resolve spontaneously; however, severe cases may require dose interruptions and/or adjustments [22]. Non-progressive increases in serum creatinine (rising above the mean of measurements before treatment by >33% on two consecutive occasions) have been observed in approximately one third of patients treated with deferasirox [8]. However, these increases were dose dependent and often resolved spontaneously. It is recommended that serum creatinine levels are assessed in duplicate before therapy begins and monthly thereafter with any significant increases managed by dose reductions and/or interruptions [22,23].

Patient Preferences

Compliance with iron chelation therapy is an important issue for patients, as with many chronic conditions. Patients need to be educated about the risks of iron overload and the benefits of remaining compliant with therapy. As deferasirox is an oral therapy, it may be expected that patient compliance would be superior to that seen with DFO infusions [6]. Assessment of patient preferences demonstrated satisfaction and convenience with deferasirox therapy as compared with DFO, with 97% of patients with β-thalassemia who switched to deferasirox from DFO preferring deferasirox. Patients preferred deferasirox due to convenience (37%), absence of injection site soreness (25%) and less disruption to their day (23%) [24]. Greater satisfaction and convenience with deferasirox may translate into improvements in patient compliance and increased effectiveness of chelation therapy.

Deferasirox Therapy in Pediatric Patients with β-Thalassemia

The efficacy and safety of deferasirox have been evaluated in pediatric β-thalassemia patients as young as 2 years of age. The pharmacokinetic profile of deferasirox in pediatric patients (aged 2–7 years) also supports a once-daily dosing regimen; however, the steady-state exposure to deferasirox in children and adolescents is ∼20–30% lower than in adults [4,9]. A conservative dosing strategy was used in preliminary trials in children resulting in an overall gradual increase in LIC [9]; 10 mg/kg/day was used irrespective of the degree of iron overload at baseline with dose adjustments allowed only after 12 weeks of treatment. Longer-term follow-up data in pediatric patients treated with deferasirox for up to 5 years have now demonstrated a dose-dependent reduction in iron burden [25,26].

The safety profile of deferasirox in pediatric patients is similar to that of adult patients during the 5-year follow-up at doses of up to 30 mg/kg/day [25,26]. The recommended starting dose and dosing modifications are the same for pediatric and adult patients [23]. To date, neither progressive renal, hepatic, or bone marrow dysfunctions nor deferasirox-induced negative impacts on growth and sexual development have been reported [26].

Deferasirox Therapy in β-Thalassemia Patients with Cardiac Siderosis

Iron-induced cardiac failure and arrhythmia are responsible for as many as 71% of deaths in patients with β-thalassemia major [1,27]. The ability of deferasirox to remove iron from the heart is therefore of particular interest. Initial studies in animal models demonstrating the efficacy of deferasirox to reduce cardiac iron content [28] were followed by clinical data to support the efficacy of deferasirox in the removal of cardiac iron and prevention of myocardial siderosis in patients with β-thalassemia major [29,30,31,32]. After 1 year of deferasirox treatment (mean dose: 32.6 mg/kg/day) in 114 patients with baseline myocardial T2* of 20 ms (indicative of cardiac iron accumulation), myocardial T2* was shown to improve significantly from a geometric mean baseline of 11.2 to 12.9 ms while left ventricular ejection fraction was maintained at ∼67% [30]. In a cohort of 78 patients with normal myocardial iron levels (T2* >20 ms), myocardial T2* was maintained after treatment with deferasirox for 1 year (32.0 ms at baseline and 32.5 ms after 12 months of therapy at a mean dose of 27.6 mg/kg/day), left ventricular ejection fraction significantly increased from 67.7 to 69.6% (p < 0.0001) and body iron burden as assessed by serum ferritin and LIC were significantly reduced [32].

Iron Chelation Therapy in Patients with Thalassemia Intermedia

Defects in the β-globin gene may also result in a diagnosis of β-thalassemia intermedia, which has a wide clinical spectrum with patients often remaining asymptomatic until adult life [33]. In contrast to patients with β-thalassemia major, thalassemia intermedia patients are rarely transfusion dependent; however, they are susceptible to gradual iron overload through increased intestinal absorption of iron secondarily due to chronic anemia and decreased serum hepcidin caused by GDF15 overexpression, which may be exacerbated by occasional blood transfusions. Therefore patients need to be assessed for iron overload. Cardiac iron loading appears to be less of an issue in patients with thalassemia intermedia [34]; however, iron overload should still be monitored in both the liver and the heart. As the clinical consequences of iron overload in thalassemia intermedia are the same as in transfused patients with β-thalassemia major, patients may benefit from iron chelation therapy. Few studies have assessed chelation therapy in thalassemia intermedia [35,36]; however, there is an ongoing 1-year trial of deferasirox in >150 patients with thalassemia intermedia, representing the first large-scale study of an iron-chelating agent in this patient population.

MDS is a group of heterogeneous disorders characterized by impaired blood cell production by the bone marrow. Managing MDS is often complicated by the generally advanced age of patients (median age 65–70 years) [37]. Red blood cell transfusions are the mainstay of supportive care for MDS [38] and up to 90% of MDS patientswith chronic anemia become dependent on transfusions to manage the symptoms of anemia [38]; however, blood transfusion therapy is associated with increased risk of iron toxicity.Chelation therapy is recommended by several treatment guidelines in patients who have an International prognostic Scoring System risk of low or intermediate-1 and serum ferritin levels of >1,000–2,000 ng/ml, depending on transfusion requirements [37,39,40]. Response to chelation therapy may not be the same as in β-thalassemia patients due to differences in the magnitude of directly chelatable iron pools, and thus specific data are required to evaluate efficacy and safety [5]. There are a limited number of small-scale studies on the use of DFO and deferiprone in this patient population; however, several larger clinical trials with deferasirox have provided more robust data [5,41,42,43].

Deferasirox Therapy in Patients with MDS

Deferasirox has been shown to maintain or reduce body iron in patients with MDS in several clinical trials [5,42,43,44]. In one study of 176 patients, deferasirox decreased mean serum ferritin over 1 year and normalized LPI levels [42]. In another study comparing responses to iron chelation among various disease groups, a similar pattern of dose-dependent iron excretion was observed in patients with MDS compared with β-thalassemia (fig. 2) [5]. More recently, the EPIC trial enrolled the largest cohort of MDS patients to date (n = 341). Despite a high transfusion requirement and iron burden in this cohort, almost 50% had received no prior chelation therapy. Deferasirox provided significant reduction in serum ferritin over the 1-year treatment period with appropriate dose adjustments every 3 months as required (table 1) [7,13,43,45,46,47]. The most common AEs considered related to treatment included mild-to-moderate gastrointestinal symptoms consistent with those identified in patients with β-thalassemia. However, the discontinuation rate was higher and investigations are ongoing to determine possible contributing factors such as existing co-morbidities and the advanced age of this patient subgroup [43].

Table 1

Efficacy of deferasirox across a variety of transfusion-dependent anemias included in the EPIC trial

Efficacy of deferasirox across a variety of transfusion-dependent anemias included in the EPIC trial
Efficacy of deferasirox across a variety of transfusion-dependent anemias included in the EPIC trial
Fig. 2

Deferasirox is effective in reducing serum ferritin and LIC across a range of transfusion-dependent anemias. Other anemias include AA (n = 5), α-thalassemia (n = 3), sideroblastic anemia (n = 3), myelofibrosis (n = 2), pure red cell aplasia (n = 2), pyruvate kinase deficiency (n = 2), autoimmune hemolytic anemia (n = 1), Fanconi’s anemia (n = 1), hereditary sideroblastic anemia (n = 1), erythropenia (n = 1), and unspecified anemia (n = 1). DW = Dry weight.

Fig. 2

Deferasirox is effective in reducing serum ferritin and LIC across a range of transfusion-dependent anemias. Other anemias include AA (n = 5), α-thalassemia (n = 3), sideroblastic anemia (n = 3), myelofibrosis (n = 2), pure red cell aplasia (n = 2), pyruvate kinase deficiency (n = 2), autoimmune hemolytic anemia (n = 1), Fanconi’s anemia (n = 1), hereditary sideroblastic anemia (n = 1), erythropenia (n = 1), and unspecified anemia (n = 1). DW = Dry weight.

Close modal

SCD is a group of inherited disorders caused by the sickle mutation affecting the β-globin chain of hemoglobin. Erythrocytes containing hemoglobin S have irregular morphology and under low oxygen conditions, hemoglobin S polymerizes leading to ‘sickled’ cells [48]. The pathogenesis of SCD relates to the shortened lifespan of the sickled erythrocytes (16–20 days in contrast to a lifespan of 120 days for normal erythrocytes) and adhesion of the sickled erythrocytes to the microvascular endothelium. Transfusion of red blood cells on a chronic or intermittent basis is therefore important in the management of SCD. There is increasing evidence of the value of transfusions particularly in reducing the risk of stroke in pediatric patients with SCD [49,50]. However, progressive iron loading and tissue injury as a result of frequent blood transfusions appear to be similar to those in other transfusion populations [51].

Deferasirox Therapy in Patients with SCD

In comparison with DFO, deferasirox has been shown to have similar efficacy and a well-defined, manageable safety profile in both adult and pediatric patients (aged 3–54 years) with SCD [6]. After 1 year of treatment with deferasirox (10–30 mg/kg/day), LIC was significantly reduced compared with baseline (p < 0.05) and serum ferritin was also decreased, although with intrapatient variability. The incidence of AEs including sickle cell crisis was also similar in both groups (46.2% with deferasirox and 42.9% with DFO) [6]. As part of this phase II study, patient-reported outcomes were also evaluated. Throughout the study, significantly more patients receiving deferasirox reported being ‘satisfied’ or ‘very satisfied’ with treatment compared with those on DFO (p < 0.001) [52]. Similar outcomes were also reported regarding convenience of deferasirox therapy. Cumulative 3.5-year data of deferasirox in SCD patients have now demonstrated continued reduction in body iron (based on serum ferritin levels) without any exposure-associated increased risk of AEs, renal dysfunction, or progressive increases in serum creatinine [53].

Deferasirox Therapy in Patients with DBA

DBA is a rare type of congenital erythroid aplasia that occurs in 5–10 of every 1 million births, where anemia occurs due to the failure of erythropoiesis [54]. In a 1-year study of deferasirox in patients with DBA, doses of 20 and 30 mg/kg/day induced a negative iron balance in a similar pattern to patients with other underlying anemias such as β-thalassemia and MDS (fig. 1; n = 30) [5]. These data were supported by results from the prospective EPIC trial, where a significant reduction in serum ferritin from baseline was observed in patients with DBA receiving an average daily dose of ≥20–<30 mg/kg/day (–1,095.0 ng/ml; p = 0.0015; table 1) [47]. The majority of DBA patients (86%) in the EPIC trial had received prior chelation therapy with DFO and/or deferiprone; however, median baseline serum ferritin was still elevated. The AE profile was similar to that observed in other patient groups [5,47].

Deferasirox Therapy in Patients with AA

AA often results from other bone marrow disorders (such as MDS) as a result of complete bone marrow failure. The worldwide annual incidence is estimated at 2 of every 1,000,000 births [55]. AA can be treated with bone marrow transplantation or immunosuppressive therapy; however, the main supportive therapy involves regular blood transfusions [56]. Over a 1-year treatment period, deferasirox significantly reduced iron burden in patients with AA at an average actual dose of 17.6 ± 4.8 mg/kg/day (table 1) [45]. Interestingly, 68% of AA patients enrolled in this trial had received no prior treatment with chelation therapy even though they had an elevated median serum ferritin at baseline (3,254 ng/ml) associated with significant negative outcomes [1], thereby indicating a need for iron chelation therapy in this patient population [45]. Deferasirox was generally well tolerated, with the most common (>10%) drug-related AEs including nausea, diarrhea, and rash; most AEs (>95%) were of mild-to-moderate severity.

To date, the deferasirox clinical development program has focused on the treatment of patients with transfusional iron overload; however, a wider perspective is now being taken with the investigation of deferasirox in a number of other conditions including hereditary hemochromatosis (HH; characterized by progressive iron overloading through increased intestinal absorption [57]), chronic hepatitis C [58], porphyria cutanea tarda (a common type of porphyria which can be associated with hemochromatosis [59]), and mucormycosis.

Phlebotomy is the standard of care in HH patients to reduce serum ferritin levels and prevent clinical complications of iron overload. However, compliance with phlebotomy tends to decrease with time due to the inconvenience of frequent clinic visits and discomfort of the procedure; some patients may also be poor candidates due to underlying medical disorders and/or poor venous access. A study is ongoing to evaluate the safety and efficacy of deferasirox as a further treatment option in patients with HH (adult patients homozygous for the C282Y mutation) [60] and preliminary results suggest that deferasirox doses of 5, 10 and 15 mg/kg/day are effective at reducing iron burden with an acceptable safety profile [61]. Preliminary studies in the treatment of chronic hepatitis C infection with interferon/ribavirin have suggested that previous treatment with deferasirox may improve early viral response rates [58]. A pilot trial to investigate the efficacy and tolerability of deferasirox in the treatment of porphyria cutanea tarda is currently recruiting patients ( identifier: NCT00599326). Deferasirox has also been shown to significantly improve survival and decrease tissue fungal burden in mice infected with mucormycosis [62]. A clinical study to determine whether the addition of deferasiroxto standard antifungal therapy, liposomal amphotericin B (LAmB; AmBisome), is safe and effective for the treatment of mucormycosis is also currently recruiting patients (DEFEAT Mucor study; identifier: NCT00419770).

Additionally, the benefits of reduced iron levels in bone marrow transplant patients before and after transplantation have been recognized [63] and, therefore, deferasirox also has a potential application in this patient population.

Long-term red blood cell transfusions are required for the treatment of many anemias including β-thalassemia, MDS, SCD, DBA, and AA. Frequent transfusions inevitably lead to iron overload, which has serious clinical sequelae. The oral iron chelator deferasirox has been evaluated in heterogeneous populations of patients with a variety of underlying anemias demonstrating consistent efficacy and safety profiles. The results from the large-scale EPIC trial and data from long-term studies further support these observations as well as the importance of timely dose adjustments based on serum ferritin trends to adapt therapy for individual patients. Emerging data on the cardiac efficacy of deferasirox are also encouraging in both the prevention and treatment of cardiac iron accumulation. Deferasirox therefore represents a significant advance in the treatment of a wide variety of patients with chronic iron overload, with further potential applications still to be explored.

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Dr. Rebecca Helson for medical editorial assistance.

Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, Martin M, Koren G, Cohen AR: Survival in medically treated patients with homozygous β-thalassemia. N Engl J Med 1994;331:574–578.
Olivieri NF, Brittenham GM: Iron-chelating therapy and the treatment of thalassemia. Blood 1997;89:739–761.
Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Séchaud R, Krebs-Brown AJ, Anderson JR, Alberti D, Sizer KC, Nathan DG: Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 2003;361:1597–1602.
Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R: Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 2003;43:565–572.
Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD, Olivieri N, Piga A, Cunningham MJ, Soulières D, Gattermann N, Tchernia G, Maertens J, Giardina P, Kwiatkowski J, Quarta G, Jeng M, Forni GL, Stadler M, Cario H, Debusscher L, Della Porta M, Cazzola M, Greenberg P, Alimena G, Rabault B, Gathmann I, Ford JM, Alberti D, Rose C: Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-year prospective study. Eur J Haematol 2008;80:168–176.
Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, Files B, Hassell K, Kelly P, Wilson F, Bernaudin F, Forni GL, Okpala I, Ressayre-Djaffer C, Alberti D, Holland J, Marks P, Fung E, Fischer R, Mueller BU, Coates T: A randomized comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007;136:501–508.
Cappellini MD, El-Beshlawy A, Kattamis A, Lee JW, Seymour JF, Li CK, Habr D, Domokos G, Hmissi A, Elalfy MS: Efficacy and safety of deferasirox (Exjade®) in patients with transfusion-dependent anemias: 1-year results from the large, prospective, multicenter EPIC study (abstract). Blood 2008;112:3875.
Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, Aydinok Y, Kattamis A, Kilinc Y, Porter J, Capra M, Galanello R, Fattoum S, Drelichman G, Magnano C, Verissimo M, Athanassiou-Metaxa M, Giardina B, Kourakli-Symeonidis A, Janka-Schaub G, Coates T, Vermylen C, Olivieri N, Thuret I, Opitz H, Ressayre-Djaffer C, Marks P, Alberti D: A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with β-thalassemia. Blood 2006;107:3455–3462.
Galanello R, Piga A, Forni GL, Bertrand Y, Foschini ML, Bordone E, Leoni G, Lavagetto A, Zappu A, Longo F, Maseruka H, Hewson N, Sechaud R, Belleli R, Alberti D: Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with β-thalassemia major. Haematologica 2006;91:1343–1351.
Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A, Donato G, Bordone E, Lavagetto A, Zanaboni L, Sechaud R, Hewson N, Ford JM, Opitz H, Alberti D: Randomized phase II trial of deferasirox (Exjade®, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006;91:873–880.
Taher A, El-Beshlawy A, Elalfy MS, Al Zir K, Daar S, Damanhouri G, Habr D, Kriemler-Krahn U, Hmissi A, Al Jefri A: Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study. Eur J Haematol 2009;82:458–465.
Cohen AR, Glimm E, Porter JB: Effect of transfusional iron intake on response to chelation therapy in β-thalassemia major. Blood 2008;111:583–587.
Cappellini MD, Elalfy MS, Kattamis A, Seymour JF, Lee Lee C, Porter JB, El-Beshlawy A, Habr D, Domokos G, Hmissi A, Taher A: Efficacy and safety of once-daily, oral iron chelator deferasirox (Exjade®) in a large group of regularly transfused patients with β-thalassemia major (abstract). Blood 2008;112:3878.
Cappellini MD, Taher A, Vichinsky E, Galanello R, Piga A, Lawniczek T, Jehl V, Rojkjaer L, Porter JB: Efficacy and tolerability of deferasirox doses >30 mg/kg/day in patients with transfusion-dependent anaemia and iron overload (abstract). Haematologica 2008;93(suppl 1):845.
Porter J: Pathophysiology of iron overload. Hematol Oncol Clin North Am 2005;19 (suppl 1):7–12.
Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI: Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood 2003;102:2670–2677.
Daar S, Pathare A, Nick H, Kriemler-Krahn U, Hmissi A, Habr D, Taher A: Reduction in labile plasma iron during treatment with deferasirox, a once-daily oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia. Eur J Haematol 2009;82:454–457.
Porter JB, Cappellini MD, El-Beshlawy A, Kattamis A, Seymour JF, Lee JW, Nick H, Habr D, Domokos G, Hmissi A, Taher A: Effect of deferasirox (Exjade®) on labile plasma iron levels in heavily iron-overloaded patients with transfusion-dependent anemias enrolled in the large-scale, prospective 1-year EPIC trial (abstract). Blood 2008;112:3881.
Cappellini MD, Vichinsky E, Galanello R, Piga A, Williamson P, Porter JB: Long-term treatment with deferasirox (Exjade®, ICL670), a once-daily oral iron chelator, is effective in patients with transfusion-dependent anemias (abstract). Blood 2007;110:2777.
Cappellini MD, Galanello R, Piga A, Cohen A, Kattamis A, Aydinok Y, Williamson P, Rojkjaer L, Porter JB: Efficacy and safety of deferasirox (Exjade®) with up to 4.5 years of treatment in patients with thalassemia major: a pooled analysis (abstract). Blood 2008;112:5411.
Taher A, El-Beshlawy A, Elalfy MS, Al Zir K, Daar S, Damanhouri G, Habr D, Kriemler-Krahn U, Hmissi A, Al Jefri A: Efficacy and safety of once-daily oral deferasirox (Exjade®) during a median of 2.7 years of treatment in heavily iron-overloaded patients with β-thalassemia (abstract). Blood 2008;112:5409.
Vichinsky E: Clinical application of deferasirox: Practical patient management. Am J Hematol 2008;83:398–402.
Exjade (deferasirox) Prescribing Information. Novartis Pharmaceuticals Corporation.
Cappellini MD, Bejaoui M, Agaoglu L, Porter J, Coates T, Jeng M, Lai ME, Mangiagli A, Strauss G, Girot R, Watman N, Ferster A, Loggetto S, Abish S, Cario H, Zoumbos N, Vichinsky E, Opitz H, Ressayre-Djaffer C, Abetz L, Rofail D, Baladi JF: Prospective evaluation of patient-reported outcomes during treatment with deferasirox or deferoxamine for iron overload in patients with β-thalassemia. Clin Ther 2007;29:909–917.
Piga A, Forni GL, Kattamis A, Kattamis C, Aydinok Y, Rodriguez M, Rojkjaer L, Galanello R: Deferasirox (Exjade®) in pediatric patients with β-thalassemia: update of 4.7-year efficacy and safety from extension studies (abstract). Blood 2008;112:3883.
Piga A, Kebaili K, Galanello R, Jehl V, Rebischung C, Maseruka H, Rojkjaer L, Forni GL: Cumulative efficacy and safety of 5-year deferasirox (Exjade®) treatment in pediatric patients with thalassemia major: a phase II multicenter prospective trial (abstract). Blood 2008;112:5413.
Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga A, Melevendi C, Di Gregorio F, Burattini MG, Terzoli S: Survival and causes of death in thalassaemia major. Lancet 1989;ii:27–30.
Wood JC, Otto-Duessel M, Gonzales I, Aguilar MI, Shimada H, Nick H, Nelson M, Moats R: Deferasirox and deferiprone remove cardiac iron in the iron-overloaded gerbil. Transl Res 2006;148:272–280.
Garbowski M, Eleftheriou P, Pennell D, Tanner M, Porter JB: Impact of compliance, ferritin and LIC on long-term trends in myocardial T2* with deferasirox (abstract). Blood 2008;112:116.
Pennell D, Porter JB, Cappellini MD, Li CK, Aydinok Y, Lee Lee C, Kattamis A, Smith G, Habr D, Domokos G, Hmissi A, Taher A: Efficacy and safety of deferasirox (Exjade®) in reducing cardiac iron in patients with β-thalassemia major: results from the cardiac substudy of the EPIC trial (abstract). Blood 2008;112:3873.
Wood JC, Thompson AA, Paley C, Kang B, Giardina P, Harmatz P, Virkus J, Coates TD: Deferasirox (Exjade®) monotherapy significantly reduces cardiac iron burden in chronically transfused β-thalassemia patients: an MRI T2* study (abstract). Blood 2008;112:3882.
Pennell D, Sutcharitchan P, El-Beshlawy A, Aydinok Y, Taher A, Smith G, Habr D, Kriemler-Krahn U, Hmissi A, Porter JB: Efficacy and safety of deferasirox (Exjade®) in preventing cardiac iron overload in β-thalassemia patients with normal baseline cardiac iron: results from the cardiac substudy of the EPIC trial (abstract). Blood 2008;112:3874.
Taher A, Isma’eel H, Cappellini MD: Thalassemia intermedia: revisited. Blood Cells Mol Dis 2006;37:12–20.
Origa R, Barella S, Argiolas GM, Bina P, Agus A, Galanello R: No evidence of cardiac iron in 20 never or minimally transfused patients with thalassemia intermedia. Haematologica 2008;93:1095–1096.
Cossu P, Toccafondi C, Vardeu F, Sanna G, Frau F, Lobrano R, Cornacchia G, Nucaro A, Bertolino F, Loi A, De Virgiliis S, Cao A: Iron overload and desferrioxamine chelation therapy in beta-thalassemia intermedia. Eur J Pediatr 1981;137:267–271.
Olivieri NF, Koren G, Matsui D, Liu PP, Blendis L, Cameron R, McClelland RA, Templeton DM: Reduction of tissue iron stores and normalization of serum ferritin during treatment with the oral iron chelator L1 in thalassemia intermedia. Blood 1992;79:2741–2748.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology v.2: Myelodysplastic Syndromes.
Hellström-Lindberg E: Management of anemia associated with myelodysplastic syndrome. Semin Hematol 2005;42(suppl 1):S10–S13.
Bennett JM: Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol 2008;83:858–861.
Gatterman N: Iron overload in myelodysplastic syndromes. Hematol Oncol Clin North Am 2005;19(suppl 1):1–26.
Min YH, Kim HJ, Lee KH, Yoon SS, Lee JH, Park HS, Kim JS, Kim HY, Shim H, Seong CM, Kim CS, Chung J, Hyun MS, Jo DY, Jung CW, Sohn SK, Yoon HJ, Kim BS, Joo YD, Park CY, Cheong JW: A multi-center, open label study evaluating the efficacy of iron chelation therapy with deferasirox in transfusional iron overload patients with myelodysplastic syndromes or aplastic anemia using quantitative R2 MRI (abstract). Blood 2008;112:3649.
List AF, Baer MR, Steensma D, Raza A, Esposito J, Virkus J, Paley C, Feigert J, Besa EC: Iron chelation with deferasirox (Exjade®) improves iron burden in patients with myelodysplastic syndromes (MDS) (abstract). Blood 2008;112:634.
Gattermann N, Schmid M, Della Porta M, Taylor K, Seymour JF, Habr D, Domokos G, Hmissi A, Guerci-Bresler A, Rose C: Efficacy and safety of deferasirox (Exjade®) during 1 year of treatment in transfusion-dependent patients with myelodysplastic syndromes: results from EPIC trial (abstract). Blood 2008;112:633.
Greenberg PL, Schiffer C, Koller CA, Glynos T, Paley C: Change in liver iron concentration (LIC), serum ferritin (SF) and labile plasma iron (LPI) over 1 year of deferasirox (DFX/Exjade®) therapy in a cohort of myelodysplastic patients (abstract). Blood 2008;112:5083.
Lee JW, Yoon SS, Shen ZX, Hsu HC, Ganser A, Habr D, Domokos G, Hmissi A, Porter JB: Iron chelation in regularly transfused patients with aplastic anemia: efficacy and safety results from the large deferasirox EPIC trial (abstract). Blood 2008;112:439.
Porter JB, Lin KH, Habr D, Domokos G, Hmissi A, Thein SL: Deferasirox efficacy and safety for the treatment of transfusion-dependent iron overload in patients with a range of rare anemias (abstract). Blood 2008;112:1419.
Porter JB, Forni GL, Beris P, Taher A, Habr D, Domokos G, Hmissi A, Cappellini MD: Efficacy and safety of 1 year’s treatment with deferasirox (Exjade®): assessment of regularly transfused patients with Diamond-Blackfan anemia enrolled in the EPIC study (abstract). Blood 2008;112:1048.
Claster S, Vichinsky EP: Managing sickle cell disease. Br Med J 2003;327:1151–1155.
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D: Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998;339:5–11.
Adams RJ, Brambilla D: Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353:2769–2778.
Vichinsky E, Butensky E, Fung E, Hudes M, Theil E, Ferrell L, Williams R, Louie L, Lee PD, Harmatz P: Comparison of organ dysfunction in transfused patients with SCD or β thalassemia. Am J Hematol 2005;80:70–74.
Vichinsky E, Pakbaz Z, Onyekwere O, Porter J, Swerdlow P, Coates T, Lane P, Files B, Mueller BU, Coic L, Forni GL, Fischer R, Marks P, Rofail D, Abetz L, Baladi JF: Patient-reported outcomes of deferasirox (Exjade®, ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis: substudy of a randomized open-label phase II trial. Acta Haematol 2008;119:133–141.
Vichinsky E, Coates T, Thompson AA, Bernaudin F, Rodriguez M, Rojkjaer L, Heeney MM: Deferasirox (Exjade®), the once-daily oral iron chelator, demonstrates safety and efficacy in patients with sickle cell disease (SCD): 3.5-year follow-up (abstract). Blood 2008;112:1420.
Diamond Blackfan Anemia Support Group. Diamond Blackfan Anemia Syndrome.
Risks of agranulocytosis and aplastic anemia. A first report of their relation to drug use with special reference to analgesics. The International Agranulocytosis and Aplastic Anemia Study. JAMA 1986;256:1749–1757.
Marsh JC, Ball SE, Darbyshire P, Gordon-Smith EC, Keidan AJ, Martin A, McCann SR, Mercieca J, Oscier D, Roques AW, Yin JAL: Guidelines for the diagnosis and management of acquired aplastic anaemia. Br J Haematol 2003;123:782–801.
Beutler E: Iron storage disease: facts, fiction and progress. Blood Cells Mol Dis 2007;39:140–147.
Goubran HA, Essmat G, Morcos HH, Amin SN: Pilot results: pre-treatment with deferasirox increases the chances of rapid viral response in patients with chronic hepatitis C infection treated with PEG-interferon/ribavirin (abstract). Blood 2007;110:2281.
Kostler E, Wollina U: Therapy of porphyria cutanea tarda. Expert Opin Pharmacother 2005;6:377–383.
Pietrangelo A, Brissot P, Bonkovsky H, Niederau C, Rojkjaer L, Weitzman R, Bodner J, Bailey S, Phatak PD: Design of an ongoing phase I/II open-label, dose-escalation trial using the oral chelator deferasirox to treat iron overload in HFE-related hereditary hemochromatosis (HH) (abstract). Blood 2007;110:2680.
Pietrangelo A, Brissot P, Bonkovsky H, Niederau C, Rojkjaer L, Weitzman R, Williamson P, Schoenborn-Kellenberger O, Phatak P: A phase I/II, open-label, dose-escalation trial using the once-daily oral chelator deferasirox to treat iron overload in HFE-related hereditary hemochromatosis. J Hepatol 2009, submitted.
Ibrahim AS, Gebermariam T, Fu Y, Lin L, Husseiny MI, French SW, Schwartz J, Skory CD, Edwards JE Jr, Spellberg BJ: The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest 2007;117:2649–2657.
Jastaniah W, Harmatz P, Pakbaz Z, Fischer R, Vichinsky E, Walters MC: Transfusional iron burden and liver toxicity after bone marrow transplantation for acute myelogenous leukemia and hemoglobinopathies. Pediatr Blood Cancer 2008;50:319–324.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.