Iron chelators: Choice of agent, dosing, and adverse effects

INTRODUCTION — Phlebotomy cannot be used to remove excess iron in transfusion-dependent patients (eg, beta thalassemia major, severe beta thalassemia intermedia, sickle cell anemia, myelodysplasia, aplastic anemia) with iron overload or in the rare patient with hemochromatosis and an unstable hemodynamic status (eg, severe cardiac involvement) [1]. Thus, if treatment for iron overload is deemed necessary in such patients, one must use an iron chelating agent.

The use of chelating agents for the treatment of iron overload states in children and adults will be discussed here, with an emphasis on iron chelation therapy in thalassemia [2,3]. The following subjects are discussed separately:

●Overviews of the causes and diagnosis of iron overload. (See "Approach to the patient with suspected iron overload" and "Methods to determine hepatic iron content".)

●Treatment of iron overload using phlebotomy, which is available for non-anemic patients (eg, hereditary hemochromatosis). Such treatment is also available for formerly transfusion-dependent individuals (eg, thalassemia, sickle cell disease, myelodysplasia, aplastic anemia) who have been cured of their underlying disease following successful hematopoietic cell transplantation (HCT). (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores'.)

●Monitoring iron stores and use of iron chelation in patients with sickle cell disease. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

●Treatment of acute iron poisoning, a medical emergency, which includes supportive care, gastrointestinal decontamination, and intensive iron chelation with intravenous deferoxamine. (See "Acute iron poisoning".)

CLINICAL OVERVIEW

Indications for iron chelation — Decisions to begin treatment with iron chelation require clinical judgment since both the prognosis of the underlying disease and the potential benefit of chelation must be taken into account [4]. The level of evidence to guide the clinician in initiating chelation therapy is quite variable as shown by the following examples in disorders associated with iron overload:

●Myelodysplasia – The role of iron chelation in patients with MDS and transfusional iron overload is presented separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS" and "Sideroblastic anemias: Diagnosis and management", section on 'Iron overload'.)

●Thalassemia – Institution of vigorous chelation therapy early in childhood has been responsible for a marked improvement in survival of patients with transfusion-dependent beta thalassemia major and beta thalassemia intermedia and is considered the standard of care in this disorder. (See 'Iron chelation in transfusion-dependent thalassemia' below.)

Individuals with transfusion-independent thalassemia (non-transfusion-dependent thalassemia [NTDT]; also called thalassemia intermedia in some studies) accumulate iron due to increased absorption of dietary iron rather than via repeated blood transfusions. These individuals also may require chelation therapy, although complications generally occur at an older age (by 10 to 15 years) and we evaluate them for iron overload when they are 10 years of age or older. (See 'Iron chelation in transfusion-independent thalassemia' below.)

In contrast, individuals with alpha or beta thalassemia minor (also called thalassemia trait) do not develop iron overload and do not require screening. However, it is important that these individuals are not inappropriately diagnosed as being iron deficient due to microcytosis and are not inadvertently given iron for an incorrect diagnosis of iron deficiency. (See "Diagnosis of thalassemia (adults and children)", section on 'Differential diagnosis'.)

●Sickle cell disease – This subject is discussed in detail separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

●Post-transplantation management – The use of iron chelation is being increasingly employed for those with iron overload who are being considered for hematopoietic cell transplantation (HCT), or who have been cured of their underlying disorder following HCT, since iron overload is known to be associated with increased complications and a poor prognosis [5,6]. (See 'Iron chelation in other iron overload conditions' below and "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores'.)

Goals of iron chelation therapy — The goal of iron chelation therapy is to reduce the body burden of iron, especially iron within labile compartments in plasma as well as in various tissues. By decreasing iron in these sites, the specific aim is to minimize the production of reactive oxygen species, thus reducing damage to critical organs such as the liver, heart, and endocrine organs, resulting in reduced morbidity and improved survival [7].

●Primary goal – As increased availability of iron chelators and the ability to quantify specific organ iron has become available, the primary goal of chelation therapy has become the prevention of toxic iron burden and the maintenance of safe iron levels. This is achieved using chelator doses that balance iron intake from transfusions with iron excretion by chelation.

●Rescue therapy – When unsafe levels of iron have developed, the goal of iron chelation is no longer iron maintenance therapy but is instead iron rescue therapy. This requires a more aggressive approach to iron chelation, with doses higher than used in iron maintenance. Toxic levels of tissue iron, even if temporary, are likely to induce some irreversible damage. Since only a small amount of body iron is available for iron chelation at any one time, iron chelation therapy cannot rapidly lower body iron stores, even with regimen adjustment. While removal of iron from the liver may be relatively rapid, lowering iron in the heart and other organs is a much slower process.

Since iron chelation must be given over extended periods of time in those with iron overload and must be rigorously followed, the choice of a chelating agent must take into account the ability of the patient to tolerate and pursue the chosen regimen with high compliance and to obtain continuous follow-up evaluation of its efficacy and safety. (See 'Choice of initial therapy' below and "Approach to the patient with suspected iron overload", section on 'Sequence and interpretation of testing'.)

IRON CHELATION IN TRANSFUSION-DEPENDENT THALASSEMIA — Currently, there are three iron chelating agents in wide use and numerous ways in which iron chelation therapy can be given to patients with transfusion-dependent thalassemia. No agent or combination of agents is considered the "gold standard" of therapy for all patients or programs. The optimal chelator regimen is not solely determined by the drug used, but by the regimen which results in chronic optimal patient adherence, in which continuous effective therapy is administered safely, providing protection from labile iron.

Deferoxamine is an excellent iron chelator, but it is not commonly chosen as the primary chelator because its requirement for continuous infusion often results in non-adherence. While there is no universal gold standard in chelation therapy, there are consensus recommendations from experts and thalassemia organizations that share similar approaches in most instances [8-10].

The following sections present the available information concerning such therapeutic options. A comparison of the variously available guidelines for such care has been published, which concluded that there were "notable variations in the recommendations for iron chelation therapy" [11].

Indications — Prior to the advent of hypertransfusion regimens in the 1960s, beta thalassemia major was a disease fatal in infancy. Hypertransfusion regimens transformed this disorder into a more chronic disease, with patients usually dying in their second decade of life from the complications of transfusional iron overload. Iron chelation therapy, begun in the 1970s, transformed this into a chronic disease permitting prolonged survival (figure 1). Accordingly, the mainstays of therapy for beta thalassemia major are chronic hypertransfusion combined with iron chelation and supportive measures directed at the complications of the expanded erythron and iron overload. (See "Management of thalassemia".)

Transfusion-dependent beta thalassemia (previously beta thalassemia major) — Indications for initiating chelation therapy are listed below:

●After 10 units of packed red blood cells (PRBC), or greater than 100cc/Kg per year (PRBC hematocrit 60).

●Ferritin is greater than 1000ug/L.

●An magnetic resonance imaging (MRI) of the liver iron concentration >3mg/g/dry weight, or the cardiac T2* is less than 20 milliseconds [3,12,13].

General recommendations are to initiate chelation therapy at two years of age or older based on the criteria above. Neither of the oral medications are US Food and Drug Administration-approved for children under two years of age. Data on young children is very limited and largely based on deferoxamine experience and limited reports on the oral chelators [14]. Recent data suggests both deferiprone and deferasirox can be used in children two years of age and older. The prospective, non-inferiority trial between deferiprone and deferasirox (DEEP-2) followed 393 randomized patients, with 30 percent of patients younger than six years and 6 percent younger than two years. Both drugs had a good safety profile [15].

Non-transfusion dependent thalassemia (NTDT) — In NTDT, the ferritin alone underestimates the iron burden and can result in patients with significant iron overload being untreated. The liver iron concentration (LIC) is the preferred method to determine iron stores and the initiation of chelation. [3]. (See 'Iron chelation in transfusion-independent thalassemia' below and "Approach to the patient with suspected iron overload", section on 'Post-diagnostic testing'.) Chelation is initiated when the MRI measurement of the LIC is equal to or greater than 5 mg/g dry weight. If quantitative measurement is not available, a ferritin of 800ug/L is utilized.

Choice of initial therapy — There are three options for initial chelating therapy. Each is approved for the treatment of transfusion-dependent thalassemia and each has its own set of side effects and requirements for monitoring.

In general, deferasirox is our standard recommendation. However, patient age, drug toxicity, and adverse events may result in a preference for deferiprone or deferoxamine as initial or maintenance therapies. If iron balance cannot be maintained or specific organ injury occurs, reassessment of the dose and/or consideration of combination therapy may be appropriate.

●Deferasirox – Deferasirox is licensed as a first-line monotherapy in most countries [8]. The long half-life allows once daily dosing. Deferasirox is the most common choice for initiating chelation therapy in the United States [2].

There are two formulations:

•Jadenu is a film-coated tablet that has better absorption and is better tolerated than Exjade. Due to enhanced absorption, the Jadenu dose is 0.7 times the recommended dose of Exjade. The starting dose for Jadenu is 14 mg/kg/day, which can be gradually increased to 28 mg/kg/day.

•The original formulation, Exjade, was a tablet dispersed in a glass of water. The starting dose for Exjade is 20 mg/kg/day, titrated to a maximum dose of 28 mg/kg/day.

●Deferoxamine – Deferoxamine (DFO) has been available since the late 1970s and is considered a first-line therapy for young children by the Thalassaemia International Federation (TIF) and other organizations, due to its known safety profile and toxicities, especially in children <2 years of age. It is equally effective as deferasirox but must be given parenterally.

The recommended method of administration is a slow subcutaneous infusion of a 10 percent solution over 8 to 12 hours for a minimum of five days per week. Prefilled balloon infusors increase patient adherence. The average daily dose in children is 20 mg/kg day; this can be increased to 40 mg/kg /day. Higher doses are not recommended because of the adverse impact on skeletal growth. In adults, DFO dosing may be increased to 60 mg/kg/day. Low dose deferoxamine (2 to 3mg/kg/day on the days it is used) increases iron excretion and may be beneficial. High-dose vitamin C (eg, >200 mg) is avoided due to a potential risk of rapid iron mobilization and toxicity [16].

●Deferiprone – Oral Deferiprone has been available throughout the world (United Kingdom, India, Far East) since the 2000s. It is a rapidly absorbed tablet that is typically given three times daily. Some data suggest twice daily dosing is acceptable and may improve adherence. In many countries, deferiprone is a second-line therapy for patients who cannot tolerate other chelators. It has less gastrointestinal toxicity than deferasirox but carries the rare risk of agranulocytosis. It is widely used throughout the world, especially in resource-limited settings, due to its lower cost and ease of administration.

There are no randomized trials that give guidance with regard to the choice of agent for initial iron chelation therapy. As a result, the choice is largely dependent on local experience, availability, age of the patient, comorbidities, drug side effect profile, and patient preference, especially with regard to the route of administration [2,11]. Cost may also be an issue for some individuals, especially in resource-limited settings.

Most patients in North America and Europe have chosen deferasirox over deferoxamine as initial therapy. Compared with deferoxamine, deferasirox has been associated with greater patient satisfaction, adherence to therapy, and increased time available for normal activities [17]. Full compliance with deferoxamine has been noted in only approximately 59 to 78 percent of patients, with poorer survival for those unable to adhere fully to a chelation program [18,19].

In the United Kingdom and Far East, where there is more experience with deferiprone, deferiprone alone or in combination with deferoxamine is used by a substantial proportion of patients, a regimen that has been shown to have greater efficacy than other single agents or combinations of agents in those with severe degrees of cardiac iron overload.

Monitoring iron overload — The following tests should be employed in the individual with transfusion-dependent thalassemia, according to 2021 guidelines from the British Society for Haematology (BSH) [9]:

●Rate of iron loading (ROIL) from transfusion – To determine the appropriate dosing of chelation therapy, knowledge of iron loading should be calculated for each patient. Patients with high iron loading will require greater chelation than patients with low iron loading. The ROIL in mg/kg/day can be calculated from the number of units of blood transfused over a measured time period. Patients with an average ROIL (range, 0.3 to 0.5 mg/kg/day) will require average chelator doses, whereas those with ROIL <0.2 mg/kg/day or >0.5 mg/kg/day may require dose adjustments.

The rate in mg/kg/day is calculated as follows:

Based on number of units transfused - ROIL = (number of units transfused x 200) ÷ (weight [in kg] x number of days over which the transfusions were administered).

Based on number of mLs transfused – ROIL = (number of mLs transfused x 1.08) ÷ (weight [in kg] x number of days over which the transfusions were administered).

●Serum (or plasma) ferritin – This test should be performed in duplicate before chelation therapy is initiated to establish a valid baseline level. It should be repeated every three months thereafter or more frequently if ferritin levels have been fluctuating erratically because of the presence of infectious or inflammatory episodes.

●Cardiac T2* by MRI – It is reasonable to defer determination of cardiac iron overload status by MRI until 8 to 10 years of age if the child has been well chelated according to levels of ferritin. This is because children younger than this age may require sedation to perform the testing. However, such testing should be initiated earlier in the child when significant degrees of iron overload are present and/or when levels of ferritin and/or LIC are worsening under treatment. A formula for converting between cardiac T2* MRI in milliseconds and mg/g dry weight has been derived: Iron concentration in mg/g dry weight = 45 x (T2* MRI in milliseconds, raised to the power -1.22); online calculators are available [20,21]. Optimal comparisons are those made between similar measurements (eg, T2* MRI compared with T2* MRI done using the same imaging parameters).

•If the individual has had stable levels of ferritin and LIC and a prior normal level of cardiac T2*, this test should be repeated every two years.

•If significant iron overload is present, this test should be repeated annually.

•If at any time the cardiac T2* falls below 15 milliseconds, the test should be repeated immediately and additional cardiac monitoring initiated. (See 'When to modify dosing' below.)

●Additional monitoring – Depending upon the chelating agent(s) chosen, additional monitoring (eg, growth retardation, renal and hepatic function, complete blood count, absolute neutrophil count) is required as outlined separately under each of the available agents.

When to modify dosing — Successful iron chelation is present when serum ferritin levels fall below 1000 mcg/L, LIC is in the range of 3 to 7 mg/g dry weight, and cardiac T2* is >20 milliseconds. Repeated testing of ferritin and LIC as per the above schedules will determine whether these levels are falling, steady, or increasing with time, whether important drug toxicities have occurred, and whether iron chelation is interfering with growth.

●Dose adjustments and monitoring of treatment – Dosing should be tailored to achieve serum ferritin levels <1000 mcg/L, LIC <7 mg Fe/g dry weight, and a cardiac T2* by MRI >20 milliseconds. While non-invasive testing for LIC by MRI is preferred, more studies are needed of standardized MRI protocols to determine the effects of MRI surveillance on the development of chronic liver disease and overall patient survival [22]. There is some evidence from the analysis of multiple studies that the efficacy of cardiac iron removal via chelation therapy is better when LIC is low (eg, <7 mg Fe/g dry weight) than when it is high (eg, >15 mg Fe/g dry weight) [23-26]. (See 'Monitoring iron overload' above.)

Current dosing is continued if these levels remain stable or are improving with time and is held if the ferritin is <300 to 500 mcg/L or LIC becomes <3 mg/g dry weight.

Chelation therapy is held or reduced when the ferritin level falls to less than 300 to 500 mcg/L and/or LIC falls below 3 mg/g dry weight, as it is not clear that the benefits of continued chelation therapy at these levels outweigh the potential risks [2].

●Intensification of treatment – LIC >15 mg Fe/g, serum ferritin >2500, a cardiac T2* MRI <15 milliseconds, or a fall in the left ventricular ejection fraction (LVEF) because of cardiac siderosis, cardiac failure, or arrhythmia indicates inadequate chelation, requiring intensification of treatment. Options include escalation to maximal allowed doses, switching to another chelating agent if compliance with the current agent has been inadequate, or use of combined chelating agents. We usually add another agent, and we prefer deferiprone in this setting, alone or in combination with deferoxamine; adding deferasirox (rather than deferoxamine) to deferiprone is also reasonable. There is less information regarding long-term efficacy and safety of the combination of deferiprone plus deferasirox.

Prospective randomized trials have confirmed the superiority of deferiprone, either alone or in combination with deferoxamine, compared with deferoxamine alone, for the treatment of established iron-induced cardiac disease [24,27,28]. (See "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)

Increases in dosing are appropriate when ferritin and LIC levels are increasing when averaged over a minimum period of six months. Expert guidance on this issue does not exist, but it is reasonable to increase dosing only when major changes in ferritin and LIC have occurred (eg, doubling of these levels during a period of one year) [13].

●Development of acute decompensated heart failure is the major cause of death in beta thalassemia major and constitutes a medical emergency. We and others suggest that treatment be initiated with high-dose continuous intravenous deferoxamine accompanied by oral deferiprone.

Overview of single-agent therapy

Deferoxamine — Current regimens for deferoxamine (DFO) treatment in transfusion-dependent beta thalassemia call for a nightly 10- to 12-hour continuous subcutaneous infusion of approximately 2 g of deferoxamine using a small battery-driven pump [29]. An adequate dose of deferoxamine can usually be injected through a 25-gauge butterfly needle, thus minimizing discomfort. Local irritation and hives at the injection site are occasional complications, but these are usually transient or can be controlled by reducing the dose or rate of infusion. To be effective, deferoxamine should be administered approximately 250 nights each year.

Some centers begin continuous deferoxamine infusions at age five to six years, while some begin these infusions even earlier [13], although the effects of earlier initiation on growth and development are uncertain [29-33]. Starting chelation early appears to delay cardiac symptoms and perhaps prolong survival.

Serum ferritin levels should be monitored and therapy should be maintained or increased until levels fall substantially. Based on studies of iron-associated disease in patients with hereditary hemochromatosis, one should attempt to reduce the ferritin level to less than 1000 ng/mL. Three to five years of therapy are often required to obtain this level.

There is increasing evidence that the use of this regimen or even more aggressive regimens will delay the onset of, or actually reverse, cardiac hemosiderosis [34,35]. Ultra-intense regimens of >15 mg/kg per hour of intravenous deferoxamine have been reported to reverse early cardiac hemosiderosis, while more conventional doses (eg, 43 mg/kg per day averaged out over a mean of three years) improved LVEF and prevented death in a group of patients followed with annual determination of LVEF [34]. A retrospective analysis of a patient database has indicated that the 2.6 to 3.1 percent improvements in LVEF observed in randomized trials of iron chelation have been associated with risk reductions of 26 to 46 percent for the development of heart failure over a 12-month period [36].

A meta-analysis of available studies in patients with transfusion-dependent thalassemia has concluded that iron chelators significantly reduced myocardial iron content by approximately 24 percent (95% CI 17-30 percent) [37]. There was no significant difference between the amount of iron reduced by deferoxamine and deferiprone. LVEF was not significantly changed by chelation, although this meta-analysis indicated that a publication bias existed for LVEF, but not for myocardial iron.

Although deferoxamine therapy is effective and relatively nontoxic, it is extremely expensive and cumbersome to use, and compliance with prolonged infusion regimens is difficult, particularly when children reach adolescence. Furthermore, complications related to iron overload still occur and the long-term effects of deferoxamine remain a concern. In a long-term follow-up of 97 children with beta thalassemia major, 36 developed cardiac disease and 18 died [38]. Only the proportion of serum ferritin measurements that were below 2500 ng/mL were of prognostic value for cardiac disease. Patients in whom less than one-third of serum ferritin values exceeded 2500 ng/mL had estimated 10- and 15-year rates of survival without cardiac disease of 100 and 91 percent.

Long-term studies indicate that full compliance with iron chelation therapy has been accomplished in only approximately 50 to 80 percent of patients, with overall survival to age 30 of approximately 55 percent [39,40]. This compares with survivals of 25 percent prior to the advent of iron chelation as standard treatment (figure 1). The Torino data indicate survivals to age 30 of 88 and 10 percent for those able (60 percent of patients) or unable (40 percent) to adhere fully to a chelation program, respectively [41]. Clearly, present chelation programs are burdensome and inconvenient, and alternative, more tolerable approaches are required [42].

Deferoxamine versus deferasirox — Results from a randomized phase III trial in 586 regularly transfused patients with beta thalassemia indicate that chronic use of deferasirox, via a single oral dose of 30 mg/kg per day, induced decreases in LIC in most patients, similar to that achieved with deferoxamine (DFO, ≥50 mg/kg per day), with minimal short-term toxicity [43-45]. Specific results of this trial included the following [43]:

●For both deferoxamine and deferasirox, iron excretion increased linearly with increasing dose. At the rate of iron intake seen in the patients with beta thalassemia (0.4 mg/kg per day), negative iron balance was achieved in approximately 50 percent of patients at a deferasirox dose of 20 mg/kg per day or 40 mg/kg per day of deferoxamine.

●Doses of 5 and 10 mg/kg per day of deferasirox were too low to maintain or reduce absolute LIC or to achieve negative iron balance at any level of transfusional iron intake [43,45]. Differences in bioavailability may have explained inadequate responses to this agent in some of these patients [46].

●A four-year extension study was made available to all patients who completed the initial one-year trial [47]. In those with four or more years of exposure to deferasirox, mean LIC and serum ferritin levels decreased significantly. Adverse events (increased creatinine, abdominal pain, nausea) were generally mild-to-moderate, transient, and reduced in frequency over time. No adverse effect was observed on pediatric growth or adolescent sexual development.

The CORDELIA study was a prospective, randomized phase II non-inferiority trial of the safety and efficacy of subcutaneous deferoxamine (starting dose 50 to 60 mg/kg per day) versus oral deferasirox (starting dose 20 mg/kg per day escalating to 30 and then 40 mg/kg per day in subsequent weeks) in 197 iron overloaded patients with thalassemia major with myocardial T2* in the range of 6 to 20 milliseconds but without clinical symptoms of cardiac dysfunction. Observations and results of this study include the following [48]:

●All patients (mean age 20 years) had received prior iron chelation therapy for a mean period of 14 years. At the time of initiation of the study, one-third had myocardial T2* in the range of 6 to <10 milliseconds, while the remainder had values in the range of 10 to <20 milliseconds. Mean LICs were 30 mg Fe/gram dry weight, while the median serum ferritin levels were 4878 ng/mL.

●After one year of treatment, the geometric mean myocardial T2* improved in both groups (deferoxamine: 11.6 to 12.3 milliseconds; deferasirox: 11.2 to 12.6 milliseconds). Normalization of myocardial T2* (ie, to >20 milliseconds) was seen in 6.2 versus 17.6 percent of those treated with deferoxamine or deferasirox, respectively, while improvement (ie, from values of 6 to <10 milliseconds to values of 10 to ≤20 milliseconds) was seen in 20.0 versus 35.5 percent, respectively.

●Serious adverse events were noted in 11.0 and 10.4 percent of those treated with deferoxamine or deferasirox, respectively. Increases in serum creatinine >33 percent above baseline were infrequent (1.1 versus 3.1 percent, respectively), transient, and managed with dose reduction and/or interruption.

The modest improvements in T2* seen in this study at one year suggested that longer periods of treatment would be necessary to achieve normal T2* values in most individuals. This was shown in the non-randomized extension of the CORDELIA study in which the following observations were made [49]:

●For those treated with deferoxamine, 6.2 and 17.2 percent achieved a normal cardiac T2* after one and two years of treatment, respectively.

●For those treated with deferasirox, 17.6 and 24.3 percent achieved a normal cardiac T2* after one and two years of treatment, respectively.

●Importantly, 72.7 percent of patients treated with deferasirox for two years and 54.5 percent of those treated with deferoxamine for the same period improved from severe myocardial iron overload (T2* <10 milliseconds) to mild-to-moderate iron overload (T2* 10 to 20 milliseconds). This change is clinically significant for both agents as the relative risk of heart failure has been shown to be 160 times higher for those with severe, as compared with mild-to-moderate, myocardial iron overload [50].

Deferiprone — Although deferiprone does not appear to adequately control the total iron burden in some patients with thalassemia, the following clinical trials appear to support the relative safety and utility of deferiprone [23,24,51-57] and suggest that deferiprone may be superior in removing myocardial iron compared with deferoxamine [23,24,55,57]:

●The largest series treated 532 patients with transfusion-dependent thalassemia major [53]. For the 151 patients completing three years of therapy with deferiprone, mean ferritin levels at the start of treatment, and at 12, 24, and 36 months were 2579, 2671, 2472, and 2320 ng/mL, respectively. Ferritin decrease was significant at all three time points for those with initial ferritin values >4000 ng/mL, while those with initial values of 2000 to 4000 ng/mL showed a significant decrease after 24 months. Overall, 20 percent of patients showed a worsening of ferritin during the first 12 months of treatment.

●A randomized trial compared deferiprone with deferoxamine in 144 patients with thalassemia major and serum ferritin between 1500 and 3000 ng/mL [54]. After one year of treatment, there were no differences in reduction of serum ferritin, reduction of liver or myocardial iron by an indirect MRI technique, or LIC by biopsy.

●In a small comparative study of 15 patients receiving chelation with deferiprone alone for >3 years and 30 matched controls treated with deferoxamine, the deferiprone-treated group had significantly higher estimated LIC (MRI), but significantly lower estimated myocardial iron concentration, associated with a greater LVEF [55].

●In 56 deferiprone-treated patients, serial liver biopsies disclosed no evidence for progression of liver fibrosis during long-term therapy (median time of treatment 3.5 years) [56].

There is evidence that compliance with deferiprone (79 to 80 percent) is higher than that for deferoxamine (59 to 78 percent) [40]. However, the efficacy and safety of deferiprone remained controversial, such that routine use had not been recommended as of 2000 [58,59]. While a 2003 retrospective analysis had shown superior efficacy for deferiprone over deferoxamine [52], a Cochrane analysis of the available literature concluded that deferiprone is indicated for the treatment of iron overload in thalassemia when deferoxamine is contraindicated or inadequate [60]. Studies reported after this 2007 meta-analysis are presented below.

●Results are available from the first 550 patients enrolled in the Myocardial Iron Overload in Thalassemia network, dealing with a retrospective analysis of selected patients who had been receiving only one of the three agents for longer than one year (24, 42, and 89 treated with deferasirox, deferiprone, or deferoxamine, respectively). The three groups were not entirely comparable, with the main difference being the duration of active treatment, which was 2±1, 4±4, and 24±10 years for those in the deferasirox, deferiprone, and deferoxamine treatment groups, respectively. Observations include the following [61]:

•The global heart T2* value was significantly higher, meaning less cardiac iron overload, in the deferiprone group than in the two other groups.

•LVEFs were significantly greater in the deferiprone and deferoxamine groups than in the deferasirox group.

•LICs were significantly lower in the deferoxamine group than in the two other groups.

●Preliminary results are available from the same authors on a prospective evaluation of 193 patients with thalassemia major who had received only one of the three chelating agents between two MRI scans of the liver and heart [62].

•Among those with no significant myocardial iron overload at baseline (ie, global heart T2* ≥20 milliseconds), there were no significant differences in all three groups in the ability to maintain the patients without significant iron overload.

•Among those with myocardial iron overload at baseline (ie, global heart T2* <20 milliseconds), there was a significant improvement in the global heart T2* in all three groups, with the greatest improvement being in those treated with deferiprone.

•In patients with liver iron overload at baseline (liver T2* <5.1 milliseconds), the change in liver T2* was not different among the three treatment groups. Similarly, changes in mean serum ferritin levels were not significantly different among treatment groups.

Deferasirox — As a part of a larger EPIC trial in patients with various transfusion-dependent anemias [63], deferasirox was employed in a one-year prospective, open-label, multicenter study of 192 patients with beta thalassemia and iron overload (serum ferritin >2500 ng/mL, LIC >10 mg Fe/g dry weight, >50 transfused blood units, and an LVEF ≥56 percent). Results included the following [25]:

●In the 114 patients with cardiac siderosis (ie, MRI myocardial T2* from 5 to 20 milliseconds, cardiac iron reduction arm), treatment with deferasirox for one year at a mean dose of 32.6 mg/kg per day resulted in a significant improvement in myocardial T2* from 11.2 to 12.9 milliseconds, with no significant change in LVEF.

●In the 78 patients with iron overload whose myocardial T2* was ≥20 milliseconds (prevention arm), treatment with deferasirox for one year at a mean dose of 27.6 mg/kg per day resulted in no significant worsening or improvement in myocardial T2*. LVEF increased from 67.7 to 69.6 percent.

●Ferritin values after one year of treatment increased in 17 and 20 percent of patients in the cardiac iron reduction and prevention arms, respectively.

●Seventy-one patients in the EPIC cardiac substudy continued chelation therapy with deferasirox into the third year [64]. In those with baseline T2* values of 10 to <20 milliseconds, 68.1 percent normalized (ie, T2* >20 milliseconds), while 50 percent of those with baseline T2* in the range of >5 to <10 milliseconds improved to 10 to <20 milliseconds. There was no significant variation in LVEF over the three years. Only one serious cardiac adverse event was noted during this interval (atrial fibrillation in a patient with improved cardiac T2*, decreasing LIC, and decreasing serum ferritin level).

In a separate study, 28 patients with abnormal T2* and LVEF were treated with deferasirox at initial doses of 30 to 40 mg/kg per day [65]. Cardiac iron improved 24 percent in patients having LIC in the lower two quartiles, but worsened by 8.7 percent in those having LIC in the upper two quartiles. LVEF was unchanged at all time points.

Overview of chelating agent combinations — In some patients, the use of a single iron chelating agent may not be sufficient to achieve the required treatment goals. As alternatives, the dose of the chosen agent might be increased or the patient may be switched to a different agent. If these changes are not effective, the use of two chelating agents at the same time is appropriate. As examples:

●Combined treatment has been shown to be more effective than single-agent iron chelation for those with mild to moderate degrees of hepatic and cardiac iron overload [23,66,67]. Combination therapy also takes advantage of the fact that available iron chelators appear to remove iron from tissue stores via different mechanisms [68].

●Combination therapy has also been effective in smaller studies in unstable patients with severe degrees of cardiac siderosis and impaired left ventricular function [1,69]. As an example, one study in 52 patients with beta thalassemia major employed "very intensive" combined chelation therapy consisting of deferoxamine 20 to 60 mg/kg per day by subcutaneous infusion plus deferiprone 75 to 100 mg/kg per day in three divided doses. Results included [70]:

•Patients' iron load normalized, as judged by cardiac and hepatic MRI findings. Baseline and post-treatment ferritins (mean±SD) were 3422±882 and 97±25, respectively, indicating full normalization of ferritin levels with this dosing regimen.

•Symptoms reversed in all 12 patients receiving treatment for cardiac dysfunction, enabling 9 of the 12 to discontinue heart medications.

•Glucose metabolism was normalized in 44 percent of the 39 patients with baseline abnormal glucose metabolism.

•A high percentage of those with hypothyroidism or hypogonadism improved. Of the 19 females who were hypogonadal on deferoxamine monotherapy, six were able to conceive.

Deferoxamine plus deferiprone — Whether alternative dosing schedules of deferiprone or combination therapy with deferoxamine (given at the time of blood transfusion) would be more effective has not been extensively studied [23,66,67,71,72].

●One report evaluated the effects of increasing the dose of deferiprone and combined therapy with deferoxamine in 13 transfusion-dependent patients who were inadequately chelated by the usual deferiprone dose of 75 mg/kg per day [66]. Both raising the daily dose of deferiprone to 83 to 100 mg/kg and combination therapy with deferoxamine lowered the serum ferritin in all patients.

●Combined treatment with deferoxamine (40 to 50 mg/kg subcutaneously at least five nights per week) plus deferiprone (75 mg/kg per day orally in three divided doses [ie, given as 25 mg/kg three times daily]) was compared with treatment with deferoxamine plus placebo in a randomized trial that included 65 patients with thalassemia major and mild-to-moderate myocardial iron loading as judged by myocardial T2* cardiovascular magnetic resonance [23]. Following 12 months of treatment, there were significant improvements in the combined treatment group compared with the deferoxamine alone group in myocardial T2*, absolute LVEF, absolute endothelial function, liver T2*, and serum ferritin levels.

●A multicenter randomized open-label trial assessed the long-term effectiveness of sequential deferiprone-deferoxamine (DFP-DFO: DFP 75 mg/kg per day orally for four days/week plus DFO 50 mg/kg per day by subcutaneous infusion for the remaining three days/week) versus deferiprone alone (DFP 75 mg/kg per day for seven days/week) in 213 patients with thalassemia major [67]. The decrease in serum ferritin during the five-year treatment period was significantly greater for the DFP-DFO treatment arm than for the DFP arm.

However, there were no overall differences between treatment arms for T2* MRI signals of the heart and liver, overall survival, adverse events, or costs, suggesting the value of oral deferiprone alone in countries in which subcutaneous deferoxamine is unavailable.

Deferoxamine plus deferasirox — A number of small studies have investigated the efficacy and safety of combined iron chelation with deferoxamine and deferasirox, mainly because of a failure of response or adverse events following monotherapy.

●Seven transfusion-dependent individuals with beta thalassemia were treated with a combination of deferasirox (20±2 mg/kg per day) and deferoxamine (32±4 mg/kg per day for three or four days per week) [73]. After one year of therapy, there were marked reductions in median serum ferritin levels (from 2254 to 1346 ng/mL), LIC (from 11.4 to 6.5 mg/g dry weight), and improvement in cardiac T2* (from 20 to 26 milliseconds). There were no alterations in renal or hepatic function and no adverse events.

●A 34-day iron balance study in six thalassemic patients indicated that supplementing the daily use of deferasirox (30 mg/kg per day) with two to three days of deferoxamine per week (40 mg/kg per day) placed all patients into net negative iron balance, whereas four of the six remained in positive iron balance when treated with deferasirox alone [74].

●A 40-year-old male with transfusion-dependent beta thalassemia who had failed prior monotherapy with deferoxamine, deferiprone, and deferasirox was treated with a combination of deferasirox (30 mg/kg per day for seven days per week) and deferoxamine (2500 mg/day for four days per week) [75]. After 18 months of combination chelation therapy, his serum ferritin fell from 2515 to 681 ng/mL, estimated LIC fell from 46 to 10 mg/g dry weight, and cardiac T2* improved from 5.8 to 12.6 milliseconds. The treatment was well tolerated with no adverse events.

Deferiprone plus deferasirox — There are only a few reports on the combined use of the two orally active iron chelating agents deferiprone and deferasirox [76,77]. Impressive results were obtained in a 34-year-old patient with beta thalassemia major, a life-long transfusion requirement, and severe iron overload (cardiac MRI T2* 9.36 milliseconds, serum ferritin >2800 ng/mL) who was treated with the combination of deferiprone (75 mg/kg/day) plus deferasirox (30 mg/kg/day) after having suboptimal response to treatment with deferiprone alone [76]. After 12 months of combined therapy, her cardiac T2* returned to within the normal range at 21.1 milliseconds, and her serum ferritin was markedly improved at 397 ng/mL. No renal or hepatic abnormalities or episodes of neutropenia were noted on repeat testing.

IRON CHELATION IN TRANSFUSION-INDEPENDENT THALASSEMIA

Development of iron overload — Individuals with transfusion-independent thalassemia (non-transfusion-dependent thalassemia [NTDT]; also called thalassemia intermedia in some studies) accumulate iron due to increased absorption of dietary iron rather than via repeated blood transfusions. As an example, iron overload in beta thalassemia intermedia has been estimated at 1.0 to 3.5 grams/year, compared with 2 to 12 grams/year in regularly transfused patients with thalassemia major [45,78,79].

Compared with transfusion-dependent thalassemia patients, NTDT patients deposit relatively more iron in hepatocytes and less in macrophages, a condition associated with a smaller increase in serum ferritin for the same total hepatic iron load [80]. Serum ferritin measurements may therefore underestimate the severity of iron overload in NTDT.

Whereas those with transfusion-dependent thalassemia may show signs and symptoms of iron overload as early as two to three years of age, those with NTDT develop the same complications by 10 to 15 years of age (eg, cardiac dysfunction, end-stage liver disease including hepatocellular carcinoma, endocrine dysfunction), necessitating the institution of iron chelation therapy at this later age [79,81].

However, at the present time there are no prospective, randomized trials available for determining which treatment regimen is most appropriate for those with NTDT. Other than the THALASSA trial using deferasirox (described below), most reports of the use of iron chelation in NTDT are small, open label, and single arm, limiting their applicability to wider populations [79].

Deferasirox — The randomized, double-blind, placebo-controlled THALASSA trial established the efficacy and safety of two different doses of deferasirox taken over a one-year period in 166 patients with NTDT. Eligible patients were ≥10 years of age, had serum ferritin levels >300 ng/mL, magnetic resonance imaging (MRI)-measured liver iron concentrations (LIC) ≥5 mg Fe/g dry liver weight, and had not received transfusions within six months or iron chelation within one month before study entry. Results included the following [82]:

●An absolute reduction in LIC of ≥3 mg Fe/g dry liver weight between baseline and 52 weeks, the primary study endpoint, was reached in 11, 33, and 56 percent of those treated with placebo, deferasirox at a starting dose of 5 mg/kg per day, and deferasirox at a starting dose of 10 mg/kg per day, respectively.

●At one year, the mean change from baseline in LIC was -1.95 and -3.80 mg Fe/g for those receiving the 5 or 10 mg/kg per day doses, respectively. In the extension study, patients received deferasirox at escalated doses of 10 to 20 mg/kg per day. The mean absolute change in LIC from baseline to month 24 for those enrolled in this extension study was -7.1 mg Fe/g [83]. Those receiving an average actual dose in the range of >12.5 to ≤17.5 mg/kg per day achieved greater decreases in LIC than those receiving average actual doses ≤12.5 mg/kg/day.

●The median change in serum ferritin from baseline to 52 weeks, one of the secondary study endpoints, was +81, -102, and -202 for the placebo and the two deferasirox-treated groups, respectively.

●Investigator-assessed drug-related adverse events were reported in 24 percent of the patients, were similar among the three treatment groups, were of mild to moderate severity, and resolved without discontinuing treatment.

Evaluation and treatment — Although patients with alpha or beta thalassemia intermedia may be either transfusion-independent or require only infrequent transfusions, they have increased absorption of dietary iron and may ultimately develop signs and symptoms of iron overload. (See "Diagnosis of thalassemia (adults and children)".)

Based upon results from the THALASSA and ORIENT studies, which documented iron overload-induced organ damage in NTDT, the following preliminary goals have been proposed for iron chelation in NTDT [79,81,84]. (See "Diagnosis of thalassemia (adults and children)", section on 'Iron overload'.)

●Patients with beta thalassemia intermedia and NTDT should be evaluated for iron overload when they are 10 years of age or older. Those with hemoglobin H (Hb H) disease (ie, alpha thalassemia intermedia) should begin monitoring at age 15 because they typically accumulate iron slower than those with beta thalassemia intermedia. Chelation therapy should be initiated when the serum ferritin is ≥800 ng/mL and/or the LIC is ≥5 mg Fe/g dry weight.

●For those with a serum ferritin <300 ng/mL or those with a serum ferritin in the range of 300 to 800 ng/mL along with LIC <5 mg Fe/g dry weight, chelation is not indicated. Such individuals should have a serum ferritin monitored every three months and LIC estimated once yearly.

●For those undergoing iron chelation, chelation therapy should be interrupted when the serum ferritin drops below 300 ng/mL and/or the LIC falls below 3 mg Fe/g dry weight, as safety data are not available to support the use of continued iron chelation below these levels.

IRON CHELATION IN OTHER IRON OVERLOAD CONDITIONS

Aplastic anemia — The adverse effects of iron overload in multiply transfused patients with aplastic anemia (AA) and iron overload, and the benefits of iron chelation therapy in such patients, are generally unknown, and there are no guidelines available concerning the use of iron chelation in this disorder. However, the following observations suggest a possible benefit of iron chelation in those with AA:

A prospective one-year Evaluation of Patients' Iron Chelation with Exjade (EPIC) study evaluated the efficacy and safety of deferasirox in 116 patients with AA and transfusional iron overload [85]. Results included:

●Median serum ferritin decreased significantly from 3254 ng/mL at baseline to 1854 ng/mL at one year. Decreases occurred in both chelation-naïve and previously chelated patients.

●Decreases in mean alanine aminotransferase levels at one year correlated significantly with reduction in serum ferritin.

●In other reports, the most common drug-related adverse events were nausea (22 percent) and diarrhea (16 percent). Serum creatinine increases above the upper limit of normal occurred in 25 percent; concomitant use of cyclosporine had a significant adverse impact on serum creatinine levels [86].

In a post hoc analysis of hematologic responses in 72 patients with AA receiving deferasirox in the EPIC study, partial hematologic response (eg, transfusion independence) was observed in 11 of 24 patients (46 percent) with chronic non-severe AA not receiving concomitant immunosuppressive therapy and in 19 of 48 patients (40 percent) who did receive concomitant immunosuppressive therapy [86]. Prospective controlled studies are needed to confirm these interesting findings and to clarify the mechanisms leading to hematologic improvement in almost one-half of these patients after use of deferasirox.

Diamond-Blackfan anemia — Other than hematopoietic cell transplantation-related mortality, transfusion-associated iron overload is the leading cause of death in patients with Diamond-Blackfan anemia (DBA) [87]. Approximately 40 percent of children with DBA are transfusion-dependent and may develop laboratory evidence of iron overload as early as two years of age [88]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

The following treatment regimen has been suggested [87]:

●Chelation therapy is started after approximately 15 transfusions or after the age of two years, with an aim to keep the ferritin level between 1000 and 1500 ng/mL, a liver iron concentration (LIC) <7 mg Fe/g dry weight, and a cardiac T2* >20 milliseconds.

●While the "traditional" chelation regimen used deferoxamine at 40 to 60 mg/kg per day given subcutaneously over 8 to 12 hours/night for four to seven nights per week, excellent results have been obtained with deferasirox (starting dose 20 mg/kg per day, with cautious escalation to a maximum of 30 to 40 mg/kg per day).

●Deferasirox failures are treated with subcutaneous deferoxamine. For those with severe degrees of iron overload (eg, LIC >12 to 15 or cardiac T2* <12 milliseconds), deferoxamine is given intravenously. Because of the risk of agranulocytosis, deferiprone is reserved for those with severe cardiac hemosiderosis.

Hematopoietic cell transplant recipients — Prior retrospective studies had indicated that the five-year survival of patients following hematopoietic cell transplantation (HCT) was worse in those with higher pre-transplant ferritin levels as well as in those who had iron overload but did not receive iron chelation [5,89,90]. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Transfusion support'.)

Accordingly, a prospective study of the short-term efficacy and safety of deferasirox was initiated in 30 adult patients with transfusional iron overload who were at least six months past allogeneic HCT. Most had undergone HCT for acute myeloid leukemia, myelodysplasia, non-Hodgkin lymphoma, or aplastic anemia. Results for the 22 patients completing treatment included the following [89]:

●After treatment with deferasirox (10 mg/kg per day for 52 weeks or until serum ferritin was <400 ng/mL on two consecutive occasions), there was a significant reduction from baseline in median serum ferritin from 1440 to 756 ng/mL and in median LIC from 14.5 to 4.6 mg Fe/g dry weight.

●The majority of adverse events related to treatment were mild or moderate in severity (eg, increases in serum creatinine [40 percent], and increases in liver enzymes [17 percent]).

Additional studies are warranted to determine the impact of iron chelation on long-term outcomes in this population [5,89,90]

Myelodysplasia — This subject is discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS" and "Sideroblastic anemias: Diagnosis and management", section on 'Iron overload'.)

Sickle cell disease — The indications for iron chelation, choice of agent, administration, and monitoring in individuals with sickle cell disease are presented separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

AVAILABLE CHELATING AGENTS — The three commercially available chelating agents are described below. Deferoxamine must be given by continuous infusion, either subcutaneously or intravenously, while deferiprone and deferasirox are orally active. Each has its own benefits, toxicities, and requirements for monitoring of side effects [2].

Deferoxamine — Deferoxamine (DFO, Desferal) is a clinically approved and effective iron chelator for long-term therapy in patients with beta thalassemia and other iron overload states [12,91]. Deferoxamine is a relatively specific and nontoxic iron chelating agent [30,31], which has also been utilized for the diagnosis or treatment of aluminum-induced toxicity associated with chronic kidney disease. (See "Aluminum toxicity in chronic kidney disease", section on 'Treatment'.)

Although deferoxamine is absorbed orally, the pharmacokinetics of intermittent oral doses are unfavorable for effective iron chelation. Continuous intravenous or subcutaneous infusion is therefore necessary. Previous regimens that attempted intermittent intramuscular administration, frequently at the time of transfusion, have proved unworkable. The likely reason is that deferoxamine has a very short plasma half-life.

In the circulation and tissues, deferoxamine binds iron and the iron-bound form is excreted efficiently in the urine and bile [30,31]. The key mechanisms involved in iron chelation by deferoxamine are [92]:

●Deferoxamine is a hexadentate iron-chelating molecule, meaning that one molecule of deferoxamine can bind one iron atom (figure 2).

●Iron derived from senescent red cells is released by macrophages of the reticuloendothelial system, chelated by deferoxamine, and immediately excreted in the urine.

●Iron-free deferoxamine is internalized by hepatic parenchymal cells, interacts with the chelatable intracellular iron pool, binds iron, and is excreted in bile.

●Deferoxamine is able to remove iron directly from myocardial cells.

However, deferoxamine has a relatively short half-life in the body, but the release of iron for chelation from tissue iron stores is continuous. As a result, it has been necessary to develop continuous infusion protocols designed to achieve iron excretion rates of at least 115 mg/day in patients who were previously iron overloaded [29-32,91,93]. The use of ascorbic acid to increase iron excretion is controversial and may be dangerous.

Dosing — For typical chelation regimens, approximately 40 to 60 mg/kg of deferoxamine is placed into a small battery-driven pump, which is then adjusted to deliver the infusion subcutaneously over 8 to 12 hours each night for at least four days per week. Doses higher than this have been associated with worsening pulmonary disease, pulmonary hypertension, and neurologic toxicity and should be avoided.

●To avoid visual or auditory loss, no more than 2.5 g of deferoxamine should be used with each infusion. (See 'Side effects' below.)

●Ototoxicity of this agent can be minimized or avoided if the ratio of the daily dose of deferoxamine (in mg/kg) to the current serum ferritin (in mcg/L) is less than 0.025 at all times [94].

Nightly deferoxamine infusion should result in 20 to 50 mg/day (600 to 1500 mg/month) of iron loss in the urine and stool [95]. It can therefore minimize further iron accumulation and may even reduce iron stores if the transfusion rate can be kept under four units of red cells (800 mg of iron) per month. Dosing should be tailored based on iron overload status as described above. (See 'Monitoring iron overload' above and 'When to modify dosing' above.)

An alternative approach in patients who already have severe iron overload (eg, cardiac arrhythmias, left ventricular dysfunction) or do not tolerate subcutaneous therapy is continuous 24-hour deferoxamine infusion via an indwelling intravenous catheter. This approach was successfully used in 17 high-risk patients with beta thalassemia who were treated for one to five years; the infection and thrombosis rates were 1.2 and 0.5 per 1000 catheter days, respectively, and there was no treatment-related mortality [96].

Side effects — Side effects of deferoxamine include visual and auditory neurotoxicity with chronic therapy and acute complications such as abdominal discomfort/pain, diarrhea, nausea, vomiting, hypotension, and anaphylaxis. In one report of 89 patients receiving nightly subcutaneous deferoxamine for transfusional iron overload, 13 presented with the acute onset of visual loss and/or deafness [97]. Detailed ophthalmologic, audiologic, and evoked-potential studies uncovered abnormalities caused by neurotoxicity in another 27 patients.

Visual loss and ototoxicity following the use of deferoxamine are directly related to the dose of deferoxamine and inversely related to the degree of iron overload. This risk can be minimized by adjusting the daily dose of deferoxamine to the patient's serum ferritin concentration [94]. (See 'Dosing' above.)

Fortunately, deferoxamine is well tolerated by most patients. Chronic administration of 100 mg/kg per day of deferoxamine has been associated with the development of cataracts in animals but not in thalassemic patients. However, decreasing visual and auditory acuity has been associated with prolonged use; fortunately, much of this toxicity appears to be reversible upon discontinuing deferoxamine.

Monitoring — In addition to frequent monitoring of iron stores during treatment, the following is a reasonable plan for monitoring for deferoxamine toxicities [2,81]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Monitoring for adverse events'.)

●Audiology – A formal audiology exam should be given prior to initiation of a chelator. A screening hearing exam should be performed in clinic every six months and a formal audiogram every 12 months. Those with new onset hearing loss or tinnitus should be evaluated. Early detection of hearing loss followed by dose modification may result in reversal of damage. Irreversible hearing loss requiring hearing aids does occur [97].

●Ophthalmology – Visual loss has been most clearly linked to deferoxamine, especially at high doses. An evaluation by an ophthalmologist should be performed in children every six months and annually in adults. Individuals should be routinely questioned about visual acuity, changes in color vision, and visual fields.

●Kidney – Creatinine/BUN, serum chemistry, and urine protein and creatinine should be monitored every three months in those on deferoxamine. We discontinue therapy immediately if the serum creatinine is greater than two times the upper limit of normal. Any patient who experiences a serum creatinine increase >50 percent above baseline should have the dose held temporarily, and an increase in serum creatinine of 33 to 50 percent should prompt dose reduction. We temporarily hold the chelator if the urine protein/creatinine ratio is >0.6 mg/mg.

●Growth – Growth of children can sometimes be affected by chelators. Ongoing measurements of height and weight velocity, including sitting height compared with total height, should be performed to detect early spinal growth defects.

●Liver function – Hepatic enzymes should be monitored every three months. We hold chelation therapy if the serum alanine aminotransferase (ALT, formerly called SGPT) is greater than five times the upper limit of normal.

Risk of infection — Deferoxamine administration may be associated with an increased risk of infection with mucormycosis (zygomycosis), Yersinia, and Vibrio vulnificus. The presumed reason for the susceptibility to these infections is that the deferoxamine-iron chelate, called feroxamine, is a siderophore for these species; the resulting increase in iron uptake stimulates their growth, possibly leading to clinical infection [98-100]. This complication may not be seen with the other iron chelators deferiprone and deferasirox, which do not act as siderophores [101]. (See "Mucormycosis (zygomycosis)", section on 'Deferoxamine and iron overload' and "Vibrio vulnificus infection".)

Deferiprone — An orally effective iron chelator, deferiprone (DFP, Ferriprox), has been tested in patients with thalassemia and sickle cell anemia [51,102-104]. Deferiprone is a bidentate chelating agent, which means that three molecules are required to bind one atom of iron (figure 2). It is in regular use in much of the world but was approved only in 2011 by the US Food and Drug Administration (FDA) for use in the treatment of transfusional iron overload due to thalassemia syndromes with inadequate response to other chelation therapy.

One series evaluated 26 patients who were unable to take or were not compliant with deferoxamine; the administration of deferiprone for a mean of 39 months was associated with stable iron stores as evidenced by no significant change in serum ferritin or urine iron excretion [102]. However, 8 of 17 patients tested had hepatic iron levels above 15 mg/g, a level at which hepatic and cardiac injury are likely to occur. The major side effects were joint symptoms, gastrointestinal complaints (particularly nausea), and neutropenia or agranulocytosis. In a multicenter study, the incidence of agranulocytosis (absolute neutrophil count [ANC] <500/microL) and neutropenia (ANC 500 to 1500/microL) was 0.6 and 5.4 per 100 patient-years; all resolved after drug discontinuation [105].

A similar limitation in efficacy was noted in another report in which 19 patients with thalassemia major treated continuously with deferiprone for a mean of 4.6 years were compared with 20 patients treated with parenteral deferoxamine; multiple liver biopsies were performed in some of the patients [103]. In 7 of 18 patients, deferiprone was associated with hepatic iron concentrations in the range associated with increased risk of cardiac disease and early death. However, many of the liver biopsy specimens were subsequently judged to be suboptimal, and many of these patients were infected with hepatitis C. Accordingly, it was not possible to separate the effect of hepatic iron deposition versus that of hepatitis C on hepatic fibrosis [58]. (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Liver disease'.)

The study cited above [103] raised the serious concern that deferiprone might enhance the propensity for hepatic and perhaps cardiac fibrosis in patients with beta thalassemia major and resulted in intense debate [51,58]. This issue is of great clinical importance since, for some patients, deferoxamine is not a realistic option; its high cost and complex administration make it virtually unavailable in some countries. Deferiprone is thus a potentially useful alternative for these patients, especially for those in whom current chelation therapy with deferoxamine has been inadequate or where deferoxamine and deferasirox are not available [15].

Dosing — The recommended initial oral dose of deferiprone is 75 mg/kg total daily dose, divided into two or three doses (a twice-daily dosing formulation became available in 2020) [106]. The maximum recommended total daily dose is 100 mg/kg per day.

Absolute neutrophil counts must be performed every week while the patient is receiving this medication to monitor for evolving neutropenia/agranulocytosis [13]. (See 'Side effects' below.)

Dosing should be tailored based on iron overload status as described above. (See 'Monitoring iron overload' above and 'When to modify dosing' above.)

Side effects — The most common adverse events included increased hepatic enzymes, gastrointestinal discomfort, and arthralgia. Incidences of neutropenia and agranulocytosis were 2.1 and 0.4 events per 100 patient-years, respectively; both were reversible upon interruption of therapy [53]. Similar rates of neutropenia (2.8) and agranulocytosis (0.2) were found in a second long-term study involving 187 patients [104], although a report from the US FDA indicated that agranulocytosis occurred in 1.7 percent of patients in clinical trials. Ten fatal cases of agranulocytosis have been reported with this agent, one with Diamond-Blackfan anemia [107] and nine with thalassemia [108].

Gastrointestinal symptoms (eg, nausea, vomiting, abdominal pain) were more common in the group of patients taking both deferoxamine and deferiprone (38 versus 24 percent) but were generally mild in severity [23]. There was one episode of agranulocytosis and two episodes of neutropenia in the combined treatment group.

A potential problem with the use of deferiprone was raised by cell culture studies in iron-loaded liver cells that showed potentiation of oxidative DNA damage by the drug [109]. This occurs when the concentration of the chelator is low relative to the iron concentration. The clinical implications of this in vitro observation are not known. Despite these concerns, deferiprone continues to be tested in clinical trials, particularly in countries where there are no alternatives given the cost and complexity of parenteral administration of deferoxamine [110].

Monitoring — In addition to monitoring iron levels, the following should be performed [2,81,111]:

●Hematologic – Individuals taking deferiprone require regular monitoring of the complete blood count (CBC) during therapy to detect a decrease in the neutrophil count (ANC) (calculator 1) that could progress to severe neutropenia or agranulocytosis. The product information specifies monitoring the ANC weekly for the first six months, once every two weeks for the next six months, and every two to four weeks after one year (or at the time of transfusion, if receiving regular transfusions) [112]. If the ANC is <1500 cells/microL, therapy should be stopped and not resumed unless there is a clear indication that benefits outweigh the risks. All individuals with fever who are on deferiprone require immediate assessment of their ANC.

●Liver function – Hepatic enzymes should be monitored every month. We hold chelation therapy if the serum ALT is greater than five times the upper limit of normal and discontinue the medication if transaminases are persistently greater than two times the upper limit of normal.

●Arthropathy – The drug should be stopped in the presence of arthropathy and restarted at a lower dose.

●Zinc levels – Zinc deficiency is a rare complication, most often seen in those with diabetes mellitus. Accordingly, plasma zinc levels should be obtained every three to six months in those with diabetes who are taking deferiprone as well as in those with growth retardation. If low levels are found (ie, <60 mcg/dL), zinc supplements can be given in an oral dose of 1 to 2 mg/kg per day and deferiprone continued. (See "Zinc deficiency and supplementation in children", section on 'Treatment'.)

Deferasirox — Deferasirox is an orally active iron chelator; it is available in two formulations as Exjade and Jadenu. Utility and safety of deferasirox (administered as Exjade) has been shown in short-term pharmacokinetic studies [113,114] as well as in nonrandomized and randomized trials in patients with thalassemia major, thalassemia intermedia, and other transfusional iron overload states (eg, sickle cell disease, myelodysplastic syndrome, Diamond-Blackfan anemia) [43,78,115-117]. Deferasirox is approved for the treatment of chronic iron overload due to multiple blood transfusions or non-transfusion-dependent thalassemia syndromes with a liver iron concentration (LIC) ≥5 mg Fe/gram of liver dry weight and a serum ferritin >300 mcg/L.

Deferasirox is a tridentate chelating agent, which means that two molecules are required to bind one iron atom (figure 2). It has a high affinity for iron and a much lower affinity for copper and zinc.

Dosing — Dosing for deferasirox depends on the formulation and the indication (transfusional iron overload versus non-transfusion-dependent thalassemia [NTDT] syndromes). Dosing for Jadenu is approximately 30 percent lower than Exjade because of greater bioavailability [118,119].

The recommended starting doses are as follows (rounded to the nearest whole tablet or sachet of granules):

●Exjade – Exjade requires dispersion in a liquid such as water or juice [118].

•Transfusional iron overload – 20 mg/kg daily (maximum dose 40 mg/kg daily) [120,121]

•NTDT syndromes – 10 mg/kg daily

●Jadenu – Jadenu tablets can be swallowed whole but cannot be made into a suspension; Jadenu granules can be sprinkled on soft foods [122].

•Transfusional iron overload – 14 mg/kg daily (maximum dose 28 mg/kg daily)

•NTDT syndromes – 7 mg/kg daily (maximum dose 14 mg/kg daily)

Deferasirox has monitoring of (and potential dose adjustments based on) serum ferritin levels, creatinine, and hepatic transaminases. (See 'Monitoring' below.)

Side effects — Potentially serious adverse events with deferasirox include potentially fatal gastrointestinal hemorrhage, renal toxicity (including renal failure), and hepatic toxicity (including hepatic failure). More commonly observed adverse events include abdominal pain, nausea, vomiting, diarrhea, back pain, and skin rash; gastrointestinal adverse events are generally transient in nature, lasting not more than one week.

Of importance, patients with baseline serum creatinine above the upper limit of normal were excluded from clinical trials. Post-marketing reports include cases of acute renal failure, cytopenias (eg, agranulocytosis, neutropenia, thrombocytopenia), hepatic failure, and gastrointestinal hemorrhage, some of which were fatal [123,124]. Leukocytoclastic vasculitis, urticaria, hypersensitivity reactions, including anaphylaxis and angioedema, and ocular disturbances have also been reported. These reactions were more frequently observed in patients with advanced age, high-risk myelodysplastic syndromes, underlying renal or hepatic impairment, or low platelet counts.

Acquired proximal renal tubular dysfunction (acquired Fanconi syndrome) has been described as a complication of treatment with deferasirox (eg, severe degrees of metabolic acidosis, hypocalcemia, hypokalemia, and hypophosphatemia) [125-127]. Cessation or reduction in the dose of deferasirox and initiation of replacement therapy resulted in prompt normalization of electrolyte imbalances in all of the four cases in one report [125] and in all of the five patients in a second report [127]. Accordingly, it is reasonable to check for this complication in patients treated with this agent.

Monitoring — In addition to monitoring iron parameters, the following should be performed [2,81,85,124,128]:

●Kidney – Creatinine/BUN, serum chemistry, and urine protein and creatinine should be monitored monthly in individuals on deferasirox. We discontinue therapy immediately if the serum creatinine is greater than two times the upper limit of normal. Any patient who experiences a serum creatinine increase >50 percent above baseline should have the dose held temporarily, and an increase in serum creatinine of 33 to 50 percent should prompt dose reduction. We temporarily hold the chelator if the urine protein/creatinine ratio is >0.6 mg/mg.

●Hematologic – A complete blood count with differential should be obtained at baseline and repeated monthly thereafter as deferasirox has been associated with neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events. We hold therapy with deferasirox in individuals who develop cytopenias until the cause of the cytopenias has been determined. Deferasirox is contraindicated in patients with platelet counts below 50,000/microL [129].

●Liver function – Hepatic enzymes should be monitored every two weeks for the first month and monthly thereafter. We hold chelation therapy if the serum ALT is greater than five times the upper limit of normal.

●Auditory and ophthalmic function – Baseline and annual auditory and ophthalmic function (including slit lamp examinations and dilated fundoscopy) should be performed.

Other chelators — A potential alternative to these agents is the hexadentate phenolic aminocarboxylate iron chelator HBED [130,131]. Another potential chelator is ascorbic acid (vitamin C). Ascorbic acid can mobilize iron but may do so too quickly and cause iron toxicity. At this time, neither of these agents is approved by the US FDA for the treatment of iron overload. (See 'Deferoxamine' above.)

Calcium channel blockers as adjuvant agents — Since iron uses high-capacity calcium channels to enter the heart, pancreas, and other organs, blocking these channels might help to prevent the accumulation of tissue iron under iron overload conditions [132-134]. A potential benefit of adding a calcium channel blocker to chelation therapy has been suggested; however, we await additional data before routinely adding calcium channel blockers to chelation therapy in individuals with severe iron overload, especially given the potential adverse effects, such as hypotension and peripheral edema, which might be poorly tolerated in these individuals. The following examples illustrate the available evidence:

●In a 2016 trial that randomly assigned 62 patients with thalassemia and transfusional iron overload to receive amlodipine (5 mg daily) or placebo in addition to chelation therapy for one year, a benefit from amlodipine was observed in the subgroup with preexisting cardiac iron overload [135]. In patients with baseline myocardial iron >0.59 mg/g dry weight (equivalent to greater than approximately 35 ms on T2* MRI), addition of amlodipine to chelation was associated with a statistically significant reduction in cardiac iron (from 1.31 to 1.05 mg/g dry weight; approximately equivalent to an increase on T2* MRI from 18 to 22 ms; an approximately 20 percent improvement). It should be noted that the most clinically meaningful differences are those in which similar measurements are compared (eg, T2* compared with T2* using the same imaging parameters). The most dramatic reductions occurred in individuals with the highest baseline cardiac iron. In contrast, individuals with baseline cardiac iron overload receiving placebo plus chelation therapy did not have a significant reduction in cardiac iron, and individuals with baseline cardiac iron ≤0.59 mg/g dry weight had no statistically significant changes in cardiac iron with amlodipine or placebo added to chelation. There were no changes in cardiac ejection fraction in any group.

●Prior to this, a 2013 open-label pilot trial that randomly assigned 15 patients with thalassemia-related iron overload who were receiving chelation therapy to receive or not receive amlodipine(5 mg daily) in addition to chelation therapy for one year found improvements in cardiac T2* MRI and serum ferritin in the amlodipine arm [136]. There were no serious adverse events.

Changes in liver iron were not observed with amlodipine in either trial, consistent with less dependence on calcium channels for iron uptake in the liver.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Beta thalassemia (The Basics)")

●Beyond the Basics topics (see "Patient education: Hereditary hemochromatosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General indications – Iron chelation is a supportive treatment modality employed to reverse or reduce the adverse effects of iron deposition in critical organs (eg, heart, liver, endocrine organs) in patients with iron overload who cannot be treated with therapeutic phlebotomy. Such patients include:

•Transfusion-dependent patients (eg, thalassemia, sickle cell anemia, myelodysplastic syndrome).

•Non-transfusion-dependent thalassemic patients who have evidence for clinically important iron overload. (See 'Iron chelation in transfusion-independent thalassemia' above.)

•Non-anemic patients with iron overload who cannot tolerate therapeutic phlebotomy (eg, hemochromatosis with severe cardiac involvement and/or an unstable hemodynamic status).

●Transfusion-dependent thalassemia – We recommend iron chelation therapy in transfusion-dependent patients with thalassemia (Grade 1A). This treatment has been shown to significantly reduce tissue iron overload and prolong overall survival in such patients (figure 1). (See 'Indications' above.)

•Choice of chelating agent – There is no current consensus on which agent to choose when initiating chelation therapy. The age of the patient, presence or absence of comorbidities, side effects of the available agents, and patient preferences will determine which agent is chosen. We prefer deferasirox for this purpose and employ deferiprone when there is evidence for increasing cardiac iron overload. (See 'Choice of initial therapy' above.)

•When to start therapy – Chelation therapy is generally started when the serum ferritin is >1000 mcg/L, the liver iron concentration (LIC) is greater than 3 mg Fe/g dry weight, and/or the cardiac T2* is <20 milliseconds. It is reduced or held when the ferritin level falls to <500 mcg/L and/or the LIC is <3 mg Fe/g dry weight. (See 'Goals of iron chelation therapy' above.)

•When to modify therapy – LIC >15 mg Fe/g, serum ferritin >2500, a cardiac T2* MRI <15 milliseconds, or a fall in the left ventricular ejection fraction (LVEF) requires intensification of treatment. This may include escalation to maximal allowed doses, switching to another chelator, or use of combined chelating agents. In this setting we prefer the use of deferiprone, with or without deferoxamine; deferiprone with or without deferasirox is also reasonable. (See 'When to modify dosing' above.)

●Acute decompensated heart failure – Development of acute decompensated heart failure is the major cause of death in beta thalassemia major and constitutes a medical emergency. We suggest that treatment be initiated with high-dose intravenous deferoxamine accompanied by deferiprone (Grade 2B).

●Transfusion-independent thalassemia – While iron chelation therapy improves survival in patients with transfusion-dependent thalassemia, those with transfusion-independent thalassemia regularly develop the same complications of iron overload, although at a later age. Accordingly, we recommend iron chelation in transfusion-independent thalassemia once evidence for iron overload has developed (Grade 1B). (See 'Iron chelation in transfusion-independent thalassemia' above.)

●Sickle cell disease – Management of excess iron stores in patients with sickle cell disease is discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

●Myelodysplastic syndrome – For patients with myelodysplastic syndrome who have received at least 20 to 30 red cell transfusions and have a serum ferritin >1000 mcg/L, an iron chelating agent is an option. However, a survival benefit from iron chelation has not been demonstrated and the optimal agent to use is unclear. (See "Myelodysplastic syndromes/neoplasms (MDS): Management of hematologic complications in lower-risk MDS".)

●Acute iron poisoning – The treatment of this potentially fatal condition is presented separately. (See "Acute iron poisoning".)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.