review
Current approach to iron chelation in children Yesim Aydinok,1 Antonis Kattamis2 and Vip Viprakasit3 1
Department of Paediatric Haematology/Oncology, Ege University Children’s Hospital, Ege University School of Medicine, Izmir, Turkey, 2First Department of Paediatrics, University of Athens School of Medicine, ‘Agia Sofia’ Children’s Hospital, Athens, Greece and 3 Haematology/Oncology Division, Department of Paediatrics & Thalassaemia Centre, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Summary Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusiondependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores’ depletion. Keywords: children, iron, chelation, thalassaemia, sickle. A range of congenital and acquired anaemias and other conditions are associated with iron overload in childhood (Table I). The rate of iron deposition differs according to the source of excess iron (transfusional versus non-transfusional), the underlying condition and the type of iron chelation therapy. While non-transfusional iron loading is slow and mostly becomes clinically evident after the second decade of life, transfusional iron loading is rapid. One hundred millilitres of pure concentrated packed red blood cells (with a haematocrit
Correspondence: Professor Yesim Aydinok, Department of Paediatric Haematology/Oncology, Ege University Children’s Hospital, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey.
of 100%) is estimated to contain 108 mg of iron, which is approximately 35–100 times the daily requirement for iron (Porter, 2001). Consequently, iron overload becomes evident very early in the transfusion history. Transferrin saturation exceeds the normal range after 4–6 transfusions in newly diagnosed patients. Significant and continuous efflux of iron overwhelms the carrying capacity of transferrin, resulting in the generation of harmful iron species, such as non-transferrin bound iron (NTBI) and labile plasma iron (LPI), and deposition of excess iron in tissue, which eventually leads to iron toxicity (Tavazzi et al, 2001; Cighetti et al, 2002). Susceptibility to iron toxicity differs between organs, with the most vulnerable being the endocrine glands, the heart and the liver. In this article, we review the current practices and possible modifications to iron chelation therapy that are relevant to children with iron overload associated with transfusiondependent and non-transfusion-dependent anaemias.
Iron overload and its consequences in childhood From the available data, it is clear that many patients develop cardiac, pancreatic and pituitary iron overload early in their transfusion history, but few actually develop dysfunction. It has been suggested that iron is initially sequestered safely within intracellular compartments and the volume and the function of the target organs is maintained. The observed changes are reversible with proper chelation, without longterm sequelae. In the longer term, cumulative iron toxicity leads to cellular apoptosis and eventual loss of function. At this stage, damage can be, at best, partially reversed. The clinical consequences of iron toxicity have been reported in previous epidemiological studies (Borgna-Pignatti et al, 2004; Voskaridou et al, 2012). Baseline data from large prospective cohort studies demonstrate that children ≥2 years of age with transfusiondependent anaemias may have severe iron burden as estimated by serum ferritin (SF) and liver iron concentration (LIC) (Kattamis et al, 2005; Taher et al, 2009). Non-invasive imaging methods, particularly magnetic resonance imaging (MRI), have provided useful information on the progress of
E-mail: [email protected]
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doi:10.1111/bjh.12825
Review Table I. Congenital and acquired anaemias and specific conditions associated with iron overload in childhood. Congenital Transfusion-dependent thalassaemia (TDT) b-thalassaemia major, transfusion-dependent HbH disease, severe HbE/b thalassaemia Non-transfusion-dependent thalassaemia (NTDT) b-thalassaemia intermedia, deletional and non-deletional HbH disease, HbE/b thalassaemia Sickle cell anaemia Rare anaemia; Diamond Blackfan anaemia, Fanconi anaemia, sideroblastic anaemia, congenital dyserythropoietic anaemia Congenital haemolytic anaemia, e.g. pyruvate kinase deficiency Acquired Acquired aplastic anaemia Pure red cell aplasia Neoplastic diseases and bone marrow transplantation Neuro-degenerative disorders
iron overload in susceptible patients. A recent retrospective survey reported transfusional liver siderosis in patients younger than 35 years. More specifically, the median LIC was found to be 14 (n = 12), 13 (n = 7), 66 (n = 3) and 29 mg Fe/g dry weight (d.w.) (n = 3) in this very young cohort with thalassaemia major (TM), Diamond-Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA) and sickle cell disease (SCD), respectively. Among 125 patients 5 9 upper limit of normal) was observed in 17% of patients, in whom the majority had an elevated alanine transaminase at baseline (El-Beshlawy et al, 2012). Although clinical studies reported nonprogressive increases in serum creatinine, a recent report on a small group of children demonstrated proximal tubular dysfunction and a drop in glomerular filtration, which were reversible upon either discontinuation of DFX or reducing the dose (Dubourg et al, 2012). As a precaution, serum creatinine, proteinuria and liver function should be monitored monthly during DFX treatment. Intensification of DFX chelation for treatment of massively iron loaded TDT patients—Prospective data provided strong evidence that higher doses of DFX >30 mg/kg and up to 40 mg/ kg/d may be required in heavily iron loaded patients with TDT (Taher et al, 2011; Pennell et al, 2012; Porter et al, 2013). A prospective study conducted in heavily iron loaded patients with TM demonstrated less reduction in SF in children (2– 15 years old) than in adults at starting DFX doses of 20 mg/ kg/d with dose escalation up to 30 mg/kg/d (Taher et al, 2009). Longer follow-up from this study confirmed that DFX ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doses >30 mg⁄kg⁄d are necessary to achieve greater decreases in LIC in heavily iron-overloaded patients (Taher et al, 2011). DFX doses of >30 mg/kg/d are also associated with a continuous and significant improvement in myocardial T2* with a significant decrease in baseline LIC over 3 years in patients with severe baseline liver iron and cardiac siderosis aged >10 years (Pennell et al, 2012). Previous reports on DFX demonstrate that liver iron removal is more rapid than cardiac iron removal and the rate of cardiac iron removal is slowest when liver iron loads are high (Wood et al, 2010; Pennell et al, 2012). Combined therapy with DFX and DFO or DFP—Small studies have explored the combination of DFX and DFO or DFP, showing a rapid reduction in systemic and myocardial iron and the potential of a synergistic or additive effect on iron removal (Farmaki et al, 2011; Lal et al, 2013). Recent preliminary data from a prospective randomized 1-year study suggested SF, cardiac T2*, compliance and quality of life were improved in children with TM who received DFP and DFX compared to those who received DFP and DFO (El-Alfy et al, 2013). The first results from a large prospective study show that combined therapy of DFX and DFO resulted in an improvement in cardiac T2* during 12 months of treatment with a considerable decrease in LIC in patients with transfusional severe cardiac and liver iron (Aydinok et al, 2013b). These treatments did not show any significant toxicity or unexpected adverse events.
Managing iron chelation in children with nontransfusion-dependent thalassaemia b-thalassaemia intermedia Several studies have shown that patients with b-thalassaemia intermedia (b-TI), who receive fewer or no blood transfusions, are at risk of complications due to chronic anaemia, ineffective erythropoiesis and on-going haemolysis. Iron overload is an important risk factor for some of these complications (Musallam et al, 2011). Clinical experiences in b-TI represent a prototype for other types of thalassaemia that are now classified as nontransfusion-dependent thalassaemia (NTDT). Three major thalassaemia syndromes are at present included into this category: b-TI, HbE/b thalassemia and HbH disease. The evaluation of iron overload in NTDT patients is problematic as SF underestimates the degree of tissue iron overload, in particular LIC (Taher et al, 2013a). One recent recommendation is to start iron chelation when SF ≥800 lg/l and/or LIC ≥5 mg/g d.w. Chelation therapy should be discontinued when the level of SF ≤300 lg/l and/or LIC ≤3 mg/ g d.w. (Taher et al, 2013b). DFO and DFX (10–20 mg/kg/d) are currently licensed for iron chelation therapy in NTDT. With the exception of growth retardation and post-splenectomy complications, such as overwhelming infections and 5
Review thrombocytosis, other NTDT-related complications infrequently develop in childhood. The efficacy of iron chelation, as determined by SF and LIC in NTDT patients, in the treatment of patients
Current approach to iron chelation in children Yesim Aydinok,1 Antonis Kattamis2 and Vip Viprakasit3 1
Department of Paediatric Haematology/Oncology, Ege University Children’s Hospital, Ege University School of Medicine, Izmir, Turkey, 2First Department of Paediatrics, University of Athens School of Medicine, ‘Agia Sofia’ Children’s Hospital, Athens, Greece and 3 Haematology/Oncology Division, Department of Paediatrics & Thalassaemia Centre, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Summary Transfusion-dependent children, mostly with thalassaemia major, but also and occasionally to a more significant degree, with inherited bone marrow failures, can develop severe iron overload in early life. Moreover, chronic conditions associated with ineffective erythropoiesis, such as non-transfusiondependent thalassaemia (NTDT), may lead to iron overload through increased gut absorption of iron starting in childhood. Currently, the goal of iron chelation has shifted from treating iron overload to preventing iron accumulation and iron-induced end-organ complications, in order to achieve a normal pattern of complication-free survival and of quality of life. New chelation options increase the likelihood of achieving these goals. Timely initiation, close monitoring and continuous adjustment are the cornerstones of optimal chelation therapy in children, who have a higher transfusional requirements compared to adults in order to reach haemoglobin levels adequate for normal growth and development. Despite increased knowledge, there are still uncertainties about the level of body iron at which iron chelation therapy should be started and about the appropriate degree of iron stores’ depletion. Keywords: children, iron, chelation, thalassaemia, sickle. A range of congenital and acquired anaemias and other conditions are associated with iron overload in childhood (Table I). The rate of iron deposition differs according to the source of excess iron (transfusional versus non-transfusional), the underlying condition and the type of iron chelation therapy. While non-transfusional iron loading is slow and mostly becomes clinically evident after the second decade of life, transfusional iron loading is rapid. One hundred millilitres of pure concentrated packed red blood cells (with a haematocrit
Correspondence: Professor Yesim Aydinok, Department of Paediatric Haematology/Oncology, Ege University Children’s Hospital, Ege University School of Medicine, 35100 Bornova, Izmir, Turkey.
of 100%) is estimated to contain 108 mg of iron, which is approximately 35–100 times the daily requirement for iron (Porter, 2001). Consequently, iron overload becomes evident very early in the transfusion history. Transferrin saturation exceeds the normal range after 4–6 transfusions in newly diagnosed patients. Significant and continuous efflux of iron overwhelms the carrying capacity of transferrin, resulting in the generation of harmful iron species, such as non-transferrin bound iron (NTBI) and labile plasma iron (LPI), and deposition of excess iron in tissue, which eventually leads to iron toxicity (Tavazzi et al, 2001; Cighetti et al, 2002). Susceptibility to iron toxicity differs between organs, with the most vulnerable being the endocrine glands, the heart and the liver. In this article, we review the current practices and possible modifications to iron chelation therapy that are relevant to children with iron overload associated with transfusiondependent and non-transfusion-dependent anaemias.
Iron overload and its consequences in childhood From the available data, it is clear that many patients develop cardiac, pancreatic and pituitary iron overload early in their transfusion history, but few actually develop dysfunction. It has been suggested that iron is initially sequestered safely within intracellular compartments and the volume and the function of the target organs is maintained. The observed changes are reversible with proper chelation, without longterm sequelae. In the longer term, cumulative iron toxicity leads to cellular apoptosis and eventual loss of function. At this stage, damage can be, at best, partially reversed. The clinical consequences of iron toxicity have been reported in previous epidemiological studies (Borgna-Pignatti et al, 2004; Voskaridou et al, 2012). Baseline data from large prospective cohort studies demonstrate that children ≥2 years of age with transfusiondependent anaemias may have severe iron burden as estimated by serum ferritin (SF) and liver iron concentration (LIC) (Kattamis et al, 2005; Taher et al, 2009). Non-invasive imaging methods, particularly magnetic resonance imaging (MRI), have provided useful information on the progress of
E-mail: [email protected]
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doi:10.1111/bjh.12825
Review Table I. Congenital and acquired anaemias and specific conditions associated with iron overload in childhood. Congenital Transfusion-dependent thalassaemia (TDT) b-thalassaemia major, transfusion-dependent HbH disease, severe HbE/b thalassaemia Non-transfusion-dependent thalassaemia (NTDT) b-thalassaemia intermedia, deletional and non-deletional HbH disease, HbE/b thalassaemia Sickle cell anaemia Rare anaemia; Diamond Blackfan anaemia, Fanconi anaemia, sideroblastic anaemia, congenital dyserythropoietic anaemia Congenital haemolytic anaemia, e.g. pyruvate kinase deficiency Acquired Acquired aplastic anaemia Pure red cell aplasia Neoplastic diseases and bone marrow transplantation Neuro-degenerative disorders
iron overload in susceptible patients. A recent retrospective survey reported transfusional liver siderosis in patients younger than 35 years. More specifically, the median LIC was found to be 14 (n = 12), 13 (n = 7), 66 (n = 3) and 29 mg Fe/g dry weight (d.w.) (n = 3) in this very young cohort with thalassaemia major (TM), Diamond-Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA) and sickle cell disease (SCD), respectively. Among 125 patients 5 9 upper limit of normal) was observed in 17% of patients, in whom the majority had an elevated alanine transaminase at baseline (El-Beshlawy et al, 2012). Although clinical studies reported nonprogressive increases in serum creatinine, a recent report on a small group of children demonstrated proximal tubular dysfunction and a drop in glomerular filtration, which were reversible upon either discontinuation of DFX or reducing the dose (Dubourg et al, 2012). As a precaution, serum creatinine, proteinuria and liver function should be monitored monthly during DFX treatment. Intensification of DFX chelation for treatment of massively iron loaded TDT patients—Prospective data provided strong evidence that higher doses of DFX >30 mg/kg and up to 40 mg/ kg/d may be required in heavily iron loaded patients with TDT (Taher et al, 2011; Pennell et al, 2012; Porter et al, 2013). A prospective study conducted in heavily iron loaded patients with TM demonstrated less reduction in SF in children (2– 15 years old) than in adults at starting DFX doses of 20 mg/ kg/d with dose escalation up to 30 mg/kg/d (Taher et al, 2009). Longer follow-up from this study confirmed that DFX ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
doses >30 mg⁄kg⁄d are necessary to achieve greater decreases in LIC in heavily iron-overloaded patients (Taher et al, 2011). DFX doses of >30 mg/kg/d are also associated with a continuous and significant improvement in myocardial T2* with a significant decrease in baseline LIC over 3 years in patients with severe baseline liver iron and cardiac siderosis aged >10 years (Pennell et al, 2012). Previous reports on DFX demonstrate that liver iron removal is more rapid than cardiac iron removal and the rate of cardiac iron removal is slowest when liver iron loads are high (Wood et al, 2010; Pennell et al, 2012). Combined therapy with DFX and DFO or DFP—Small studies have explored the combination of DFX and DFO or DFP, showing a rapid reduction in systemic and myocardial iron and the potential of a synergistic or additive effect on iron removal (Farmaki et al, 2011; Lal et al, 2013). Recent preliminary data from a prospective randomized 1-year study suggested SF, cardiac T2*, compliance and quality of life were improved in children with TM who received DFP and DFX compared to those who received DFP and DFO (El-Alfy et al, 2013). The first results from a large prospective study show that combined therapy of DFX and DFO resulted in an improvement in cardiac T2* during 12 months of treatment with a considerable decrease in LIC in patients with transfusional severe cardiac and liver iron (Aydinok et al, 2013b). These treatments did not show any significant toxicity or unexpected adverse events.
Managing iron chelation in children with nontransfusion-dependent thalassaemia b-thalassaemia intermedia Several studies have shown that patients with b-thalassaemia intermedia (b-TI), who receive fewer or no blood transfusions, are at risk of complications due to chronic anaemia, ineffective erythropoiesis and on-going haemolysis. Iron overload is an important risk factor for some of these complications (Musallam et al, 2011). Clinical experiences in b-TI represent a prototype for other types of thalassaemia that are now classified as nontransfusion-dependent thalassaemia (NTDT). Three major thalassaemia syndromes are at present included into this category: b-TI, HbE/b thalassemia and HbH disease. The evaluation of iron overload in NTDT patients is problematic as SF underestimates the degree of tissue iron overload, in particular LIC (Taher et al, 2013a). One recent recommendation is to start iron chelation when SF ≥800 lg/l and/or LIC ≥5 mg/g d.w. Chelation therapy should be discontinued when the level of SF ≤300 lg/l and/or LIC ≤3 mg/ g d.w. (Taher et al, 2013b). DFO and DFX (10–20 mg/kg/d) are currently licensed for iron chelation therapy in NTDT. With the exception of growth retardation and post-splenectomy complications, such as overwhelming infections and 5
Review thrombocytosis, other NTDT-related complications infrequently develop in childhood. The efficacy of iron chelation, as determined by SF and LIC in NTDT patients, in the treatment of patients
