New Advances in Iron Chelation Therapy

Iron chelation therapy certainly has not lacked attention. Synthetic chemists have searched diligently for new compounds, and clinical investigators have spent several decades characterizing the long-term effects of deferoxamine and conducting clinical trials with newer agents. Much of this effort has been obscured in the past 10 years by disputes about the rights and responsibilities of investigators and sponsors that have been chronicled in journals, newspapers, television shows, a non-fictional account and, obliquely, in a popular novel. However, the current flurry of activity in the field, including the introduction of new orally active agents, the emerging interest in combining different chelators and the development of novel methods for assessing tissue iron has returned the emphasis to preventing the organ damage and early death that is inevitable when long-term red cell transfusion therapy occurs in the absence of iron chelation.

With its 40-year history in the treatment of iron overload, deferoxamine (Desferal^®) might not be considered a new advance. However, the current role of deferoxamine sets the context for consideration of newer agents. In addition, new technologies make it possible to reconsider previously reported benefits of deferoxamine. Finally, since the most important outcome of iron chelation therapy is long-term survival, new data about cohorts treated with deferoxamine over several decades will continue to be informative.

Deferoxamine, if administered regularly by subcutaneous infusion in appropriate doses, is a safe and effective approach to the treatment of transfusional iron overload (Table 1 ). As demonstrated consistently in studies of a large cohort of patients with thalassemia, the introduction of deferoxamine had a profound effect on long-term survival, and Kaplan-Meier survival plots for patients who began treatment with deferoxamine at a young age look remarkably similar to those for children receiving bone marrow transplants from matched siblings.¹ However, compliance with a daily subcutaneous infusion has plagued the use of deferoxamine since its introduction. In the absence of regular use of the chelator, iron stores steadily increase and patients die from iron-induced cardiac disease.² 

New technologies for assessing cardiac iron have confirmed the ability of intensive therapy with deferoxamine to reduce cardiac iron and improve cardiac function in patients with severe iron overload.³ In 6 of 7 surviving patients with heart failure, continuous intravenous administration of deferoxamine over 12 months improved myocardial T2*, a cardiovascular magnetic resonance technique to assess myocardial iron and identify patients with iron-induced cardiac dysfunction. In addition, these surviving patients showed improvement in left ventricular ejection fraction and ventricular remodeling parameters, reduction in cardiac symptoms and clinical findings, and a decrease of 75% in the liver iron concentration. Currently, deferoxamine is the only chelator for which there is strong evidence of reversal of iron-induced heart failure.⁴ Unfortunately, poor compliance with deferoxamine occurs even in this serious clinical situation and consistently leads to death.⁵ 

From extensive synthetic chemistry studies of a class of compounds known as hydroxypyridones, deferiprone (L1, Ferriprox^®) emerged as the first orally active chelator to enter extensive human trials (Table 2 ). A bidentate chelator, 3 molecules of deferiprone are required to fill the 6 binding sites of iron. In Europe, deferiprone is licensed for the treatment of iron overload in patients with thalassemia major when deferoxamine therapy is contraindicated or inadequate. Indications differ somewhat in other countries such as Turkey and Australia in which the chelator is licensed. Deferiprone is generally administered 3 times daily, and most of the chelator-induced iron excretion is found in the urine.^6,7 Early balance studies showed a dose-related effect on total iron excretion.⁸ At the usual therapeutic doses, deferiprone and deferoxamine promote similar amounts of urinary iron excretion in patients with transfusional iron overload.^6,7,9 However, total iron excretion is generally higher with deferoxamine because of the additional stool iron loss.

Numerous small studies during the 1990s showed that deferiprone could create negative iron balance (iron excretion in excess of iron intake) in patients with thalassemia and could reduce excessive iron stores as measured by ferritin level or liver iron concentration.¹⁰ However, two factors slowed its clinical development. First, the well-documented controversy that surrounded the development of deferiprone sometimes clouded the conventional analysis of the data from these trials. Second, deferiprone was never subjected to the classic Phase III study in which its safety and efficacy were compared directly with deferoxamine. Nonetheless, the published studies of deferiprone, with few exceptions, produce a consistent picture of the chelator’s clinical usefulness, and this picture is largely predictable from balance studies.

In regard to efficacy, deferiprone, at a dose of 75 mg/kg/day, reduces or maintains iron stores in the majority of patients receiving regular red cell transfusions.^11,–14 However, some patients, particularly those whose iron overload is less severe, continue to accumulate iron at this dose. Raising the dose of deferiprone to 100 mg/kg/day or combining therapy with deferiprone and deferoxamine has usually proven very effective in reducing iron stores in such patients.^15,16 The latter approach is based on balance studies demonstrating additive iron excretion when the two chelators are combined.⁹ Strategies for combination therapy have varied widely but usually include at least 5 days of deferiprone and 2 days of deferoxamine weekly. A recently completed prospective, randomized study compared deferiprone, 75 mg/kg/day and deferoxamine, 40–50 mg/kg/day with deferoxamine alone.¹⁷ In this group of patients selected on the basis of increased cardiac iron loading as measured by T2*, combination therapy more rapidly reduced hepatic and cardiac iron stores than deferoxamine alone and toxicity did not increase.

Deferiprone alone readily achieves reductions in iron stores in patients with lower rates of transfusional iron loading than are found in thalassemia major. Studies of deferiprone in thalassemia intermedia and irregularly transfused patients with Hb E-beta thalassemia have consistently demonstrated a reduction in liver iron concentration.^18,19 

Retrospective studies first suggested that deferiprone might be more effective than deferoxamine in chelating cardiac iron, the cause of most of the mortality in transfusional iron overload.^20,21 A subsequent multicenter study of cardiac-related morbidity and mortality and a multicenter, randomized, prospective trial of cardiac iron and function have confirmed this finding.^22,23 The former study employed a time-to-event methodology in an analysis of 516 patients with thalassemia, of whom 157 received deferiprone at some point.²² No cardiac events, defined as heart failure or an arrhythmia requiring drug therapy, and no cardiac-related deaths occurred among the patients in the deferiprone group, while 52 cardiac events and 10 deaths occurred in the deferoxamine group. In the latter study, patients were randomly assigned to treatment with deferiprone, 100 mg/kg/day (actual prescribed dose 92 mg/kg/day) or deferoxamine, 50 mg/kg/day 5 to 7 days per week (actual prescribed dose 43 mg/kg for 5.7 days per week).²³ Myocardial T2* values improved in both groups but significantly more so in the deferiprone-treated patients. Deferiprone-treated patients also showed a significantly greater improvement in the left ventricular ejection fraction. Liver iron concentrations fell significantly in deferoxamine-treated patients but not in patients receiving deferiprone.

The study of combination therapy described above showed that the favorable effects of both deferiprone and deferoxamine can be utilized in patients with more severe iron overload by addressing cardiac iron (deferiprone) and hepatic iron (deferoxamine). Thus combination therapy may have a dual rationale: increasing total iron excretion and taking advantage of some organ selectivity.

Single center studies, multicenter trials and post-marketing surveillance have defined the safety profile of deferiprone.^10,13 Gastrointestinal symptoms occur early in therapy in about one-third of patients and usually resolve without specific intervention. The incidence of joint symptoms varies widely across studies, perhaps due to different degrees of iron overload in the treated populations. Joint symptoms are not confined to the first year of therapy and may be severe enough to require the reduction or temporary interruption of chelation therapy. Sudden or gradual increases in ALT levels occasionally occur in the absence of other causes of hepatic dysfunction. With interruption of deferiprone, the levels usually return to baseline values and re-initiation of chelation therapy, beginning with lower doses and carefully monitoring liver function tests, is a reasonable strategy. Concerns about drug-induced hepatic fibrosis have not been supported by subsequent studies, and progressive liver disease attributable to deferiprone has not been reported in clinical trials or post-marketing surveillance.

Agranulocytosis remains the major concern for patients receiving deferiprone. This complication occurs in less than 1% of patients who undergo weekly monitoring of their blood counts during chelation therapy with deferiprone.¹³ Milder neutropenia (500–1500/mm³) is more common, occurring in about 8% of patients. Although reported deaths related to agranulocytosis are extremely rare, the severely depressed neutrophil count, even though reversible, clearly represents a significant risk for sepsis and therefore leads to hospitalization and, in some cases, administration of G-CSF. Three important questions about deferiprone and agranulocytosis remain incompletely answered. First, does the currently recommended weekly monitoring of blood counts during deferiprone therapy reduce the risk of agranulocytosis by identifying a preceding period of neutropenia and allowing early cessation of the chelator? Asked another way, are the milder forms of neutropenia that are identified with monitoring harbingers of agranulocytosis or are they due to other causes such as viral infections or hyper-splenism? In the absence of a good answer, weekly monitoring remains the standard of care. Second, should weekly monitoring continue indefinitely? Although most of the cases of agranulocytosis occur during the first year of treatment with deferiprone, some have occurred much later. At present, there is no recommended time to reduce the frequency of blood counts, although this might change as more data accumulate. Third, should patients who develop agranulocytosis be re-treated with deferiprone after their neutrophil counts return to normal? Although second episodes of agranulocytosis do not always occur, they are common enough to warrant extreme caution when considering re-treatment. Deferiprone should be resumed after recovery from agranulocytosis only when absolutely required by clinical need and only when very frequent monitoring of the neutrophil count is readily available.

Deferasirox (ICL670, Exjade^®) is the first orally active iron chelator available for routine use in the United States (Table 3 ). It is approved for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. As a tridentate chelator, two molecules of deferasirox bind one molecule of iron. The half-life of 8–16 hours allows once daily administration of the slurry that is formed when tablets of deferasirox are added to water, apple juice or orange juice. Iron excretion is mainly in the feces. The primary findings in Phase I and II studies of deferasirox were dose-related increases in iron excretion and the absence of significant acute side effects other than gastrointestinal disturbances that were generally mild and a diffuse rash that appeared to be more common at higher doses.²⁴ 

The Phase III or pivotal study of deferasirox enrolled 586 patients with thalassemia in 65 sites and was designed to test non-inferiority to deferoxamine.²⁵ The primary endpoint was built around the change in liver iron concentration as measured by biochemical analysis of liver biopsies in most patients and by biomagnetic liver susceptometry (SQUID) in a subset of patients. The initial dose of either deferasirox or deferoxamine was chosen on the basis of the initial liver iron concentration. However, patients in the deferoxamine arm were allowed to remain on their pre-trial dose of the chelator, which was frequently higher than the dose to which they would otherwise have been assigned based on their liver iron concentration. As a result, the patients who entered the study with lower liver iron concentrations received a higher dose of deferoxamine relative to deferasirox in comparison with patients who entered the trial with higher liver iron concentrations. This quirk in the design of the trial may have contributed to the failure of the overall study to meet the predefined criteria for non-inferiority of deferasirox to deferoxamine while still showing non-inferiority in patients with more severe iron overload (liver iron concentration greater than 7 mg/g dry weight). The mean decrease in liver iron concentration in the latter group was 5.3 mg/g dry weight in response to 20 or 30 mg/kg/day of deferasirox, a value that did not differ significantly from the mean decrease of 4.3 mg/g dry weight in patients receiving 35 mg/kg/day or more of deferoxamine. Several findings in this study, in addition to the non-inferiority of deferasirox to deferoxamine at higher doses of the chelators, will influence clinical decision making. First, lower doses of deferasirox (5 and 10 mg/kg/day) are unlikely to achieve negative iron balance in patients with thalassemia major and their use in this disorder should probably be restricted to patients with very mild iron overload either as a result of limited transfusions in young patients or previously successful chelation in older patients. Second, even at doses of 20 and 30 mg/kg/day, approximately 50% and 10% of patients, respectively, will still gain iron and therefore all patients need careful monitoring of their iron stores during treatment with deferasirox (see below). Third, the rate of transfusional iron intake strongly influences the effectiveness of deferasirox in controlling liver iron concentration. For example, at a dose of 20 mg/kg/day, 75% of patients whose transfusional iron intake is less than 0.3 mg/kg/day (156 mL/kg/year of packed red cells with a hematocrit of 65%) will achieve a reduction in liver iron concentration over one year. However, at the same dose of deferasirox, only 47% of patients with a transfusional iron intake greater than 0.5 mg/kg/day (260 mL/kg/yr of packed red cells with a hematocrit of 65%) will achieve a reduction in liver iron concentration. Thus, careful assessment of the patient’s transfusion requirements is important in choosing a dose of deferasirox and estimating the chances of successful control of body iron.

Smaller studies of patients with sickle cell disease and congenital and acquired transfusion-dependent disorders such as Diamond-Blackfan anemia and myelodysplasia demonstrate similar effectiveness of deferasirox,^26,27 and the same general guidelines for dose selection and monitoring should apply. However, for some patients with these diseases, the transfusion requirements may be much smaller than in thalassemia major, and therefore lower doses of deferasirox may be more effective. For example, children with sickle cell disease who receive regular red cell transfusions to maintain their hemoglobin S levels below 30% have transfusion requirements that are similar to those of patients with thalassemia major and will likely need 20–30 mg/kg/day of deferasirox to achieve neutral or negative iron balance. In contrast, adults with sickle disease who receive sporadic transfusions for pain or other complications may have an annual intake of transfusional iron that is markedly lower than in thalassemia major, and a lower dose of deferasirox may prevent the gradual accumulation of excessive iron. Similarly, patients with thalassemia intermedia may only receive transfusions during exacerbations of anemia associated with acute illness or during pregnancy, and control of their iron loading (including gastrointestinal absorption) may be achieved with 10–20 mg/kg/day of deferasirox.

In the phase III trial, acute side effects of deferasirox mirrored those found in earlier studies.²⁵ Gastrointestinal symptoms were reported by 15% of patients and skin rash was reported by 11% of patients. Cessation of therapy for those complications was rare. Laboratory monitoring demonstrated a 33% or greater increase in serum creatinine level in 38% of patients in comparison with 14% of patients receiving deferoxamine. The higher creatinine levels did not exceed twice the upper limits of normal and were not accompanied by clinical or biochemical evidence of progressive renal disease. Attention to creatinine levels may be particularly important in patients with well controlled iron stores because some evidence suggests that renal toxicity occurs more commonly after major reductions in liver iron concentration. However, renal toxicity in preclinical studies and the dose-dependency of the rise in creatinine levels in the pivotal trial suggest the need for long-term assessment of renal function in clinical trials and regular monitoring of serum creatinine levels during treatment with deferasirox. Specific guidelines for monitoring are shown in Table 3 .

Elevations of ALT levels have occurred in a small number of patients, rarely leading to cessation of treatment. This laboratory finding may be particularly challenging to the clinician since two possible causes of a rising ALT level, drug toxicity and increasing liver iron concentration, may require dramatically opposed interventions of stopping deferasirox or increasing the dose. The presence of hepatitis C infection in many patients receiving deferasirox may add to the difficulty in identifying the cause of an acute change in ALT level. Pretreatment trends in ALT levels and careful assessment of liver iron concentration should guide further therapy. Serum ferritin levels may be less helpful because rising levels may reflect liver toxicity, active hepatitis C or increasing liver iron deposition.

Frequent assessment of iron stores is essential until more information about long-term efficacy becomes available. New methods for noninvasive measurement of liver and heart iron by magnetic resonance imaging are therefore a timely addition to the management of iron overload.

For the clinician using deferasirox, several key issues remain. First, what is the approach to the compliant patient whose iron stores are increasing despite the use of the currently highest recommended dose of deferasirox (30 mg/kg/day)? Will higher doses be both effective and safe? Can treatment with deferasirox be combined with deferoxamine or, where available, deferiprone to achieve an additive effect on iron excretion without increasing toxicity? Second, what is the impact of deferasirox on the key organ, the heart? Will studies show the benefits that have been demonstrated for intensive therapy with deferoxamine or for regular therapy with deferiprone? Third, will the doses of 20–30 mg/kg/day that are required for effectiveness be safe in younger, less heavily iron-loaded patients who were assigned lower doses in the pivotal study? At least some of these questions are likely to arise in clinical practice before they can be answered in further clinical trials.

Two iron chelators are currently in earlier stages of clinical trials. Attaching deferoxamine to hydroxyethyl starch creates a high molecular weight compound with a longer circulation time. Studies are underway to seek a dose that would allow acceptable intervals between intravenous infusions while still promoting an effective level of iron excretion. Deferitrin is an orally active tridentate compound from the ferrithiocin class of chelators. Phase I and II studies have not shown evidence of renal toxicity that had been noted in animal studies with some ferrithiocin analogues, and a current dose-escalation study is designed to identify the appropriate strategy for a pivotal trial.

The availability of new iron chelators presents new opportunities to the clinician treating patients with transfusional iron overload. For patients beginning iron chelation therapy and those with good control of iron stores and preservation of normal cardiac function, treatment with deferasirox is appropriate, but regular assessment of the iron burden is essential to achieve the correct dose. Some patients who have undergone successful therapy with deferoxamine may prefer to remain on daily infusions of this chelator since they are comfortable with its administration and may not wish to alter their management. Patients with severe iron overload or significant organ toxicity despite treatment with deferoxamine present a particular challenge. Deferiprone, licensed in some countries and available for compassionate use elsewhere, is particularly effective in preventing the onset of cardiac disease or removing pre-existing cardiac iron in this group of patients. The combination of deferiprone and deferoxamine brings both the beneficial effects on the heart and a more rapid removal of iron from the liver. Future studies should help to determine the long-term success of deferasirox, the role of deferiprone in patients with less severe iron overload, and the effectiveness and safety of new combinations of these chelating agents.