Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. 1253-1256 (doi:10.1542/peds.2007-1824)
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COMMENTARY

Oral Iron Chelators and the Treatment of Iron Overload in Pediatric Patients With Chronic Anemia

Elliott Vichinsky, MD

Hematology/Oncology Department, Children's Hospital and Research Center, Oakland, California

Abbreviations: SCD, sickle cell disease • RBC, red blood cell • NTBI, non–transferrin-bound iron

Transfusion-dependent hemoglobinopathies, such as thalassemia and sickle cell disease (SCD), represent a major global health burden, with >300000 infants born with SCD or thalassemia annually. Approximately 5% of the world's population are carriers of a potentially pathologic hemoglobin gene.1 In the United States, sickle cell anemia is the most common type of SCD, with a birth prevalence in black individuals of 1 in 375, whereas that of hemoglobin SC disease is 1 in 835, hemoglobin S/β-thalassemia is 1 in 1667, and sickle cell trait is 1 in 12.2


   MANAGEMENT OF ANEMIAS
TOP
 MANAGEMENT OF ANEMIAS
IRON CHELATION THERAPY FOR...
 CONCLUSIONS
 REFERENCES
 
Along with treatment of the underlying disease, chronic anemias are commonly managed by supportive therapy with red blood cell (RBC) transfusions.3,4 Although this is a routine approach in the treatment of thalassemia, transfusions have been less common for patients with other anemias. Recent data, however, have further demonstrated the value of regular transfusions for children with SCD, significantly reducing the risk for primary and secondary stroke, total hospitalizations, vaso-occlusive events, acute chest syndrome, and growth failure.5–7 These data have had a significant impact on clinical practice, prompting widespread recommendations for transcranial Doppler screening in children and transfusion therapy for all high-risk patients.

Although the value of RBC transfusions for patients who undergo regular transfusions is increasingly recognized, this approach presents an additional clinical challenge: that of iron overload. Each unit of RBCs contains 200 to 250 mg of iron, and repeated transfusions can rapidly saturate a patient's transferrin; iron overload then develops after 10 to 20 transfusions.8 The accumulation of excess iron leads to the formation of non–transferrin-bound iron (NTBI). This is a toxic component of free (unbound) iron and is associated with progressive organ damage, including liver and heart disease9; children as young as 15 years can develop heart failure.10 In pediatric patients, iron accumulation in the anterior pituitary gland produces a wide variety of systemic endocrine disturbances, leading to delayed sexual maturation and growth failure.11

Body iron burden can be assessed by using a variety of measurements, such as serum ferritin levels and liver iron concentration by liver biopsies.12,13 Ferritin levels may not reliably indicate total body iron stores. This may impair the physician from determining the optimal iron chelator dosage. Iron chelation therapy is increasingly being monitored by noninvasive techniques such as superconducting quantum interference device and modified MRI.14–17 Threshold values have been established for each of these techniques.15,18 The use of a superconducting quantum interference device and MRI has resulted in better management of iron-overload therapy. Prompt removal of excess iron by using iron chelation therapy is essential for maintaining safe levels of body iron stores, to limit the exposure of patients to harmful NTBI, and to decrease or prevent the long-term clinical sequelae of iron overload.9


   IRON CHELATION THERAPY FOR PEDIATRIC PATIENTS
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 MANAGEMENT OF ANEMIAS
 IRON CHELATION THERAPY FOR...
CONCLUSIONS
 REFERENCES
 
The iron chelator deferoxamine (Desferal [DFO, Novartis Pharma AG, Basel, Switzerland]) has had a dramatic effect on long-term survival and morbidity of thalassemia patients. It has established an excellent safety and efficacy profile for pediatric patients through several decades of clinical use.19–21 Recent evidence indicated that continuous deferoxamine infusions may reverse iron-induced heart failure.22 Deferoxamine, however, has poor oral bioavailability and a short half-life, necessitating administration as an 8- to 12-hour overnight subcutaneous infusion 5 to 7 days per week or as a 24-hour intravenous infusion.23 Such regimens are extremely burdensome and often lead to poor compliance, particularly in adolescent patients. Those who do not comply with their treatment are usually undergo chelation inadequately, which has a significant impact on survival. This is especially a concern for iron-overloaded pediatric patients because most will require lifelong chelation therapy.23,24

The availability of oral iron chelation therapy can relieve patients from the burden of deferoxamine infusions. In 1999, deferiprone (Ferriprox [Apotex Inc, Toronto, ON, Canada]), a 3-times-daily oral chelating agent, became licensed in Europe and other regions for the treatment of iron overload. Deferiprone is not licensed in the United States or Canada and is available only on a compassionate-use basis. Deferiprone reduces or maintains total body iron stores in the majority of patients25; however, total iron excretion with deferiprone is less than with deferoxamine.26 Studies suggest that deferiprone is more effective than deferoxamine in chelating cardiac iron.27–29 In an attempt to improve control of NTBI levels, clinical trials of combined deferoxamine and deferiprone therapy have been conducted.30–33 In combination with deferoxamine, deferiprone may decrease the risk for cardiac disease and improve cardiac function.33 A National Institutes of Health prospective, randomized trial comparing continuous deferoxamine and deferiprone with continuous deferoxamine alone in patients with cardiomyopathy is ongoing.

The major adverse effects of deferiprone include gastrointestinal symptoms, joint pain, liver dysfunction, neutropenia, and agranulocytosis.25,34,35 Although safety in young pediatric patients (<6 years old) has not been extensively evaluated, results seem similar to the drug's overall safety profile. Naithani et al36 reported on the safety of deferiprone in 44 children with thalassemia major. The most common adverse events after deferiprone treatment in these patients were gastrointestinal (27% of patients), joint symptoms (9%), and neutropenia (4%). There were no cases of agranulocytosis after a median duration of treatment of 13 months36; however, agranulocytosis-associated deaths have occurred in pediatric patients.37 Because of the risk for agranulocytosis and associated rare deaths, weekly assessment of white blood cell counts is recommended for all patients who receive deferiprone.38

More recently, the oral iron chelator deferasirox (Exjade, ICL670 [Novartis Pharma AG, Basel, Switzerland]) has been approved for the treatment of iron overload in children and adults in several countries, including the United States, where it received orphan drug designation and was granted priority review status. Good bioavailability and a long half-life of 11 to 19 hours mean that deferasirox is suitable for once-daily dosing, which may overcome the compliance problems associated with deferoxamine.39 Clinical trials have established the efficacy and safety of deferasirox in a range of transfusion-dependent patients, including a large proportion of pediatric patients (42% of the total patients enrolled in the program).40–43 During a period of 2.5 years, these trials have demonstrated that deferasirox effectively reduced liver iron concentration and serum ferritin levels in pediatric, as well as adult, patients in a dosage-dependent manner.44 Deferasirox dosing recommendations are the same for pediatric and adult patients, taking into account changes in weight over time. A starting dosage of 20 mg/kg body weight is recommended.45 After commencing therapy, serum ferritin should be monitored monthly and, if required, the dosage of deferasirox adjusted in steps of 5 or 10 mg/kg every 3 to 6 months on the basis of serum ferritin trends. The dosage can tailored to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). Dosages of deferasirox should not exceed 30 mg/kg per day because there has been limited experience with dosages above this level.

Results from pharmacokinetic studies in pediatric patients (aged 2–17 years) were similar to those for older patients.46 The trials also showed that once-daily deferasirox controls labile plasma iron, a component of NTBI, during a 24-hour period. This is important because control of NTBI prevents potential damage to cells, tissues, and ultimately organs.47 In vitro and animal studies indicated that deferasirox enters cardiac tissue and removes cardiac iron.48 The efficacy of deferasirox in removing cardiac iron, in clinical studies, is limited compared with the data supporting deferiprone.49,50

The safety profile of deferasirox in pediatric patients is similar to that in adults.44 The most common drug-related adverse events were mild, transient diarrhea and vomiting (4.4%), abdominal pain and nausea (3.9%), and mild/moderate skin rash (5.5%). In general, gastrointestinal events after deferasirox therapy resolved spontaneously without the need for dosage adjustment or discontinuation of treatment; however, ~0.5% of patients needed to discontinue deferasirox treatment because of severe gastrointestinal symptoms. For patients who interrupt therapy because of severe diarrhea, deferasirox can be reinitiated at 10 mg/kg per day once the diarrhea has cleared and the dosage gradually escalated by 5 mg/kg each week until the full target dosage is reached. For adults, mild, nonprogressive increases in serum creatinine >33% above baseline were noted in 38% of deferasirox-treated patients40; however, in pediatric patients, increases in serum creatinine >33% above baseline and greater than the upper limit of normal at 2 consecutive visits were observed in a small percentage of pediatric patients (4.2%) and mostly resolved spontaneously. The rest were generally manageable with dosage reduction/interruption. The results of a randomized comparison of deferasirox with deferoxamine in pediatric and adult patients with SCD found no increased risk for renal damage.42 In that 1-year study, similar percentages of transient increases in creatinine above the upper limit of normal were observed (2.3% and 3.2%, respectively). The long-term safety of deferasirox in SCD is being studied. Patient creatinine levels should be monitored monthly. Physical and sexual development after deferasirox treatment was assessed by growth velocity and Tanner stage for pediatric patients with β-thalassemia, myelodysplastic syndromes, SCD, and rare anemias. These studies showed that physical and sexual development proceeded normally for all pediatric patients.44

During the postapproval use of deferasirox, there have been voluntary reports of cytopenia, including agranulocytosis, neutropenia, and thrombocytopenia. These reports are from a population of uncertain size, many of whom have preexisting hematologic disorders and who may be receiving concomitant medication; therefore, reliably estimating the frequency or establishing a causal relationship to deferasirox is difficult. Furthermore, cases of acute renal failure as a result of severe complications of the underlying disease have been reported.45

Because iron chelation may be required for many years or as long as the patient lives, the long-term safety of therapy is very important. In this regard, the use of deferoxamine, with a safety and efficacy profile in pediatrics garnered over several decades of clinical use, should be considered for patients who want to remain on this therapy; however, for patients with thalassemia, compliance with long-term chelation is the most important prognostic factor survival.51 Once-daily oral therapy would be expected to improve patient satisfaction and compliance with therapy. Satisfaction studies of patients with SCD and thalassemia demonstrate that deferasirox therapy is superior to deferoxamine. Eighty percent of patients with SCD and 93% of those with thalassemia found deferasirox more convenient than deferoxamine, and similar findings were observed in satisfaction scores.39,52


   CONCLUSIONS
TOP
 MANAGEMENT OF ANEMIAS
 IRON CHELATION THERAPY FOR...
 CONCLUSIONS
REFERENCES
 
Iron overload is an inevitable clinical consequence for patients with transfusion-dependent anemias. Iron chelation therapy is, therefore, an important and integral part of their supportive care. Pediatric patients who are not adequately chelated risk delayed sexual maturation, retarded growth, progressive liver and heart disease, and a reduced life expectancy. To date, the reference-standard iron chelator has been deferoxamine, but the demanding regimen of regular and prolonged infusions presents a significant challenge, particularly for pediatric patients. Recent advances have led to the development of the oral chelators deferiprone and deferasirox. The potential for deferiprone to decrease cardiac disease is important. Its benefit outweighs the risk for neutropenia for many patients. Oral chelators, such as deferasirox and deferiprone, signify a notable change in clinical practice, presenting the option of a convenient oral therapy to adults and children with a range of chronic anemias.


   FOOTNOTES
 
Accepted Oct 3, 2007.

Address correspondence to Elliott Vichinsky, MD, Children's Hospital and Research Center, Hematology/Oncology Department, 747 52nd St, Oakland, CA 94609. E-mail: evichinsky{at}mail.cho.org

Financial Disclosure: Dr Vichinsky is a scientific investigator and advisor for Novartis.

Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.


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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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