Iron overload in thalassaemia intermedia: reassessment of iron chelation strategies
Ali Taher,1 Chaim Hershko2 and Maria Domenica Cappellini3 ` American University of Beirut, Beirut, Lebanon, 2Hebrew University of Jerusalem, Jerusalem, Israel, and 3Universita di Milano, Policlinico Foundation IRCCS, Milan, Italy

Thalassaemia intermedia (TI) is a syndrome marked by its diverse underlying genetic basis although its pathophysiology remains unclear, particularly regarding the nature of iron loading and toxicity. It is, however, evident that there are key differences from the extensively studied thalassaemia major (TM) population and caution is required when assessing iron load based on serum ferritin values, as this approach is known to underestimate the true extent of iron loading in patients with TI. Although effective iron chelation therapy has been available for many years, studies in TI-specific populations are rare and evidence suggests that management of iron levels may be less rigorous than in patients with TM and other chronic anaemias. Better understanding of the need to assess and treat iron overload in both transfused and non-transfused TI patients is clearly required. Keywords: thalassaemia intermedia, iron overload, iron chelation. Thalassaemia intermedia (TI) is a syndrome marked by its diverse underlying genetic basis, associated with anaemia and a range of specific complications including extramedullary haematopoiesis, leg ulcers, gallstones, a hypercoagulable state and pulmonary hypertension (PHT), all of which are uncommon in adequately treated thalassaemia major (TM) patients (Taher et al, 2006; Cappellini et al, 2008). The clinical manifestations of TI in beta- and beta-thalassaemia/haemoglobin E patients result from three key factors: ineffective erythropoiesis, chronic anaemia and iron overload. Despite this knowledge, the need to effectively manage iron overloadrelated complications in patients with TI is often overlooked. TI is largely regarded as a clinical entity with limited complications and the prevailing approach has been avoidance of early blood transfusions and the associated need for

chelation therapy. Consequently, unlike TM, progress in the management of TI, and prevention of its late complications, has been unimpressive. Detailed documentation of the late complications of TI has revealed serious age-related cardiac problems that are mainly attributed to PHT caused by a longterm, high-output state and hypercoagulability (Aessopos et al, 2007a). These life-threatening complications are observed with increasing frequency in untreated TI patients and suggest that earlier intervention aimed at preventing chronic anaemia may benefit TI patients by avoiding the late and irreversible anaemia-related complications (Aessopos et al, 2007b). Although earlier introduction of blood transfusions will increase the rate of iron accumulation, effective methods of iron chelation are now available, and the benefits of transfusion therapy would greatly outweigh the cost and inconvenience of iron chelation therapy. Here, we discuss current attitudes to the use of blood transfusions and iron chelation in TI and suggest modifications to current practise aimed at improving the management of this unique syndrome.

Understanding iron accumulation in thalassaemia intermedia
Iron is an essential element for the functioning of a great number of proteins participating in vital redox reactions controlling energy production, mitochondrial respiration and DNA synthesis (Andrews, 2008). Throughout evolution, effective mechanisms have been developed to ensure unimpeded iron supply, facilitating iron transport and accumulation. The master regulator of iron balance in humans is hepcidin, a peptide produced by the liver (Nemeth et al, 2004). Increased production of hepcidin in response to excessive iron or inflammation prevents the absorption of intestinal iron and blocks the recycling of catabolic iron from the reticuloendothelial (RE) system. Conversely, in iron deficiency, hepcidin production is inhibited resulting in increased intestinal iron absorption and increased release of RE iron. Likewise, in hereditary haemochromatosis, mutations interfering with hepcidin regulation result in an inability to inhibit iron absorption leading to abnormal iron accumulation throughout life.

Correspondence: Ali Taher, MD, Department of Internal Medicine, Haematology-Oncology Division, American University of Beirut, Medical Centre, PO Box 11-0236, Beirut 1107 2020, Lebanon. E-mail: First published online 13 August 2009 doi:10.1111/j.1365-2141.2009.07848.x

ª 2009 Blackwell Publishing Ltd, British Journal of Haematology, 147, 634–640

most TI patients are likely to receive transfusions at some point in their lives to control symptoms and. However. 2007). 2008. However. resulting in high serum ferritin levels (Pakbaz et al. Magnetic resonance imaging (MRI) of untransfused or minimally transfused TI patients has shown that iron accumulation occurs primarily in the liver. it remains evident that many patients with TI do not receive regular transfusion therapy due to inconvenience and the perceived complications of iron overload requiring iron chelation therapy. 2008). Although specific data are limited. a study of patients with TI has shown that 5Æ4% had congestive heart failure. hepcidin production (Jenkins et al. 1990. Therefore. while heart failure as a result of iron overload is the most common cause of death in patients with TM. Taher et al. reflecting increased iron accumulation over time. 2007). and under maximal stimulation iron absorption may reach 3 or 4 mg/d. 1998. This dysregulation is caused by two newly described inhibitors of hepcidin production: growth differentiation factor 15 (GDF15). further research is required to offer firm explanations for the anomalous iron regulation observed in patients with TI. transfused blood contains 200 mg of iron per unit and. Although these hypotheses are based on recent advances in bioiron research. which predisposes to the development of fibrosis and cirrhosis. Pakbaz et al. many TI patients will become transfusion-dependent. Despite this understanding. Silvestri et al. By contrast. ultimately. secreted by erythroid precursors that are greatly expanded in thalassaemia (Tanno et al. 634–640 . likely that cardiac iron deposition will occur. In addition. may result in an annual accumulation of 5000)10 000 mg of iron. Aessopos et al. transfusion therapy will suppress ineffective erythropoiesis and the associated increase in GDF15. even in the absence of transfusion therapy (Buonanno et al. 2007). basic iron regulatory mechanisms remain intact. 2008). blood transfusions modify hepcidin production by altering all three factors responsible for the clinical manifestations of thalassaemia described above. There is. However. The situation in TI is similar to that seen in patients with hereditary haemochromatosis syndromes. By contrast. Valore & Ganz. (ii) by correcting anaemia. 2007). an important cause of secondary right heart failure (Aessopos 635 The impact of blood transfusion therapy Under normal conditions. With advancing age and increasing use of transfusion therapy it is. contributing to the serious clinical sequelae associated with iron overload. 34Æ5% had chronic pericardial changes. This results in depletion of macrophage iron. mobilising iron through hepcidin suppression by soluble hemojuvelin and supporting erythrocyte production in response to anaemia/ hypoxia (Peyssonnaux et al. it is nonetheless an ongoing process that requires regular assessment and management. amounting to an annual iron accumulation of approximately 1000 mg. HIF-1 alpha plays a useful role. patients with TI accumulate iron primarily due to increased intestinal iron absorption (Origa et al. The accumulation of iron in TI patients has been shown to be age related. while iron overload in cardiac tissue is generally absent (Origa et al. The combination of ineffective erythropoiesis (leading to increased GDF15) and chronic anaemia/hypoxia (altering the expression of HIF) results in hepcidin suppression. 147. British Journal of Haematology. leading to increased iron absorption and increased release of recycled iron from the RE system. 2007). In TM and TI. which is characterised by impaired hepcidin production. intestinal iron absorption is approximately 1 mg/d. and hypoxiainducible transcription factors (HIFs) that control iron homeostasis by downregulating hepcidin production in response to chronic anaemia/hypoxia. stimulating ferritin synthesis and its release to the circulation. in patients receiving 2)4 units of blood per month. The result will be a relative increase in hepcidin production in polytransfused TM patients countering the hepcidin-inhibitory effects of anaemia and ineffective erythropoiesis. in whom iron loading occurs mainly as a result of transfusion therapy. The degree of anaemia present in patients with TI may be mild and may not require transfusion therapy until later in life. 2007. 1984. Under normal conditions.Review In contrast to patients with TM. Complications of TI that may be related to iron loading Although the accumulation of iron in patients with TI is slower than that seen in regularly transfused patients with TM. These considerations may explain the differences in iron homeostasis characterising polytransfused TM compared with untransfused TI patients (Fig 1). 2007b). 2008). particularly in patients with more severe forms of TI (Mohamed & Jackson. more than 50% had valvular problems and 59Æ1% had signs of PHT. and may explain the relatively low levels of serum ferritin encountered in TI and underestimation of the severity of tissue siderosis. blood transfusions will prevent the hypoxia responsible for increased HIF production and hypoxia-associated suppression of hepcidin and (iii) increased body iron and transferrin saturation will stimulate ª 2009 Blackwell Publishing Ltd. in transfused TM patients. The decision to initiate transfusions is generally based on the presence of clinically relevant symptoms of anaemia and their cumulative effect on the patients’ normal life activities. however. cardiac problems due to myocardial siderosis are less apparent in patients with TI (Aessopos et al. with some studies showing no such correlation (Fiorelli et al. increasing awareness that the earlier initiation of regular transfusion therapy in patients with TI may improve quality of life. 2007a). however. the chronic anaemia and ineffective erythropoiesis associated with the thalassaemia syndromes result in abnormal iron regulation. iron is preferentially distributed to the RE system. namely: (i) by correcting anaemia. this has not been a consistent observation.

1995). 2008). P < 0Æ001) (Pakbaz et al. Wood. is the product of severe iron overload and is a marker of increased risk of siderotic myocardial disease in TM. Biomagnetic liver susceptometry. non-transferrin-bound iron (NTBI. Assessing iron levels in patients with thalassaemia intermedia The principal methods of determining body iron levels are measurement of serum ferritin and assessment of liver iron concentration (LIC) from biopsy material. the relationship between LIC and serum ferritin has been shown to lack significance in splenectomised patients with TI (Origa et al. Iron equilibrium under normal conditions and in thalassaemia. 2005). A possible explanation (C) et al. Taher et al. 147. 2005. (A) Normal conditions: Iron for baseline metabolic requirements (20– 30 mg daily) is largely derived from recycling of senescent red blood cells by the reticuloendothelial (RE) system. 636 ª 2009 Blackwell Publishing Ltd. it may be argued that because both PHT and iron overload in TI are age related. 2007). there is little doubt that the assessment of serum ferritin is likely to underestimate iron load in patients with TI. 2007). but is also significantly correlated with iron overload (Isma’eel et al. 1993. Pakbaz et al. (C) Thalassaemia major: The main difference distinguishing TM from TI is the added burden of blood transfusions. 2007. 2008) and others showing no notable correlation (Origa et al. A significant correlation between serum ferritin and LIC has been established in regularly transfused patients with TM (r = 0Æ73)0Æ76. such statistical correlation should not be regarded as evidence of a causeand-effect relationship. British Journal of Haematology. Studies of patients with TI have consistently shown serum ferritin levels to be significantly lower than in those with TM despite comparable levels of liver iron (Origa et al. with some studies demonstrating a statistically significant correlation (r = 0Æ64)0Æ83. heart and endocrine organs. This will moderate intestinal hyper-absorption but accelerate the rate of iron accumulation in the liver. (B) Thalassaemia intermedia: Ineffective erythropoiesis results in increased iron recycling through the RE system and increased intestinal absorption. Indeed. or SQUID (superconducting quantum interference device). Iron absorption is largely balanced by iron loss through cell sloughing and microscopic blood loss. 2005. When hepatic iron concentrations exceed a critical threshold and serum iron exceeds transferrin binding capacity. PHT is not only a consequence of the chronic hypoxic damage that progresses with age. 2009). 2001). PHT is present in 23–60% of TI patients but rarely evident in well-treated TM patients (Aessopos et al. 2007. 2008). is an elegant non-invasive method for measuring LIC but is available only at a limited number of centres worldwide (Fischer et al. Non-invasive approaches to determine LIC are increasingly used as an alternative to biopsy. 2001. and R2· (MRI) is a validated and standardised method that is now widely available (St Pierre et al. Only 1 mg is derived from absorption. P < 0Æ005) (Brittenham et al. toxic plasma iron compartment. Conversely. indicated by brown arrows) emerges as an additional. Taher et al. a complication that is relatively rare in TI. Non-transferrin bound iron (NTBI) or its labile plasma iron (LPI) component. While the degree of LIC/serum ferritin correlation remains debatable. 2007. Absorbed iron is filtered through the liver where a significant fraction is retained. 2007). Olivieri et al. 634–640 . in patients with TI the correlation between serum ferritin and LIC has proved equivocal. It is gaining increased recognition as a tool for identifying patients at risk of cardiac complications (Piga et al. Saturation of the liver and the emergence of NTBI result in severe cardiac siderosis. but other recent data demonstrated a positive correlation in this patient group (r = 0Æ62.Review (A) (B) Fig 1. Iron bound to transferrin is indicated by green arrows. 2008). P < 0Æ001) (Taher et al. However. 2007a). In addition.

will ultimately result in serious clinical sequelae. rash. 634–640 637 . serum ferritin levels are high. it may be expected that achieving a negative iron balance in thalassaemia intermedia will be relatively simple. several studies of TI populations have shown LIC levels above the threshold believed to be associated with increased risk of morbidity and mortality (Origa et al. Compound Molecular weight (Daltons) Chelating properties Recommended dose mg/kg/d Delivery Half-life Excretion Adverse effects DFO 657 Hexadentate 30–50 s. once daily 12–16 h Faecal Gastrointestinal upset. accompanied by substantial iron excretion despite modest serum ferritin levels (Cossu et al. Published literature includes a case report (Olivieri et al. deferiprone was studied in nine intermittently transfused TI patients. However. in patients with TI are also limited. Although the TM patient population has formed the basis of clinical evaluation of all iron-chelating agents. decreased hepcidin production allows rapid recycling of RE iron and lower ferritin production. impacting on quality of life and compliance (Treadwell & Weissman. Observations during the study indicated that patients may have positive iron balance from the age of 5 years. and our knowledge and understanding of the efficacy and application of DFO relies mainly on the extensive experience gained from studies of the TM population.c. there is general agreement regarding the need for iron chelation therapy subsequent to the initiation of blood transfusion therapy. in patients with TM. physiological differences between patients with TM and TI warrant specific investigations in order to improve our understanding of this population. Cappellini. In one 6-month study of 10 transfusion-independent patients. Despite the availability of effective iron chelation therapy. prolonged subcutaneous therapy with DFO is a key consideration. Each one has its benefits and limitations but it is likely that the use of one of the orally effective iron chelators would be optimal for TI. with or without transfusion therapy. reflecting the differing distribution of iron in the two patient groups. 1981). it is apparent that in the absence of clear guidelines iron overload may not be Table I. In these patients. Data reporting the use of the first oral iron chelator. growth retardation. which was not widely available at the time of the study (Pippard & Weatherall. allergy Deferiprone 139 Bidentate 75–100 Oral 3 times daily 3–4 h Urinary Gastrointestinal upset. 2007). arhtralgia. demonstrating significant reductions in mean serum Iron chelation therapy In the absence of a physiological mechanism for actively excreting excess iron. A second small study investigated DFO in patients with TI. 2007. 2003). anaemia in most cases precludes the use of phlebotomy. and the authors recommended that iron chelation therapy be initiated in patients over this age to prevent ongoing accumulation. auditory toxicity. but despite demonstrating efficacy. British Journal of Haematology. a concept that is increasingly recognised as a key element of effective iron chelation therapy today. guided by serum ferritin and DFO-induced excretion. 8–12 h 5 d/week 20–30 min Urinary and faecal Ocular. As the ability of a chelator to achieve a negative iron balance is closely correlated with the intensity of transfusion therapy. Table I describes the three leading iron chelators currently available for use in thalassaemic patients. local reactions. ocular. whereby iron in transfused patients with TM is preferentially distributed to the RE system. Therefore. providing some useful insights. agranulocytosis/neutropenia Deferasirox 373 Tridentate 20–40 Oral. stimulating ferritin synthesis and its release to the circulation (Pakbaz et al. 2001. the authors’ conclusions focused on the need for oral iron chelation therapy. 2005). reflecting not only hepatic siderosis but also considerable RE iron deposition as a result of long-term blood transfusions (Pakbaz et al. The authors consequently noted that serum ferritin levels were of no value in predicting iron excretion. auditory toxicity.Review for this observation is the situation discussed above. Although data are limited. or i. but it is evident that effective management of iron overload is still required. deferiprone. 1988). They also concluded that treatment should be tailored to individual patients. deferoxamine (DFO) in patients with TI are limited. The practical limitations and inconvenience of frequent. a significant decline in serum ferritin levels was seen. RE iron deposition and serum ferritin levels are relatively low. 2008). Taher et al. There are currently no clear guidelines for the management of iron overload in patients with TI.v. In the clinical trial. Data on the use of the current reference standard ironchelating agent. By contrast in TI. 147. Small studies of DFO in patients with TI have been performed. 1992) and a small clinical trial that demonstrate effective management of iron levels (Pootrakul et al. mild reversible increase in creatinine ª 2009 Blackwell Publishing Ltd. adequately managed in many patients with TI. the ongoing accumulation of iron in TI patients through increased dietary uptake. even in the absence of transfusions. Comparison of the three leading iron-chelating drugs for consideration in the management of thalassaemia intermedia. 2007) whereas in untransfused TI.

A 1-year study of more than 150 patients with TI is currently ongoing. Consequently. none requiring withdrawal of treatment. unlike TM. rather than palliation of late and irreversible anaemia-related complications (Aessopos et al. 2003). and the prevailing approach was avoidance of early blood transfusions and of the associated need for chelation therapy. Basel. In addition. including improved methods of blood transfusion. In addition.Review ferritin. Reliance on serum ferritin alone may result in a delay in initiating chelation therapy and may therefore prolong patient exposure to high iron levels and the associated risks of morbidity and mortality. judicious use of repeated serum ferritin measurements is appropriate for intra-individual monitoring of chelation efficiency on a regular basis. in TI increased pulmonary vascular resistance. Unlike TM. 2006). threshold 638 serum ferritin values of 400)500 lg/l (which have been shown to correlate with LIC levels of approximately 7 mg/g. however. 634–640 . LIC. although data in the TI-specific population are not yet available (Cabantchik et al. British Journal of Haematology. but studies have shown that levels of LPI increase between doses (Cabantchik et al. which will represent the first large-scale study of an ironchelating agent in this specific population. liver iron concentration. the recommended and preferred method of diseasespecific guidance for the management of patients with TI is direct assessment of LIC by biopsy. Fig 2. better understanding of iron toxicity and a continuous improvement in iron chelation therapy. LPI rebound following DFO transfusion has also been demonstrated and the benefits of combined deferiprone/DFO therapy have been investigated in recent years. With a pharmacokinetic profile suitable for once-daily oral dosing. Transfusion requirements were reduced in four patients. observed with increasing frequency in untreated TI patients. Where LIC measurement is not possible. The pharmacokinetic profile of deferiprone requires three-times-daily dosing to provide adequate chelator coverage. Chelation therapy should be initiated when LIC exceeds 7 mg Fe/g dry weight (Taher et al. high-output state and hypercoagulability. systemic vascular stiffness and right heart failure caused by age-related PHT dominate the clinical picture (Aessopos et al. where cardiac siderosis is the predominant cause of symptomatic heart disease and mortality. 2007). 2005. Taher et al. Recommendations for iron chelation therapy in patients with thalassaemia intermedia The initiation of chelation therapy in TI patients depends primarily on the extent of iron overload and rate of iron accumulation but. Maggio et al. clear guidelines are not available. where transfusion history can be a useful indicator of the need for iron chelation therapy. it can provide 24-h chelation coverage. The observation that serum ferritin levels do not accurately reflect the level of iron overload in patients with TI has important implications for patient management. patients with TI will require direct assessment of body iron levels in order to guide therapy. 2007. A significant rise in serum erythropoietin was also observed and in three patients there was an increase in haemoglobin values. 2005). prevention of the main complications of chronic anaemia and of ineffective erythropoiesis. 2006. a remarkable improvement in life expectancy and prevention of morbidity has been achieved in recent decades. These dismal complications. 2008). red-cell membrane iron and serum nontransferrin-bound iron levels (Pootrakul et al. Novartis Pharma AG. been largely regarded as a clinical entity with limited complications. hepatic iron. suggest that earlier intervention aimed at preventing the consequences of chronic anaemia may benefit TI patients by pre-emption. 147. Porter. or preferably by non invasive imaging methods (Fig 2). Porter et al. as with other aspects of the management of TI. Switzerland) is the most recent addition to the iron chelator options. The primary objective of this placebo-controlled study is to determine the efficacy of deferasirox in patients with non-transfusion-dependent thalassaemia as determined by changes in LIC. 2007b). Advantages over a single-agent approach have been demonstrated. 2008) may be considered as an alternative indicator for initiation of iron chelation therapy. progress in the management of TI and prevention of the late complications of TI has been unimpressive. Deferasirox (ExjadeÒ. Although earlier introduction of blood transfusions will increase the rate of ª 2009 Blackwell Publishing Ltd. Adverse events in this study were mild and included gastrointestinal symptoms in six patients and arthralgia in one. Unlike TM. better documentation of the late complications of TI disclosed serious cardiac problems unique to TI. This may be attributed to a number of key factors. Adult and paediatric patients (‡10 years of age) will be included. These severe age-related cardiac complications are mainly attributed to PHT caused by a long-term. Proposed management algorithm. and an extensive clinical development programme has demonstrated efficacy in a wide range of patient categories (Cappellini et al. TI has. 2007a). In patients with TM. As assessment of serum ferritin is evidently inappropriate in these patients. 2007. Vichinsky et al.

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