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

INTRODUCTION — 

Iron chelation is used to remove excess iron from the body in individuals who cannot undergo phlebotomy. There are many challenges to therapy, including when to initiate chelation, which agent to use, how to monitor efficacy and adverse effects, and how to adjust dosing.

This topic reviews iron chelation in thalassemia and other iron overload states. Separate topics discuss:

●Acute iron poisoning – (See "Acute iron poisoning".)

●Assessment of iron burden – (See "Approach to the patient with suspected iron overload" and "Methods to determine hepatic iron content" and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

●Management of excess iron stores using phlebotomy – (See "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores' and "Management and prognosis of hereditary hemochromatosis", section on 'Phlebotomy'.)

●Iron chelation in sickle cell disease – (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

INDICATIONS FOR IRON CHELATION — 

The main indications for iron chelation are iron overload conditions in which therapeutic phlebotomy is not a viable means of removing excess iron from the body:

●Anemias that are managed with regular red blood cell (RBC) transfusions, such as thalassemia, sickle cell disease (unless exchange transfusion is used), aplastic anemia (AA), Diamond-Blackfan anemia (DBA), and certain low-risk myelodysplastic syndromes (MDS).

●Non-transfusion-dependent anemias where iron loading develops from increased absorption of dietary iron and intermittent transfusions, such as non-transfusion-dependent thalassemia.

Iron overload typically develops earlier in transfusion-dependent patients than in non-transfusion-dependent patients. Each unit of transfused RBCs contains approximately 200 to 250 mg of iron. Iron overload becomes a concern after 10 to 20 units of RBCs (earlier in individuals with increased iron absorption).

Underlying medical conditions — The following underlying conditions often require iron chelation:

●Thalassemia – Includes transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) alpha and beta thalassemia, where transfusions and increased iron absorption contribute to iron overload. (See "Diagnosis of thalassemia (adults and children)", section on 'Overview of subtypes and disease severity'.)

●Sickle cell disease – Generally applies to individuals who have received a large number of RBC transfusions. Exchange transfusion typically does not cause transfusional iron overload. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

●Inherited bone marrow failure syndromes – Includes AA and DBA. (See "Treatment of aplastic anemia in adults", section on 'Supportive care' and "Diamond-Blackfan anemia", section on 'Transfusion therapy'.)

●Myelodysplastic syndromes – (See "Treatment of lower-risk myelodysplastic syndromes/neoplasms (MDS)", section on 'Supportive care' and "Sideroblastic anemias: Diagnosis and management", section on 'Iron overload'.)

●Severe hemolytic anemias – Includes severe enzyme deficiencies, unstable hemoglobins, and others. (See "Pyruvate kinase deficiency" and "Rare RBC enzyme disorders" and "Unstable hemoglobin variants".)

●Post-hematopoietic stem cell transplantation or some cancer treatments – Generally applies to individuals who have received numerous RBC transfusions prior to and during transplantation or for certain malignancies treated with intensive chemotherapy [1-3]. For patients who have undergone curative therapy and are no longer anemic, iron may be removed by phlebotomy rather than chelation. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy", section on 'Supportive care' and "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores'.)

●Hereditary hemochromatosis with concomitant anemia – Hereditary hemochromatosis (HH) with iron overload is generally treated with phlebotomy. However, some patients with concomitant anemia may not be able to tolerate phlebotomy. (See "Management and prognosis of hereditary hemochromatosis", section on 'Alternatives to phlebotomy'.)

●Iron poisoning – Iron poisoning is a special case that requires intensive chelation along with supportive care and gastrointestinal decontamination. (See "Acute iron poisoning", section on 'Management'.)

Severity of iron overload — Iron overload significant enough to require chelation is often defined by the degree of liver or cardiac iron, as assessed by magnetic resonance imaging (MRI) or serum ferritin. Typically, iron chelation is initiated for liver iron ≥5 mg per gram of dry weight or cardiac T2* MRI <20 milliseconds (<20 ms). (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Iron overload'.)

However, specific diseases such as Blackfan-Diamond anemia may modify iron transport and increase iron-induced organ injury requiring iron chelation at lower measurements [4].

In transfusion-dependent patients, serum ferritin levels ≥1000 ng/mL not attributable to infection or inflammation are another indication to start iron chelation. Iron chelation may be started at lower ferritin levels in non-transfusion-dependent anemias, as the serum ferritin level often does not correlate well with the liver iron concentration in these conditions [5]. (See 'Transfusion-dependent thalassemia' below.)

General criteria for when to start chelation are discussed below, although different considerations may apply to some patient populations. (See 'When to start chelation' below.)

Goals of therapy — The goal of iron chelation therapy is to maintain a safe level of iron in the body, both by removing excess stored iron and preventing accumulation of iron from ongoing transfusions.

An equally important and major goal is to detoxify iron by binding to non-transferrin-bound iron (NTBI), thereby minimizing production of reactive oxygen species and reducing damage to critical organs such as the liver, heart, and endocrine organs [6]. (See 'Role of chelation in reducing non-transferrin-bound iron' below.)

●Primary goal (prevention) – The primary goal of chelation therapy is 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 maintaining acceptable iron levels and becomes "rescue therapy." This requires a more aggressive approach to iron chelation, with doses higher than used in maintenance, to remove ongoing iron loading as well as stored iron. Toxic levels of iron may induce tissue injury that may be irreversible. 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.

Role of chelation in reducing non-transferrin-bound iron — In patients who receive regular red cell transfusions, non-transferrin-bound iron (NTBI) is often high, even as the ferritin level falls. NTBI is considered the major driver of organ damage by excess iron and should be kept as low as possible [7]. An iron chelator helps to detoxify dangerous NTBI. In the setting of ongoing transfusions, it is preferable not to hold iron chelation but rather to lower the iron chelator dose as the ferritin level falls. With low iron burden, the risk of adverse effects may be higher; ongoing monitoring is essential with dose reduction for side effects. (See 'Routine monitoring' below.)

GENERAL CONSIDERATIONS IN DECISION-MAKING

When to start chelation

Acute decompensated heart failure — Acute decompensated heart failure due to iron overload is the major cause of death in transfusion-dependent beta thalassemia and constitutes a medical emergency. Combination chelation with high-dose continuous intravenous deferoxamine accompanied by oral deferiprone is recommended. Unlike most causes of heart failure, heart failure from iron overload is often reversible if treated appropriately with iron chelation. (See 'Deferoxamine plus deferiprone' below.)

Transfusion-dependent thalassemia — Children with transfusion-dependent thalassemia (TDT) may develop elevated liver iron as early as two to three years of age, although symptoms may not be apparent until later [8]. For patients with thalassemia receiving regular red blood cell (RBC) transfusions, general recommendations are to initiate chelation therapy at two years of age or older based on the following criteria:

●After 10 to 20 RBC transfusions or at least 100 mL of RBCs per kg have been administered, plus any one of the following:

•Ferritin level of 1000 ng/mL on two consecutive tests obtained when well

•Liver iron concentration ≥5 mg/g dry weight

•Cardiac T2* magnetic resonance imaging (MRI) <20 milliseconds (<20 ms) [9-11]

●Unique considerations for specific underlying conditions are discussed in topic reviews on those conditions listed above. (See 'Underlying medical conditions' above.)

Drug-specific caveats apply to young children:

●Deferoxamine – Deferoxamine is not recommended at younger ages, largely based on reports of adverse effects on bone and growth from over-chelation with high dose in children under three years of age [12-14]. Deferoxamine safety data and use are limited to children >2 years.

●Deferasirox – Deferasirox is an oral chelator approved by the US Food and Drug Administration (FDA) for children ≥2 years of age with transfusional iron overload and for children ≥10 years with non-transfusion-dependent thalassemia (NTDT) and iron overload.

●Deferiprone – Deferiprone oral solution is approved by the FDA for children ≥3 years and transfusional iron overload. Deferiprone tablets are approved for patients ≥8 years.

Data on oral iron chelation are limited in children <2 years.

•Studies with deferiprone that include children >2 years did not report increased toxicity [15].

•Deferasirox safety data in children >2 years has been demonstrated in several large studies without negative effects on growth and development at dose regimens used in older patients.

Data from randomized trials that included children <2 years are as follows:

•A prospective trial (DEEP-2) randomly assigned 393 patients requiring chelation (most for thalassemia) to deferiprone or deferasirox; in this trial, 30 percent of patients were <6 years and 6 percent were <2 years, and both drugs had a good safety profile [16].

•A 2018 trial randomly assigned 61 infants 10 to 18 months with TDT to receive early deferiprone or delayed chelation and found that deferiprone effectively slowed the rate of ferritin increase and had a similar safety profile to that seen in older patients with a higher iron burden [17]. No adverse effects on growth were seen.

•The 2023 early-start deferiprone trial (START) randomly assigned 64 children ages 6 months to 10 years with beta thalassemia and ferritin 200 to 600 ng/mL to receive deferiprone or placebo and reported a significant reduction in iron stores with deferiprone, without significant differences in growth or adverse event rates between groups [18].

Non-transfusion-dependent thalassemia — In patients with non-transfusion-dependent thalassemia (NTDT), iron accumulates due to increased absorption of dietary iron rather than via repeated blood transfusions. Iron overload in NTDT has been estimated at 1 to 3.5 g/year, compared with 2 to 12 g/year in regularly transfused patients with TDT [19-21].

Children with NTDT often develop elevated tissue iron by 10 to 15 years of age (later than those with TDT), necessitating the institution of iron chelation therapy [21,22].

Compared with TDT, in NTDT, iron deposits to a relatively greater extent in hepatocytes and less in macrophages, a condition associated with a smaller increase in serum ferritin for the same total hepatic iron load [23].

Serum ferritin measurements may therefore underestimate the severity of iron overload in NTDT and can result with undertreatment (or lack of treatment) in patients with significant iron overload [5].

The liver iron concentration (LIC) is the preferred method to determine iron stores and when to initiate chelation in individuals with NTDT [9]. Chelation is initiated when the LIC is ≥5 mg/g dry weight. If quantitative measurement is not available, a ferritin of ≥800 ng/mL typically is used as a threshold for staring chelation.

For treatment, only deferasirox has FDA approval for NTDT, although other agents have been used.

There are no randomized trials available for determining which treatment regimen is most appropriate for people with NTDT. Other than the THALASSA trial using deferasirox, most reports are small, open label, and single arm, limiting their applicability to wider populations [21].

Other heavily transfused patients — Chronic transfusions are used in several other conditions and can lead to iron overload, generally after 10 to 20 units of packed red blood cells (pRBCs) or 100 mL pRBCs per kg.

Decisions about starting chelation incorporate the underlying disorder, patient characteristics, likelihood of curative therapy, and long-term prognosis.

●Aplastic anemia – Iron overload in aplastic anemia (AA) occurs in multiply transfused patients. Individuals who proceed quickly to hematopoietic stem cell transplantation may not need iron reduction, but some individuals who receive months of transfusions will eventually need iron removal. Guidelines are lacking; however, iron overload prior to hematopoietic stem cell transplantation adversely affects outcomes in patients with severe AA [24].

Observational studies suggest a benefit of chelation. As an example, the prospective Evaluation of Patients' Iron Chelation with Exjade (EPIC) study evaluated the efficacy and safety of deferasirox for one year in 116 patients with AA and transfusional iron overload [25]. Median serum ferritin decreased significantly from 3254 ng/mL at baseline to 1854 ng/mL. Decreases in mean alanine aminotransferase levels correlated significantly with ferritin reductions.

In a post-hoc analysis of 72 patients in the EPIC study, approximately 40 percent of patients had improvement in AA disease status [26]. Prospective trials are needed to confirm these findings and to clarify the mechanisms by which deferasirox might improve bone marrow function in AA.

●Diamond-Blackfan anemia – Iron loading is relatively rapid in Diamond-Blackfan anemia (DBA) because there is minimal erythroid activity and higher levels of non-transferrin-bound iron (NTBI). NTBI determines tissue iron distribution' cardiac iron loading occurs especially early. Transfusion-associated iron overload is a major cause of mortality in patients with DBA [27]. 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 [8]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Diamond-Blackfan anemia'.)

With deferasirox monotherapy, many patients have cardiac iron loading despite adequate adherence, ultimately leading them to require more aggressive combination chelation with intravenous deferoxamine.

Deferiprone-induced agranulocytosis is more common in DBA than in other diseases and has been fatal in some patients. Therefore, deferiprone is not used in patients with DBA [28]. In a report from the French DBA Registry, 23 of 423 patients developed agranulocytosis, for a calculated incidence rate of 2.56 per 100 patient-years; this is significantly higher than seen for thalassemia (0.24 per 100 patient-years) [29,30].

Chelation recommendations including a more aggressive approach than prior recommendations were summarized in reviews from 2021 and an international consensus statement from 2024, which recommend starting chelation for the following parameters [4,30,31]:

•Two years of age and

•Approximately 10 transfusions and

•Evidence of iron overload based on at least one of the following:

-Ferritin >500 ng/mL (aiming to keep ferritin <1000 ng/mL) or

-Liver iron concentration 3 mg/g dry weight or

-Cardiac T2* <20 milliseconds (<20 ms)

Deferasirox or deferoxamine can be used. Because of the risk of agranulocytosis, deferiprone typically is not used. (See 'Specific agents dosing and AEs' below.)

●Post-chemotherapy or hematopoietic stem cell transplantation – Individuals who had iron overload from transfusions and/or increased iron absorption and were subsequently cured with extensive chemotherapy or hematopoietic stem cell transplantation may benefit from iron removal.

If anemia is no longer present, phlebotomy can effectively remove excess iron without exposing patients to adverse effects of chelating agents. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy", section on 'Supportive care' and "Thalassemia: Management after hematopoietic cell transplantation", section on 'Iron stores'.)

For individuals who cannot tolerate phlebotomy, chelation may be used, depending on the patient's clinical status. A prospective study in 30 adults post-allogeneic transplantation for hematologic malignancies reported effective chelation with deferasirox [32]. A retrospective trial in 58 pediatric patients who underwent allogeneic transplantation for thalassemia demonstrated reduction in ferritin levels without significant safety concerns [33]. Deferiprone is avoided in post-transplant patients due to risk of agranulocytosis. (See 'Reasons to choose one agent over another' below.)

Long-term survival following hematopoietic stem cell transplantation is decreased in individuals with pretransplantation iron overload [32,34,35]. The relative benefits of removing excess iron prior to transplantation versus after transplantation in conditions other than thalassemia have not been studied and likely depends on the extent of excess iron.

●End-stage kidney disease – Many patients with chronic kidney failure develop iron overload from transfusions, and multiple studies indicate a high prevalence of liver iron overload in patients with end-stage kidney disease (ESKD), in part related to low hepcidin levels [36-41]. Iron overload in ESKD is associated with an increased risk of cardiovascular disease, infections, and multiorgan complications.

●Myelodysplastic syndromes – Transfusional iron overload is common in myelodysplastic syndromes (MDS) and may be a source of morbidity and mortality. (See "Treatment of lower-risk myelodysplastic syndromes/neoplasms (MDS)", section on 'Supportive care' and "Sideroblastic anemias: Diagnosis and management", section on 'Iron overload'.)

A report from the European LeukemiaNet MDS (EUMDS) registry described lower overall survival rates in patients with transfusion-dependent MDS relative to transfusion-independent MDS [42]. Observational studies and one randomized trial (TELESTO) reported chelation was associated with improvements in certain clinical parameters [43].

Iron chelation appears to increase erythropoiesis [44]. In the TELESTO trial, which randomly assigned 225 patients with low to intermediate risk MDS and iron overload to deferasirox or placebo, those receiving deferasirox had better outcomes than placebo, including better event-free survival (3.9 versus 3 years; hazard ratio, 0.64, 95% CI 0.42-0.96) [45,46]. A matched pair analysis study reported that individuals treated with chelation had better survival than those who were not treated with chelation (75 versus 49 months) [47].

●Sickle cell disease – Iron overload is a cause of morbidity and mortality in sickle cell disease. In general, NTBI and cardiac and endocrine iron loading is less than seen in thalassemia [7,48,49]. However, regular red cell transfusions are given to prevent or treat complications such as stroke, and people with sickle cell disease frequently develop iron overload from intermittent transfusions administered for acute complications. Exchange transfusion, either manual or automated, limits or prevents iron accumulation. Nonetheless, many patients receive simple transfusions either due to difficult intravenous access or limited availability of exchange transfusion, leading to iron overload. Sickle cell disease is an inflammatory disease that may elevate the ferritin level. Monitoring liver iron concentration is needed to adjust chelation therapy. All three iron chelators (deferasirox, deferiprone, and deferoxamine) are effective in removing iron in sickle cell disease. Details of chelation in sickle cell disease are discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Choice of chelating agent — Three drugs are approved by the FDA for iron chelation; the table summarizes and compares their properties (table 1):

●Deferasirox (Exjade or Jadenu) – Available as a dispersible tablet as well as a film-coated tablet and granule formulations. Licensed as a first-line monotherapy in most countries [50].

●Deferiprone (Ferriprox) – Available as tablets or liquid solution given three times per day or as a twice daily tablet formulation. Available throughout the world since the 2000s and approved in the United States in 2011 for patients ≥3 years with transfusional iron overload. There are regional differences in the indications for initiating this therapy. Initial indications in the United States were for iron overload that could not be adequately managed with other agents, but it was subsequently expanded to first-line therapy.

●Deferoxamine – Given as an intravenous or subcutaneous infusion. 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.

Reasons to choose one agent over another — All of these therapies can be effective if taken properly. There is no universal best choice or gold standard in chelation therapy, and a comparison of available guidelines concluded that there were "notable variations in the recommendations for iron chelation therapy" [51]. However, consensus recommendations from experts and thalassemia organizations share similar approaches in most instances [50,52,53]. Evidence for efficacy is presented below. (See 'Evidence for efficacy' below.)

The choice among available agents balances preferences and tolerability related to route of administration, dosing schedule, organ-specific iron loading, adverse effect profile, and cost and includes the following considerations, which are summarized in the table (table 1):

●Familiarity – The patient and family or caregivers may have familiarity with or preference for a certain drug.

●Route and dose frequency – Oral medications are typically preferable to subcutaneous/intravenous routes. Long-term studies indicate that full adherence with deferoxamine iron chelation (parenteral therapy) was seen in only approximately 50 to 80 percent of patients, with overall survival to age 30 of approximately 55 percent [54,55]. Less frequent dosing is simpler and may promote adherence.

•Deferasirox – Deferasirox is the most common choice for initiating chelation therapy in the United States [56]. The route is oral, and the long half-life allows once daily dosing, which may improve adherence.

There are two formulations; Jadenu is used more frequently than Exjade.

-Jadenu – The newer formulation, Jadenu, comes as a film-coated tablet and granules. The tablet may be swallowed whole or crushed and placed in soft food. The granule formulation is sprinkled into soft food and is ideal for younger children. The medication can be taken on an empty stomach or with a low-fat meal. (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' below.)

In general, patients prefer the new Jadenu formulation to the dispersible tablet Exjade [57]. These new formulations are easier to take and have reduced gastrointestinal side effects compared with Exjade. The Jadenu dose is 0.7 times the recommended dose of Exjade. The starting dose for Jadenu is 14 mg/kg/day, with a maximum dose of 28 mg/kg/day.

-Exjade – The original formulation, Exjade, is a tablet dispersed in a glass of water or juice. The starting dose is 20 mg/kg/day, titrated to a maximum dose of 40 mg/kg/day. (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' below.)

•Deferiprone – Deferiprone is available as an oral tablet or solution given three times per day. A newer twice daily tablet formulation may improve adherence. (See 'Deferiprone dosing + AEs (Ferriprox)' below.)

•Deferoxamine – Deferoxamine is administered as a slow subcutaneous infusion of a 10 percent solution over 8 to 12 hours for a minimum of five days per week. Continuous infusion over 24 hours, usually intravenously, is recommended for severe cardiac iron overload or iron-associated cardiomyopathy. (See 'Deferoxamine dosing + AEs (DFO, Desferal)' below.)

-Children – 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. Although therapy is effective, it is cumbersome to use, and adherence with prolonged infusion regimens is difficult, particularly when children reach adolescence.

-Adults – In adults, dosing may be increased to 60 mg/kg/day.

Low-dose vitamin C (2 to 3 mg/kg/day on the days chelation 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 [58].

Practical methods to improve adherence are discussed below. (See 'Deferoxamine dosing + AEs (DFO, Desferal)' below.)

●Organ specific iron loading

•Liver – With significant liver iron loading, a regimen containing deferasirox or deferoxamine should be considered.

•Heart – With significant cardiac iron loading, a regimen containing deferiprone should be considered. Deferiprone is particularly beneficial for reducing cardiac iron and the risk of cardiac complications [59,60].

●Adverse effects – If patients experience adverse effects that do not improve with dose reduction, such as gastrointestinal symptoms, nephrotoxicity, or hepatotoxicity with deferasirox or arthralgia or hepatoxicity with deferiprone, switching to another chelator is preferable.

●Comorbidities and underlying disorder – Deferasirox should be avoided in individuals with glomerular filtration rate (GFR) <40 mL/min/1.73 m².

Due to the risk of agranulocytosis, deferiprone typically is not used in patients with bone marrow failure (including DBA) or who are taking other medications that can cause cytopenias [29]. Deferiprone is usually avoided in patients who have undergone hematopoietic stem cell transplantation for at least six months post-transplantation for similar reasons.

●Cost – Cost may affect choice of medication in some individuals.

●Regional variation

•North America and Europe – In North America and Europe, deferasirox is usually chosen over deferoxamine as initial therapy [56]. Compared with deferoxamine, deferasirox has been associated with greater patient satisfaction, adherence to therapy, and increased time available for normal activities [61]. Full adherence to deferoxamine therapy 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 [62,63].

•United Kingdom and Asia – In these areas, where there is more experience with deferiprone, deferiprone alone or in combination with deferoxamine is used by a substantial proportion of patients. The combination regimen (deferiprone plus deferoxamine) has shown greater efficacy than single agents or other combinations in individuals with severe cardiac iron overload.

•Resource-limited regions – Deferiprone is widely used in resource-limited settings due to its lower cost and ease of administration.

Evidence for efficacy — All three of the chelating agents are effective in decreasing iron stores, provided adherence to therapy is good. Efficacy in improving clinical outcomes is discussed in topic reviews on specific indications. (See 'Underlying medical conditions' above.)

●Deferasirox – Numerous studies have demonstrated the efficacy and adverse effect profile of deferasirox in a variety of conditions including thalassemia, sickle cell disease, and low and moderate risk MDS [16,64-74].

In some individuals, efficacy is improved by switching from once per day dosing to twice per day dosing. (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' below.)

●Deferiprone – Studies have generally shown stabilization or reduction in serum ferritin levels with deferiprone use [75-80]. Reductions in liver iron concentration have been demonstrated [15,81]. Deferiprone has been shown to improve in cardiac iron levels [81].

●Deferoxamine – Multiple studies have shown that regular administration of deferoxamine is associated with a reduction in ferritin levels and liver and cardiac iron [64,65,82-87].

●Comparisons of chelating agents – The following pairwise comparisons illustrate the range of findings:

•Deferasirox versus deferoxamine – Efficacy was comparable for reducing liver iron [65,88]; efficacy was comparable for reducing cardiac iron [89].

•Deferoxamine versus deferiprone – In a randomized trial involving 60 patients with beta thalassemia who were receiving deferoxamine and had moderate cardiac iron loading, those assigned to switch to deferiprone had significantly better removal of cardiac iron and improvement in left ventricular ejection fraction than those assigned to continue deferoxamine [81]. In a randomized trial for treatment of transfusional iron overload in sickle cell disease and other anemias, efficacy was comparable for reducing ferritin, liver iron, and cardiac iron [15].

Avoiding chelation during pregnancy

●Pregnancy – Iron chelation generally should not be used during pregnancy and be stopped if pregnancy occurs due to the risk of teratogenicity.

However, patients with heart disease from increased myocardial iron have developed fatal heart failure, and the risk-benefit ratio must be considered.

●Specific agents – Regarding specific agents, there are no human studies, but there are case reports with deferoxamine use in the second or third trimester of pregnancy showing lack of adverse fetal effects [90,91].

●Breast milk – Deferoxamine appears in very small amounts in breast milk. Case studies suggests that it is safe, but controlled studies are lacking. There are no data regarding levels of deferasirox in breast milk, but in animal studies, high levels are found in maternal milk. Data are lacking on deferiprone in breast milk.

DOSING AND ADVERSE EVENTS

Determining the appropriate dose based on iron loading — Dosing should be based on the iron burden (ferritin, liver iron content [LIC], cardiac T2*) as well as the ongoing transfusion requirements because higher iron loading rates require higher chelator doses.

Iron loading rate can be calculated in mg/kg/day from the transfusional iron intake (mL of packed red blood cells [pRBCs] transfused) using the following formula [52]:

Hematocrit is expressed as a decimal (eg, hematocrit of 60 percent is expressed as 0.6), and 1.08 is the amount of iron in 1 mL of pRBCs. The hematocrit of a typical unit of pRBCs is approximately 55 to 65 percent. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Anticoagulant-preservative (A-P) solutions'.)

A general guideline to iron loading rates is as follows:

●Low: <0.3 mg/kg/day

●Moderate: 0.3 to 0.5 mg/kg/day

●High: >0.5 mg/kg/day

The higher end of the chelator dose will generally be needed for high iron burden [20]. However, when first starting iron chelation with deferasirox or deferiprone, the starting dose typically should be at the low end to assess tolerability and then titrated up to the goal dose as tolerated.

Starting doses are discussed below for each chelating agent. (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' below and 'Deferiprone dosing + AEs (Ferriprox)' below and 'Deferoxamine dosing + AEs (DFO, Desferal)' below.)

Specific agents dosing and AEs

Deferasirox dosing + AEs (Jadenu, Exjade)

●Initial dosing

•Film-coated tablet or granule formulation (Jadenu) – Start with 14 mg/kg/day, given as a once daily dose. If this dose is tolerated and the iron burden is high, the dose can be increased by 3 to 7 mg/kg/day every three to four weeks, not to exceed the maximum dose of 28 mg/kg/day.

•Dispersible tablet (Exjade) – Start with 20 mg/kg/day. This may be titrated to a maximum dose of 40 mg/kg/day.

Baseline serum creatinine, liver function tests, and complete blood count with absolute neutrophil count (ANC) should be documented prior to starting therapy and monitored carefully during therapy (calculator 1). (See 'Monitoring for adverse effects of chelating agents' below.)

The dose is held in children with an acute illness that can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, with increased monitoring and resumption of therapy when oral intake and volume status are normal.

●Dose intensification – Most individuals have adequate iron removal with once daily deferasirox at an appropriate dose. (See 'Monitoring iron burden' below.)

However, some patients demonstrate inadequate iron removal even at maximal dose and with good adherence. This may be due to pharmacokinetic differences influenced by lean body mass, body weight, and liver and kidney function [92,93]. If a single daily dose does not reduce iron stores adequately, the total daily dose may be split into twice daily dosing [94]. Twice daily dosing may also improve trough levels of the drug and provide better protection from toxic forms of iron. However, twice daily dosing may reduce adherence, and the product information only contains information about once daily dosing.

Other approaches may be needed if switching to twice daily dosing is ineffective or not tolerated. (See 'When to intensify therapy (increase dose, change agents, add another agent)' below.)

●Adverse effects – Gastrointestinal disturbances including abdominal pain, nausea, vomiting, and diarrhea are common and dose related and often improve over time [26,65,95]. Adverse effects (AEs) of deferasirox may be worse with dehydration. Encourage good hydration and consider holding the drug in the setting of significant vomiting/diarrheal illness or fever/increased insensible loss. Patients with baseline serum creatinine above the upper limit of normal were excluded from clinical trials.

Post-marketing reports include the following complications, which are less common but in some cases may be fatal [96]. Potentially life-threatening and other complications include:

•Acute kidney failure

•Cytopenias (agranulocytosis, neutropenia, thrombocytopenia)

•Liver failure

•Gastrointestinal hemorrhage

•Leukocytoclastic vasculitis

•Urticaria

•Hypersensitivity reactions, including anaphylaxis and angioedema

•Ocular disturbances

•Acquired proximal renal tubular acidosis (proximal RTA; acquired Fanconi syndrome), with severe metabolic acidosis, hypocalcemia, hypokalemia, and hypophosphatemia [97-99] (see "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA')

In one study in patients with aplastic anemia (AA), 25 percent had creatinine increases above the upper limit of normal; concomitant cyclosporine had exacerbated creatinine increases [26].

The product information contains a boxed warning regarding risks of kidney and liver failure and gastrointestinal hemorrhage [100]. Vasculitis, hypersensitivity reactions, and ocular disturbances were observed more frequently in patients with older age, high-risk myelodysplastic syndrome, underlying kidney or liver impairment, or thrombocytopenia.

For the proximal RTA, cessation of therapy or dose reduction along with metabolic correction resulted in prompt normalization of electrolyte imbalances in all of the four cases in one report [101] and in all of the five patients in a second report [101,102]. Proximal RTA seems to occur more commonly in the setting of low iron burden, and the deferasirox dose should be titrated to the iron burden and ongoing transfusional iron intake. It is reasonable to check for proximal RTA in patients treated with deferasirox.

Deferiprone dosing + AEs (Ferriprox)

●Initial dosing – The dose is divided into two or three doses per day, depending on tablet form. Typically, dosing is initiated at 25 mg/kg/day for one week and, if tolerated, increased to 50 mg/kg/day for one week, followed by an increase to full dose of 75 mg/kg/day.

For high iron burden or high transfusional iron intake, the dose can be increased from 75 mg/kg/day to the maximum dose of 99 mg/kg/day.

Giving the medication with food can reduce abdominal pain or gastrointestinal upset.

Baseline complete blood count should be obtained with ANC calculation (calculator 1). If possible, avoid concomitant use of medications that cause neutropenia.

●Dose escalation – (See 'When to intensify therapy (increase dose, change agents, add another agent)' below.)

●Adverse effects

•The most concerning AE is idiosyncratic drug-induced neutropenia (IDIN), which includes severe neutropenia/agranulocytosis (ANC <500/microL) and mild to moderate neutropenia (ANC 500 to 1500/microL). A 2016 analysis of patients in clinical trials from 1993 to 2014 reported agranulocytosis in 1.5 percent of patients and neutropenia in 5.5 percent [103]. A 2024 analysis of patients receiving deferiprone in 15 clinical trials from 1993 to 2021 (977 patients) found 22 cases of agranulocytosis and three serious infections; one person died of pseudomonas sepsis [104]. In post-marketing analysis, agranulocytosis was reported in 176 individuals, with a rate of 0.16 per 100 patient years; there were 19 serious infections, with 11 deaths, mostly from sepsis. In both the clinical trial and post-marketing data, lower ANC values (<200/microL) conferred the greatest risk of infection.

The risk of agranulocytosis is greatest in the first few months following initiation of therapy (eg, 61 percent of episodes within the first six months of therapy, and 78 percent within the first year) [103]. However, agranulocytosis has been reported to develop later, and in the 2024 analysis of IDIN in clinical trials, the mean time from initiation of deferiprone to IDIN was 736.2 days (SD 1461.3 days) [104].

Agranulocytosis is reversible with drug discontinuation, but there is a high risk of recurrence if the drug is restarted.

Patients must be counseled to hold the drug and seek immediate medical attention with all febrile illnesses.

The product information has a boxed warning stating that the ANC should be measured before starting therapy (calculator 1) and regularly during therapy [105]. Recommendations are to monitor the ANC as follows:

-First six months of therapy: Monitor ANC weekly.

-Next six months of therapy: Monitor ANC once every two weeks.

-After one year of therapy: Monitor ANC every two to four weeks (or at the patient's blood transfusion interval) provided the patient has not experienced an interruption in chelation therapy due to any decrease in ANC.

The product label recommends holding the drug if the ANC falls below 1500/microL, given that neutropenia can precede agranulocytosis [105]. However, mild intermittent neutropenia is common (approximately 6 percent), especially in children. One study suggested that it was safe to continue deferiprone with an ANC of 1000 to 1500/microL with close monitoring and drug discontinuation only if the ANC worsened or mild neutropenia was prolonged [106]. Thus, some clinicians follow an approach of continuing the drug if the ANC is between 1000 and 1500/microL, with close monitoring of the ANC (every two to three days). The drug should be held if the ANC falls below 1000/microL. If agranulocytosis develops, the drug should be permanently discontinued as there is a high risk of recurrence.

•Gastrointestinal symptoms including nausea, vomiting, and abdominal pain are common, but these usually improve after the first few weeks of treatment. Abdominal pain or gastrointestinal upset can be reduced by taking the dose with food.

•Arthropathy involving the knees or other large joints can occur early or late in treatment and usually is reversible with drug discontinuation.

•Elevations in alanine aminotransferase can occur.

Deferoxamine dosing + AEs (DFO, Desferal)

●Initial dosing – The starting dose is based on the degree of iron overload, ongoing transfusional iron burden, and patient age.

•If transfusional iron intake is ≤0.3 mg/kg/day, LIC <15 mg/g dry weight, ferritin <2500 ng/mL, and cardiac T2* >20 milliseconds (>20 ms), the starting dose is:

-Children – 20 to 25 mg/kg subcutaneously over 8 to 12 hours per night

-Adults – 40 mg/kg subcutaneously over 8 to 12 hours per night

Therapy is administered for five to seven nights per week.

•For higher iron intake or iron burden, the dose can be increased to 40 mg/kg/day for children and to 60 mg/kg/day for adults, five to seven nights per week.

•For severe iron overload, deferoxamine can be given intravenously (eg, LIC >15 mg/g dry weight or cardiac T2* <10 milliseconds [<10 ms]). In adults with iron-associated cardiomyopathy, continuous infusion, typically intravenously, at 60 mg/kg/day may be used. (See 'Acute decompensated heart failure' above.)

●Dose escalation – (See 'When to intensify therapy (increase dose, change agents, add another agent)' below.)

●Methods to improve adherence – Modern balloon pumps are smaller, lighter, and quieter than earlier models. For patients who find dissolving, mixing, and drawing up the drug a problem, prefilled syringes or balloons may be useful. Education should be provided on needle rotation in areas that are most optimal.

To avoid skin reactions, the strength of the solution should be 10 percent; increasing the concentration often can increase local reactions. Intravenous solutions are often infused through a central venous catheter, and a 10 percent solution can be tolerated by this route. However, in patients receiving infusions through peripheral vessels, inflammation and vessel sclerosis can occur, and a more dilute solution is used.

●Adverse effects

•Infusion site reactions including induration and erythema are the most common AEs.

•Allergic reactions also may occur.

•Growth reduction and bony changes include vertebral abnormalities and genu valgum [12].

•Ophthalmologic and audiologic toxicities include [97,107]:

-Impaired visual acuity

-Peripheral visual field loss

-Retinal abnormalities

-Abnormal visual evoked responses

-High frequency hearing loss

-Tinnitus

Ophthalmologic and audiologic toxicities, as well as AEs on growth and bony changes, occur more commonly when the deferoxamine dose is high relative to the total body iron. The ophthalmologic and audiologic AEs can be minimized by maintaining the ratio of the deferoxamine dose (mg per kg of body weight) to the serum ferritin below 0.025 [98].

•The risk of infection with Yersinia and Klebsiella seen with iron overload may be exacerbated by deferoxamine [99,108].

•Acute pulmonary and neurotoxicity have both been reported with very high doses of deferoxamine (10 to 20 mg/kg/hour), and it is recommended to avoid giving these high doses [109,110].

Calcium channel blockers — A potential benefit of adding a calcium channel blocker to chelation therapy has been suggested; however, addition of calcium channel blockers to chelation therapy in individuals with severe iron overload must be done with caution given the potential AEs, such as hypotension and peripheral edema, which might be poorly tolerated in these individuals [111].

●Rationale – 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 [112-114].

●Efficacy – 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 [115]. 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* magnetic resonance imaging (MRI) from 18 to 22 milliseconds (18 to 22 ms); an approximately 20 percent improvement). 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.

•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 for one year found improvements in cardiac T2* MRI and serum ferritin in the amlodipine arm [116]. There were no serious AEs.

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.

COMBINATION CHELATION

When to consider using two drugs — Combination chelation may be appropriate in selected individuals:

●When iron burden is high and not improving on monotherapy.

●When adverse effects of full dose chelation with a single agent are intolerable and addition of a second agent allows lower doses that are better tolerated.

●When rapid reduction in iron burden is needed, such as with very high iron levels (eg, liver iron content >15 mg/g dry weight or cardiac T2*<10 milliseconds [<10 ms]), or with iron-related organ complications, such as heart failure or diabetes.

Examples of the benefits of combination therapy include:

●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 [117-119].

●Available iron chelators appear to remove iron from tissue stores via different mechanisms [120].

Other options besides combination therapy if needed include dose escalation or switching to a different agent. (See 'When to intensify therapy (increase dose, change agents, add another agent)' below.)

Deferoxamine plus deferiprone — The combination of deferoxamine and deferiprone has been used since the early 1990s in a variety of doses and schedules. Iron balance studies have typically shown an additive effect on iron excretion when these two drugs are coadministered.

●For adults with severe cardiac iron loading and left ventricular dysfunction including decompensated heart failure, the combination of deferoxamine 50 to 60 mg/kg daily by continuous infusion plus deferiprone 99 mg/kg daily is used [121].

●In a randomized-controlled trial of 65 patients with mild to moderate cardiac iron loading (T2* magnetic resonance imaging [MRI] 8 to 20 milliseconds [8 to 20 ms]), combination deferoxamine (34.9 mg/kg given five days per week) and deferiprone (75 mg/kg daily) was superior to monotherapy with deferoxamine alone (43.4 mg/kg five days per week) for improvement in cardiac T2*, left ventricular ejection fraction, and liver iron concentration over a 12-month treatment period [117].

●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 per 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 [119]. 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.

●Observational studies also showed benefit of combination therapy [122,123].

Deferoxamine plus deferasirox — Small studies investigating this combination have been reported.

●In 60 patients with severe transfusional iron overload (cardiac T2* 5 to <10 milliseconds [<10 ms], mean liver iron concentration 33.4 mg/g dry weight, and normal left ventricular ejection fraction), treatment with combined deferasirox (29.6±6.3 mg/kg daily) and deferoxamine (37.4±5.8 mg/kg daily for five days per week) resulted in decreased liver iron concentration (mean decrease from baseline of 9.2±8.7 mg/g dry weight at month 6 and 14.4±12.1 mg/g dry weight at month 12) [124]. Cardiac T2* MRI improved from 7.2 ms at baseline to 7.7 ms at month 12, with further improvement to 9.5 ms at month 24. Worsening T2* values resulted in study discontinuation in 4 of 10 patients with cardiac T2* of 5 to <6 at baseline, calling into question the usefulness of this combination in patients with T2* <6 ms.

●In 22 patients with transfusion-dependent beta thalassemia and increased iron stores and/or iron-related organ dysfunction, the combination of deferoxamine (35 to 50 mg/kg for three to seven days per week) and deferasirox (20 to 30 mg/kg daily) was administered for one year [125]. Among the 18 who completed a full year of treatment, liver iron concentration decreased from 17.4 to 12 mg/g dry weight, and among the six with baseline cardiac T2* MRI <20 ms, T2* values improved. Non-transferrin-bound iron also improved with the combined therapy.

●In seven transfusion-dependent individuals with beta thalassemia treated for one year with deferasirox (20±2 mg/kg per day) and deferoxamine (32±4 mg/kg per day for three or four days per week), serum ferritin decreased from a median of 2254 to 1346 ng/mL [126]. Liver and cardiac iron were reduced (liver iron concentration decreased from 11.4 to 6.5 mg/g dry weight and cardiac T2* increased from 20 to 26 ms. There were no alterations in liver or kidney function and no adverse events.

●In six patients with thalassemia who underwent an iron balance study while receiving daily deferasirox (30 mg/kg per day), supplementation with two to three days of deferoxamine per week (40 mg/kg per day) resulted in net negative iron balance, whereas four of the six remained in positive iron balance when treated with deferasirox alone [127].

Deferiprone plus deferasirox — A few reports have been published on this oral agent combination.

●A 2023 systematic review concluded the combination was tolerable and feasible in patients with limited benefit from monotherapy [128].

●In a trial in 96 children and adolescents with transfusion-dependent thalassemia and severe iron overload (ferritin >2500 ng/mL) were randomly assigned to one year of treatment with one of two combinations: deferiprone (75 mg/kg daily) plus deferasirox (30 mg/kg daily) or deferiprone (75 mg/kg daily) plus deferoxamine (40 mg/kg, six days per week) [129]. Serum ferritin and liver iron concentration improved similarly in both groups, while cardiac T2* MRI showed greater improvement with the deferiprone plus deferasirox combination.

●In a study in 16 patients with transfusion-dependent thalassemia and intolerance or increased burdens from deferoxamine, treatment with the combination of deferiprone 75 to 100 mg/kg daily plus deferasirox 20 to 25 mg/kg daily for 24 months resulted in improvements in serum ferritin (from 581±346 to 103±60 ng/mL), liver iron concentration (from 1.6±1.1 to 1±0.2 mg/g dry weight), and cardiac T2* MRI (from 34.1±5.8 to 36.9±5.6 ms) [130]. Left ventricular ejection fraction improved significantly in the four individuals with baseline cardiac dysfunction, and glucose metabolism improved.

ROUTINE MONITORING — 

Patients are monitored for the efficacy and toxicity of therapy, and dosing is adjusted for rising or falling iron burden and adverse effects. Any acute illness or symptoms should be evaluated immediately considering toxicities of the specific chelator and complications of the specific underlying condition. (See 'Specific agents dosing and AEs' above.)

Monitoring iron burden

●Ferritin – Ferritin levels are easily obtained, and monitoring is recommended every one to three months. Ferritin is an acute-phase reactant that can be falsely elevated by infection or inflammation, and trends over time must be considered (typically over at least six months).

Ferritin levels do not always correlate well with the liver iron concentration (LIC), especially in non-transfusion-dependent thalassemia (NTDT). In individuals with NTDT, the LIC should be used to guide treatment decisions. (See 'Non-transfusion-dependent thalassemia' above.)

It is common when starting deferiprone to see a transient increase in serum ferritin with subsequent decline [15]. (See 'Deferiprone dosing + AEs (Ferriprox)' above.)

In patients who continue to receive red cell transfusions, as the ferritin (or LIC) declines, it is preferable to lower the iron chelator dose rather than interrupting the chelation therapy. This is because chelation is protective against non-transferrin-bound iron (NTBI). (See 'Role of chelation in reducing non-transferrin-bound iron' above.)

●Liver iron concentration – Liver magnetic resonance imaging (MRI) is the predominant method used to assess liver iron concentration (LIC). Liver R2 and R2* techniques can be used, and typically, a conversion to mg Fe/g dry weight of liver value is provided. R2 and R2* values do not correlate perfectly, especially at high LIC values. Therefore, it is best to follow one method over time.

In patients with transfusion-dependent thalassemia, liver MRI should be obtained starting by approximately age five years. In patients with sickle cell disease receiving regular red cell transfusions, transfusion initiation is often at a later age than in transfusion-dependent thalassemia; the first liver MRI usually is obtained after one year of transfusions if the patient is at least five years old. For younger children, sedation or general anesthesia often is required, and the accompanying risks need to be weighed against the information to be gained from the study. Patients with Diamond-Blackfan anemia (DBA) usually undergo MRI imaging at younger ages given the rapid iron accumulation. The liver MRI typically is obtained annually but may be performed more frequently, such as every six months, for very elevated LIC or when combination chelation is used.

Liver biopsy was the gold standard but now is uncommonly used as it is invasive and carries risks of bleeding, pain, and (rarely) more serious complications such as bile leakage. Biopsy allows assessment of histology including inflammation and fibrosis, which may be helpful in certain situations, such as with hepatitis infection or prior to hematopoietic stem cell transplantation.

●Cardiac iron – Cardiac T2* MRI is used to assess cardiac iron. The result is generally reported as a millisecond (ms) value, and lower numbers are worse. Values below 20 milliseconds (<20 ms) are considered abnormal.

This testing is usually obtained by age 10 years in patients with transfusion-dependent thalassemia, as cardiac iron loading is uncommon in younger children. The age to initiate testing in other diseases and additional disease-specific considerations are discussed below.

Cardiac T2* should be performed annually. The frequency may be reduced to every other year if the prior cardiac T2* was normal and the LIC is stable and within the target range.

A formula for converting between cardiac T2* MRI in milliseconds (ms) and mg/gram (mg/g) dry weight has been derived:

Online calculators for making this conversion are also available [131,132].

●Disease-specific considerations with monitoring iron burden

•Thalassemia – Individuals with thalassemia can develop iron overload even in the absence of transfusions. (See "Diagnosis of thalassemia (adults and children)", section on 'Iron overload'.)

The table summarizes monitoring in transfusion-dependent thalassemia (table 2), including iron stores, which is discussed in more detail separately. (See "Management of thalassemia", section on 'Assessment of iron stores and initiation of chelation therapy'.)

For thalassemia, cardiac T2* monitoring should start by age 10 years.

For children with poorly controlled LIC or where transfusion and iron chelation history is not available, cardiac T2* should be performed with their first liver iron assessment, even if younger than 10 years.

•Sickle cell disease – Iron burden in sickle cell disease depends on transfusion history. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Cardiac iron loading occurs less commonly in transfused patients with sickle cell disease compared with thalassemia. Factors that contribute to differences in iron distribution include chronic inflammation and, particularly, more effective erythropoiesis than in thalassemia [7].

Cardiac T2* should be obtained if the LIC is >15 mg/g dry weight for two years or more or in the setting of organ damage due to iron [133].

•Diamond-Blackfan anemia – Patients with transfusion-dependent Diamond-Blackfan anemia (DBA) also have early cardiac iron loading. (See "Diamond-Blackfan anemia", section on 'Transfusional iron overload'.)

In these individuals, cardiac T2* should be obtained by age 5 years or earlier if LIC is increased >15 mg/g dry weight.

When to intensify therapy (increase dose, change agents, add another agent) — Chelation is considered successful when LIC is in the range of 2 to 5 mg/g dry weight and cardiac T2* is >20 milliseconds (>20 ms). If MRI is not available, serum ferritin levels <1500 ng/mL are considered consistent with good control. Monitoring iron burden is discussed above. (See 'Monitoring iron burden' above.)

Adherence should be assessed and addressed regularly in all patients receiving iron chelation. Reasons for nonadherence including burdens and adverse effects are discussed above for each of the agents. (See 'Specific agents dosing and AEs' above.)

If adherence is adequate, chelation should be increased if there is a trend of rising iron burden or if iron burden is not in the optimal range and is not improving. If adherence is a concern, changing to another agent may alleviate burdens of therapy and allow improved adherence. (See 'Reasons to choose one agent over another' above.)

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) or lack of improvement in iron burden (ferritin levels averaged over a minimum of six months) [11].

The following may be used as criteria to intensify treatment if not improved over a period of six months:

●LIC >10 mg Fe/g

●Serum ferritin >2500 ng/mL

●Cardiac T2* MRI <20 milliseconds (<20 ms)

●Fall in the left ventricular ejection fraction because of cardiac siderosis

●Cardiac failure or arrhythmia

Options to intensify therapy include:

●Escalation to maximal allowed dose of the current chelator

●Switching to another chelating agent if adherence to the current agent has been inadequate

●Adding another chelating agent

Monitoring for adverse effects of chelating agents — Each of the available chelating agents has a different adverse effect profile. Monitoring requires familiarity with the adverse effect profile of the specific agent(s) and expertise in adjusting or holding dosing appropriate. Product information should be consulted.

●Deferasirox – The major adverse events are kidney and liver toxicity and gastrointestinal bleeding. (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' above.)

Monitoring includes:

•Complete blood count (CBC) at least monthly

•Kidney function at least monthly

•Liver function at least monthly

●Deferiprone – The most concerning adverse event is agranulocytosis. (See 'Deferiprone dosing + AEs (Ferriprox)' above.)

Monitoring includes:

•CBC weekly for the first six months, then every other week for the next six months, then every two to four weeks to coordinate with transfusions

•Liver function monthly

•Zinc levels annually

Dose interruption for neutropenia is discussed above. (See 'Deferiprone dosing + AEs (Ferriprox)' above.)

●Deferoxamine – Toxicities are discussed above. (See 'Deferoxamine dosing + AEs (DFO, Desferal)' above.)

Monitoring includes:

•Kidney function at least every three months

•Growth and development every three months

•Ophthalmologic and auditory toxicities annually

•Zinc levels annually

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

●Indications – Chelation is used to remove excess iron that cannot be treated by phlebotomy. This includes thalassemia (transfusion-dependent [TDT] and non-transfusion-dependent [NTDT]), sickle cell disease, myelodysplasia, post-hematopoietic stem cell transplantation, aplastic anemia, Diamond-Blackfan anemia, and hereditary hemochromatosis with concomitant anemia. The goal is to maintain a safe level of iron by removing excess stored iron, preventing iron accumulation from ongoing transfusions, and detoxifying non-transferrin-bound iron (NTBI). (See 'Indications for iron chelation' above.)

●When to start chelation – Acute decompensated heart failure is a medical emergency requiring immediate treatment. (See 'Acute decompensated heart failure' above.)

For other patients, the choice to use chelation is individualized based on patient age, comorbidities, and pace of iron accumulation. For those who chose chelation, it is typically initiated for liver iron concentration (LIC) ≥5 mg/g dry weight or cardiac T2* magnetic resonance imaging (MRI) <20 milliseconds (<20 ms), or ferritin ≥1000 ng/mL on two occasions. For patients receiving chronic red blood cell (RBC) transfusions, this occurs after 10 to 20 units or 100 mL of RBCs per kg. Individuals with TDT may develop iron overload as early as age 2 to 3 years and those with NTDT by 10 to 15 years. In NTDT, ferritin is less reliable and LIC is used. Considerations for other populations are discussed above. (See 'When to start chelation' above.)

●Choice of chelator – All three available chelators can be effective if taken properly; there is no universal best choice. Considerations include patient preference, burdens of administration, adverse effects, and sites of iron deposition; the table summarizes and compares these features (table 1). (See 'Choice of chelating agent' above.)

•Most patients prefer oral therapy (deferasirox in the United States or Europe, deferiprone in the United Kingdom, Asia, and resource-limited countries).

•Deferiprone is particularly good for reducing cardiac iron but is generally avoided in bone marrow failure states due to agranulocytosis risk.

•Deferasirox or deferoxamine is preferable for significant hepatic iron.

•Combinations are generally reserved for patients for whom a single agent is ineffective or to allow dose reduction and reduce adverse effects. (See 'When to consider using two drugs' above.)

●Dosing of specific agents – Starting doses and adverse effects are discussed above.

•Deferasirox – (See 'Deferasirox dosing + AEs (Jadenu, Exjade)' above.)

•Deferiprone – (See 'Deferiprone dosing + AEs (Ferriprox)' above.)

•Deferoxamine – (See 'Deferoxamine dosing + AEs (DFO, Desferal)' above.)

•Combinations – (See 'Combination chelation' above.)

●Monitoring

•Iron burden – Ferritin is monitored every one to three months and trends averaged over six months. LIC is checked annually starting by age five (for TDT). Chelation is considered successful when ferritin decreases <1500 mcg/L, LIC ≤2 to 5 mg/g, and cardiac T2* >20 milliseconds (>20 ms). (See 'Monitoring iron burden' above.)

If iron burden is not improving or rising, or if cardiac function deteriorates, the first step is to address adherence, and, if adequate, to increase the dose, change agents, or add a second agent. (See 'When to intensify therapy (increase dose, change agents, add another agent)' above.)

•Adverse effects – Patients require close monitoring of complete blood count, kidney and liver function, and for chelator-specific toxicities. (See 'Monitoring for adverse effects of chelating agents' above.)

●Other iron overload conditions – Separate topics discuss chelation in:

•Iron poisoning – (See "Acute iron poisoning", section on 'Management'.)

•Myelodysplastic syndromes – (See "Treatment of lower-risk myelodysplastic syndromes/neoplasms (MDS)", section on 'Supportive care' and "Sideroblastic anemias: Diagnosis and management", section on 'Iron overload'.)

•Sickle cell disease – (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Chelation therapy'.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Stanley L Schrier, MD, and William C Mentzer, MD, who contributed to earlier versions of this topic review.