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Real-World Use of Iron Chelators
Janet L. Kwiatkowski1

Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA

Whereas RBC transfusion therapy is lifesaving in thalassemia, obligatory iron loading accompanies such treatment and chelation therapy to remove and detoxify iron resulting from these chronic transfusions must therefore be administered. Morbidity and mortality in thalassemia is linked closely to the adequacy of chelation. Three chelators are currently available worldwide— deferoxamine, deferasirox, and deferiprone, although the latter is available in North America only in research protocols and compassionate use programs. These chelators can be used as monotherapy or in combination, although only the combination of deferiprone and deferoxamine has been extensively studied to date. Several factors, including chelator availability and its properties, drug tolerability, degree of organ-specific iron loading, ongoing transfusional iron burden, and patient preference, must be considered in the design of optimal, individualized chelation regimens, and these factors must periodically be reviewed and chelation adjusted accordingly. Ultimately, comparative effectiveness trials may help to determine the ideal strategy (eg, intensification of monotherapy or combined therapy including agents and doses) for treating various scenarios of organ-specific iron loading.

The majority of data regarding the treatment of transfusional iron overload are derived from the thalassemia population. Although this information is often extrapolated to other chronically transfused populations, clear differences exist. For example, iron-related cardiac morbidity and endocrinopathies, as well as cardiac and pancreatic iron loading, appear to be lower in sickle cell disease compared with thalassemia.1,2 In addition, susceptibility to chelator toxicities may be influenced by the underlying blood disorder. In particular, patients with bone marrow failure syndromes such as Diamond Blackfan anemia may be at higher risk of developing neutropenia with deferiprone.3 This review is intended to provide an overview of the approaches to chelation therapy in patients with transfusion-dependent thalassemia.

Goals of chelation
Multiple methods of assessing the degree of iron overload exist, including serum ferritin levels, liver iron concentration by biopsy, superconducting quantum interference device (SQUID), and magnetic resonance imaging (MRI), and cardiac iron loading assessed by MRI. Each method has benefits and limitations, and often combinations of these tests are used to monitor iron burden. Details about MRI techniques for estimation of iron burden are provided in an accompanying article in this section and will not be discussed herein. The overall goal of chelation is to maintain a “safe” iron level among patients who have increased iron loading, typically from transfusion therapy. Ideally, chelation should be administered in a way to prevent excess iron accumulation and the resulting hepatic, endocrinologic, and cardiac complications by matching the ongoing transfusional iron intake. Chelators also bind non-transferrin-bound and labile plasma iron, protecting vulnerable organs such as the heart from damage by these toxic iron forms, and continuous chelator exposure is optimal in this regard. In practice, however, chelation therapy is often used to remove excess stored iron and to reverse related complications. The level of “acceptable” iron burden to maintain in chronically

transfused individuals through the use of chelation has recently been called into question.4 In untransfused individuals, the normal liver iron concentration ranges from 0.17-1.8 mg Fe/g dry wt. Traditionally, chelation therapy has been dosed to maintain a slightly higher liver iron concentration of 3 Յ 7 mg Fe/g dry wt of liver, a level of hepatic iron burden that is seen in asymptomatic heterozygotes for hereditary hemochromatosis.5 Corresponding ferritin goals are to maintain a level between 500 and 1500 ng/mL. In recent years, however, more aggressive chelation regimens have been advocated, typically with combination deferiprone (75-100 mg/kg/d) and deferoxamine (20-60 mg/kg/d) aimed at achieving “normal” body iron stores. These regimens are accompanied by a subsequent reduction in the frequency and dose of deferoxamine while maintaining these “normal” iron levels to reduce the risk of chelator toxicity.6 With such an approach, 15 of 18 patients with cardiac dysfunction developed normal cardiac function, including 9 of 12 who had previously required cardiac medications and were able to discontinue them. In addition, no deterioration in cardiac function was seen in the 34 patients with normal cardiac function at baseline.6 Furthermore, endocrinopathies including hypothyroidism, hypogonadism, and non-insulindependent glucose intolerance were reversed in some, but not all, patients treated in this fashion.6 Nonetheless, the risk of toxicity with deferoxamine is increased among patients with lower iron burdens,7 and bone changes and growth failure can develop in children when iron burden is low compared with the chelator dose,8 calling into question whether such an aggressive approach to chelation is appropriate. It is less clear if similar toxicity is seen with deferasirox or deferiprone at low levels of iron burden. Audiological and ophthalmological toxicity were uncommon among subjects maintained on deferiprone monotherapy after achievement of normal body iron stores, suggesting that this chelator may be safer to use at lower iron levels.6 Similarly, a preliminary report showed no increase in adverse effects among subjects taking deferasirox whose serum ferritin level fell below 1000 ng/mL9; however, current prescribing guidelines recommend holding the drug when ferritin levels are below 500 ng/mL.

Hematology 2011


11 and in preventing endocrine complications. uncomfortable. and/or cytopenias. inconvenient. underlying hepatic or renal insufficiency. Chelator properties The properties of the 3 currently available chelators are summarized in Table 1.13 Longterm therapy with deferoxamine is also associated with a reduction in cardiac complications and improved survival. may be more effective †With continuous infusion. especially for subjects with high transfusional iron burden. especially with higher doses. Lack of improvement in ejection fraction with deferasirox treatment (for 1-2 years) in patients with normal cardiac function.” However. Deferoxamine Deferoxamine.Table 1. and patients with non-transfusion-dependent thalassemia Age considerations Not recommended for children Ͻ 3 years with low transfusional iron burden Studied in children as young as 2 years old Limited or no data on children ages Ͻ 6-10 years *Reports of insufficient liver iron removal in some patients at doses of 75 mg/kg/d. intravenous Urinary. because the need for parental administration is cumbersome.16 The adverse effects of deferoxamine are listed in Table 1. usually given in higher doses of up to 60 mg/kg/d as a continuous intravenous infusion. fecal ϩϩϩ ϩϩ† ϩϩ† Local reactions Audiologic Ophthalmologic Allergic reactions Bone abnormalities Pulmonary at high doses Neurological at high doses Adherence due to parental administration Licensed for the treatment of chronic iron overload due to transfusiondependent anemias (and for treatment of acute iron intoxication) Deferasirox Tridentate (2:1) 20-40 mg/kg/d once daily Tablets for oral suspension Fecal ϩϩϩ ϩϩ‡ ?§ Gastrointestinal Rash Rise in creatinine Elevated hepatic enzymes Gastrointestinal bleeding¶ Hepatic failure¶ Renal insufficiency and failure¶ Cost. not licensed in North America Availability In Europe. has now been used in routine clinical practice for more than 40 years. Furthermore. Redness and induration at the infusion site are the most common. ¶More common in patients with advanced age. Further studies are needed to determine effectiveness at cardiac iron removal compared with deferoxamine and deferiprone. deferoxamine. can reverse cardiac complications15 and reduce cardiac iron burden as measured by T2* MRI. not commercially available in all countries Licensed in Europe and Asia for the treatment of iron overload in thalassemia major where deferoxamine is contraindicated or inadequate. Clear data support its effectiveness in lowering serum ferritin levels and hepatic iron10. growth.14 In addition. may be less effective in patients with more severe hepatic iron loading. §Not studied in patients with cardiac dysfunction. the greatest challenge with deferoxamine is patient adherence with therapy. gastrointestinal side effects may limit optimal dosing In United States. and bone toxicities may be minimized by avoiding “overchelation. and approved for use when deferoxamine is inadequate or contraindicated in patients with other anemias.12. A brief description of each chelator’s properties is presented below. 6 years and older. ‡Limited data show cardiac iron removal with modest cardiac iron loading. Properties of iron chelators Property Stoichiometry (chelator:iron) Usual dose Route of administration Excretion Ability to remove liver iron Ability to remove cardiac iron Ability to reverse iron-related cardiac dysfunction Adverse effects Deferoxamine Hexadentate (1:1) 25-60 mg/kg/d over 8-24 hours Subcutaneous. but higher dosing. high-risk myelodysplastic syndrome. cardiac morbidity and mortality continue to occur in patients 452 American Society of Hematology . the first available chelator. and time-consuming. Audiological. with emphasis on data regarding the ability to remove cardiac iron. approved for the treatment of transfusional iron overload in beta thalassemia major. licensed for the treatment of transfusional iron overload in individuals ages 2 years and older Deferiprone Bidentate (3:1) 75-100 mg/kg/d in 3 divided doses Oral tablet or solution Mainly urinary ϩϩ* ϩϩϩ ϩϩϩ Gastrointestinal Neutropenia/agranulocytosis Arthralgia Elevated hepatic enzymes Challenges Need for frequent (weekly) blood count monitoring. patients 2-5 years. ophthalmological.

and iron-associated cardiac dysfunction.25. a significantly greater improvement in cardiac T2* and left ventricular function was seen after treatment with deferiprone compared with deferoxamine. cardiac T2* improved by 43.31 This level of iron overload typically occurs after 1-2 years of transfusions. should be individualized to target organ–specific iron burden.2% Ϯ 17.33 serum ferritin and ongoing transfusion burden. but rarely reach the abnormal range10. no subjects with normal cardiac T2* at baseline developed an abnormal value (T2* Ͻ 20 msec) over the follow-up period. which can be inconvenient for patients. introduced into clinical trials in the 1980s.7 to 20. with an incidence of 0.18 Some of the failures may be attributed to underdosing of the drug. in contrast to the subjects with low cardiac T2* values.14 and a central goal of iron chelation regimens is to prevent or remove cardiac iron loading.2 to 14. 27.23 Treatment with deferiprone resulted in a significantly greater overall reduction in cardiac iron compared with deferasirox. Starting chelation therapy In thalassemia major. deferasirox is approved as a second-line agent in children younger than 6 years (Table 1). in a randomized trial among patients with moderate cardiac siderosis (T2* ϭ 8 Ͻ 20 ms) and normal cardiac function. and this chelator appears to be particularly efficacious with regard to cardiac iron removal. Reversal of heart failure with deferasirox treatment in a patient with thalassemia and transfusional iron overload has been reported. Gastrointestinal disturbances often improve with continued administration of the drug. in 78 patients Tailoring chelation regimens Chelation regimens.1 ms).27 In a second report of 22 patients with cardiac T2* Ͻ 20 ms treated for 18 months with deferasirox (mean end of trial dose.8 ms over 2 years of treatment. the failure to respond was predicted by higher baseline liver iron concentration and ferritin levels. Patients who are maintaining low iron stores (normal cardiac T2*. enabling entry into myocytes.3% Ϯ 18.10 The ability to remove hepatic iron was demonstrated in several additional studies.30 Further studies are needed to delineate better the effect of deferasirox on cardiac iron. treatment with deferiprone resulted in improvement in cardiac T2* among patients with all degrees of cardiac iron loading (including severe iron loading with T2* Ͻ 8 ms). was the first oral chelator to undergo extensive testing.5 ms). Common adverse effects of deferiprone are presented in Table 1. including agent(s) and dosages. but have led to discontinuation of therapy in some patients. in that study. to maintain a net negative iron balance (or neutral balance for patients without elevated iron stores). The most serious adverse effects associated with deferiprone are agranulocytosis and neutropenia. Elevations in serum creatinine occur in approximately 1/3 of subjects. Interestingly.28 Similar to the previous study. Furthermore.7 ms) and those with mild to moderate (T2* ϭ 10 Ͻ 20 ms) siderosis (14. a significant improvement in ejection fraction (from 67.3 mg/kg).27 No significant improvement in left ventricular ejection fraction was seen after 2 years of treatment with deferasirox.5 mg/kg/d (range. 33. but not all.6 mg/kg/d) has also been shown to prevent cardiac iron accumulation. patients with transfusional iron overload.29 Moreover. to limit toxicity. A summary of one approach to treatment based on hepatic and cardiac iron loading is presented in Table 2. respectively. A dose of deferasirox of 20 mg/kg/d or deferoxamine of 25-30 mg/kg/d is often used initially to avoid the risk of toxicity with “overchelation” in growing children.7 Ϯ 4.3 to 8. as well as quality of life. likely related to difficulties with adherence. In addition. liver iron concentration Ͻ 7 mg/g dry wt) can be maintained on their current Hematology 2011 453 . which may make deferoxamine a better choice for some children.17 Deferiprone Deferiprone. no change in left ventricular ejection fraction was seen over the 18 months of treatment.7% to 69.treated with deferoxamine. Studies have shown a reduction or stabilization of serum ferritin levels and liver iron concentrations in most. Patient preference must also be addressed because this will affect adherence and ultimately the success of the therapy.5%) was seen in this group of patients with normal cardiac T2* at baseline.22 In a large clinical observational study. and to optimize adherence. although small numbers of subjects receiving deferasirox at relatively low doses (mean.19 Deferiprone is a small molecule that is lipophilic.8% in 14 patients. cardiac T2* did not worsen over 1 year of treatment (32 to 32. significant improvements were seen in both the group with severe (T2* Ͼ 5 Ͻ 10 ms) cardiac siderosis (7. cardiac T2* significantly improved from a mean of 11. oral administration may be difficult in young children due to behavioral issues. In Europe. The ability of deferasirox to reverse cardiac disease has not yet been investigated. Chelation strategies tailored to liver and cardiac iron burden with ongoing transfusion requirements.2 and 2. 26. patients currently can only receive the drug through research protocols or compassionate use programs. chelation therapy is usually initiated in children 2 years of age or older who have received 10 units of RBCs and/or have a serum ferritin level above 1000 ng/mL on at least 2 measurements (not obtained when ill). and higher doses of 90-100 mg/kg may be more effective in patients with high transfusional iron intake and/or elevated body iron stores.34 or serum ferritin level and cardiac T2*35 have been proposed.20 and lower myocardial iron deposition21 among patients treated with deferiprone compared with deferoxamine.24 Weekly blood counts are recommended. Organ-specific iron burden Cardiac complications remain the most common cause of death in transfused thalassemia patients. Administration of deferasirox (mean dose. Rare reports of fulminant hepatic failure have resulted in the recommendation to obtain liver function tests every 2 weeks for 1 month after starting therapy and then monthly thereafter.26 In a single-arm trial of 101 patients with mild to severe cardiac iron loading treated with deferasirox at a mean dose of 34. kidney function should also be monitored monthly. Common adverse effects with deferasirox are listed in Table 1.8% in 13 “responders” but worsened by 15.6 mg/kg/d) may have limited these analyses.8 per 100 patient-years. although the ejection fraction was normal at baseline. because the prior studies all required normal heart function for inclusion.23 The major challenge to treatment with deferiprone is the lack of commercial availability in North America.32 Deferasirox Deferasirox in doses of 20-30 mg/kg/d was shown to have similar efficacy to deferoxamine with regard to reduction in liver iron concentration and serum ferritin levels in a large randomized trial in thalassemia major. and therefore deferoxamine is usually prescribed initially. Retrospective studies have demonstrated reduced cardiac morbidity and mortality17. with thalassemia without evidence of cardiac iron loading (cardiac T2* Ն 20 ms).6 Ϯ 4. 30-50 mg/kg/d).

consider adding DFO at least 3 d/wk ● DFO ϩ DFP: increase dose of DFP/DFO and/or no. Iron is removed from different organs at different rates. including ascorbate deficiency and infection/inflammation. of days and duration of infusion ● DFX: increase dose ● DFP increase dose. Combination therapy with deferoxamine and deferiprone. Changes in ferritin levels often parallel changes in liver iron concentration. days infused ● DFX: increase dose ● DFP increase dose. use continuous infusion. DFP. intensification of chelation is also indicated for such elevated liver iron levels. 454 American Society of Hematology .36 Therefore. low cardiac T2* values (Ͻ 20 ms) should trigger intensification of chelation regimens regardless of liver iron burden. of days DFO Escalate chelation* ● DFO: increase dose and/or no. monitor to limit toxicity ● DFX: continue/increase dose. consider reducing DFO dose or no. deferasirox. Address adherence concerns and discuss strategies to improve adherence. Cardiac T2* values of 10 Ͻ 20 ms indicate mild to moderate iron loading and values Ͻ 10 ms indicate severe myocardial siderosis. deferiprone. add DFO at least 5 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. Similarly. although a variety of factors. the use of deferasirox in patients with low cardiac T2* and cardiac dysfunction is not recommended routinely. Strategy for adjusting chelation therapy targeting organ-specific iron loading* Liver Iron Concentration Յ 2 mg/g dry wt† Cardiac T2* Ն 20 ms Reduce chelation ● DFO: hold. of days DFO is infused Cardiac T2* Ͻ 10 ms Continue/escalate chelation* ● DFO: continue/increase dose. Liver iron concentrations Ͼ 15 mg/g dry wt predict a higher risk of cardiac disease and death37 and progression of hepatic fibrosis. serial ferritin levels. of days DFO is infused Escalate chelation* ● DFO: increase dose and/or no. of days infused. administer as continuous infusion ● DFX: increase dose¶ ● DFP increase dose. which can be obtained more easily than liver or cardiac iron estimation. resume at lower dose once ferritin reaches Ͼ 500 ng/mL or LIC Ͼ 2 mg/g dry wt ● DFP: consider continue at lower dose Continue current chelation ● DFO: continue current dose ● DFX: continue current dose ● DFP: continue current dose ● DFP ϩ DFO: continue current doses. of days. of days of DFO Escalate chelation* ● DFO: increase dose and/or no. add DFO at least 3 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. of days. resume at lower dose once ferritin reaches Ͼ 500 ng/mL or LIC Ͼ 2 mg/g dry wt ● DFX: hold. consider switching agent or combination therapy. of days DFO is infused Escalate chelation* ● DFO: increase dose and/or no. and hepatic iron levels usually improve more rapidly than cardiac iron levels with intensification of chelation. The development of cardiac dysfunction or arrhythmia should also prompt intensification of chelation. of days DFO is infused Escalate chelation* ● DFO: increase dose and/or no. so both hepatic and cardiac iron must be measured to optimize chelation. should be considered for patients with low cardiac T2* or iron-related cardiac disease (see below). Nonetheless.Table 2. Therefore. either decrease or increase ferritin levels. ‡Due to lack of data. administer as continuous infusion ● DFX: increase dose ● DFP: increase dose. DFX. intensification is indicated for a liver iron concentration above 7 mg/g dry wt that is not decreasing. consider add DFO at least 2 d/wk ● DFP ϩ DFO: continue/ increase dose of DFP or no. add DFO at least 2 d/wk if possible ● DFP ϩ DFO: increase dose of DFP or no. monitor to limit toxicity ● DFX: continue monitor to limit toxicity ● DFP: continue/increase dose ● DFP ϩ DFO: continue/increase dose of DFP Continue/escalate chelation* ● DFO: continue/increase dose and/or no. monitor to limit toxicity‡ ● DFP: increase dose. add DFO at least 3 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. add DFO at least 5 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. days infused. Patients with very low T2* values of Ͻ 6 ms have a 47% chance of developing congestive heart failure within the next year. consider add DFO at least 2 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. chelation regimen using continued monitoring of organ-specific iron burden and transfusion requirements to adjust dose (ie. of days as LIC approaches 2 mg/g dry wt ● Cardiac T2* ϭ 10 Ͻ 20 ms Continue/escalate chelation* DFO: continue increase duration of infusion. of days DFO Escalate chelation* ● DFO: increase dose and/or no. administer as continuous infusion ● DFX: increase dose‡ ● DFP: increase dose. If escalation is required and patient is receiving maximal dose or cannot tolerate due to toxicity. administer as continuous infusion ● DFX: increase dose¶ ● DFP: increase dose. of days DFO is infused Ͼ 2 Յ 7 mg/g dry wt or 7 Յ 15 mg/g dry wt and decreasing 7 Յ 15 mg/g dry wt and not decreasing Escalate chelation* ● DFO: increase dose and/or no. of days DFO is infused Ն 15 mg/g dry wt DFO indicates deferoxamine. increase for rising levels and reduce or hold dose for low iron burdens). which may be exacerbated by concomitant hepatitis C infection. use lower doses for growing children to avoid bone and other toxicity. †Close monitoring for adverse events with dose adjustments as needed. add DFO at least 3 d/wk ● DFP ϩ DFO: increase dose of DFP/DFO and/or no. of days infused and duration of infusion ● DFX: continue/increase dose ● DFP increase dose. days infused and duration of infusion ● DFX: increase dose ● DFP increase dose. *See Table 1 and text for dose ranges. if available. may be used to assess trends in iron burden and to help adjust chelator dosing.

35 Յ 50 mg/ kg/d.41 However. Adherence with deferasirox therapy has been reported to be better than with deferoxamine. and/or individual pharmacokinetics45 may result in an inadequate response. minimize/reduce toxicity.15. respectively) and in left ventricular ejection fraction (2. Adherence/patient preferences Any therapy will only be effective if the patient actually receives it. respectively. although this approach has not been tested. it is important to address side effects and adherence as well as changes in iron burden regularly to adjust chelation regimens.39 Nonetheless. not to exceed the therapeutic index of a chelator (too high a chelator dose compared with iron burden). because this is associated with an increased risk of audiological. may simply not be tolerable to some patients. Doses of deferasirox of Ͼ 30 mg/kg/d did not have apparent increased toxicity.38 Similarly. may be optimal.5 mg/kg/d) will likely need higher doses of chelator (deferasirox. and having the patient set cell phone or watch alarms to alert them to take their medication.4 to 15. Furthermore. Deferiprone with deferoxamine has been used since the 1990s at a variety of dose levels and schedules.8 Changing the chelator agent (eg. should be administered at doses of up to 100 mg/kg/d if used as monotherapy22 and preferably in combination therapy (see below). With transfusional iron intake of more than 0.43 so generally doses of Ͼ 60 mg/kg/d should be avoided. and bone toxicities.3 days/ week) combined with deferiprone (73. such as gastrointestinal upset with deferasirox or infusional site reactions with deferoxamine. Therefore. Deferiprone. deferoxamine to deferasirox or vice versa) should be considered in patients who are prescribed the highest recommended dose but still have unacceptable iron burden.39 and patients reported greater satisfaction and convenience with deferasirox compared with deferoxamine. deferasirox doses of 20 mg/kg/d were ineffective in more than half of subjects. where available. deferoxamine. A shuttling hypothesis whereby deferiprone binds iron and then redistributes it to deferoxamine has been proposed. whereas others coadminister the 2 drugs on the same day. and deviations from the prescribed course of chelation adversely affect outcome.40 A preliminary report from the Thalassemia Clinical Research Network (TCRN) showed deferasirox to be the most common chelator used (57% of subjects in participating sites). subjects receiving combination therapy had significantly greater improvement in cardiac T2* (from 11. should also be considered. all 3 currently available drugs could be used together. intensification of deferasirox therapy to 40 mg/kg/d also may be considered. Periodic monitoring of cardiac and hepatic iron is still recommended if possible. acute pulmonary and neurotoxicity may develop with higher doses. Care should be taken. for patients with significant cardiac siderosis. Careful monitoring of transfusional iron intake is needed. 30-40 mg/kg/d. Strategies to optimize adherence to treatment must be addressed as well. In the presence of iron-related cardiac disease or abnormal cardiac T2* values.5 mg/kg/d.9 Ϯ 4 mg/kg/d) was Monotherapy Intensification of chelation can be achieved by increasing the daily dose (and/or the number of days of administration for deferoxamine) of an individual chelator if the patient is currently receiving less than the upper recommended dose. such as splenomegaly or red cell antibody. Such an approach can improve cardiac T2* and reverse cardiac disease. which leads to an additive effect.46. and levels persistently above this value should trigger intensification of chelation.44 Monotherapy is not effective in all patients for a variety of reasons. increasing both the deferoxamine dose and duration of exposure (ie. in single-arm trial of 15 patients with severe myocardial siderosis (T2* Ͻ 8 ms) and myocardial dysfunction. Investigation of the reason for higher transfusional needs.Ferritin levels above 2500 ng/mL are associated with an increased risk of morbidity and mortality. theoretically. Some protocols use sequential administration of the drugs. Hematology 2011 455 . The superiority of this combination compared with deferoxamine alone was demonstrated in a randomized. 52%. nontransferrin-bound iron forms. Furthermore. Adverse drug effects may prevent optimal dosing. but this approach cannot yet be routinely recommended for patients with iron-related cardiac dysfunction given the lack of data on the ability of deferasirox to improve cardiac function. Other adverse effects. 38 Ϯ 10. respectively) than those receiving deferoxamine with placebo. almost 20% of patients in the TCRN chose to continue deferoxamine and never tried deferasirox. certain chelators cannot be used in some patients due to the development of significant toxicities such as gastrointestinal bleeding and hepatic or renal failure with deferasirox or agranulocytosis with deferiprone. having the patient keep the medication near an item frequently used (such as a toothbrush).42. Combination therapy may be effective in such situations and particularly when dangerously high levels of cardiac iron exist. poor adherence to treatment may lead to underdosing. Dual-chelator therapy may improve compliance. but doses of 30 mg/kg/d led to a reduction in liver iron concentration in 82%. treatment with deferoxamine (mean dose.38 Similar dose principles likely hold true for deferiprone. improve organ-specific iron removal. Transfusional iron burden It is clear that ongoing blood transfusion requirements influence the chelator dose needed: patients with higher transfusional iron intake generally require higher chelator doses.2 mg/kg for 5. Older children and adults with higher rates of iron loading (Ͼ 0.6%. and Ն 50 mg/kg/d were effective in 17%. because data regarding the use of deferiprone as monotherapy with severe myocardial iron loading and cardiac dysfunction are limited. ophthalmologic. and 89% of patients. continuous infusion 7 days per week) is recommended to limit exposure to toxic. at this level of transfusional iron intake. especially in patients with low ejection fractions. With cardiac iron loading (T2* Ͻ 20 ms). generally with deferiprone given in doses of 50-100 mg/kg/d (in 3 divided doses) daily and deferoxamine in doses of 20-50 mg/kg/d either subcutaneously or intravenously administered at least 2 days a week.47 and coadministration of these 2 drugs. placebo-controlled trial of 65 patients with mild to moderate cardiac iron loading (cardiac T2* ϭ 8-20 ms). and enhance iron removal if an additive or synergistic effect occurs. 40-50 mg/kg/d). if practical.48 After a 12-month treatment period.7 to 17. Therapy with more than one chelator Two chelators can be used either sequentially (on different days) or in combination (both given on the same day) and. deferoxamine doses of 25 Յ 35 mg/kg/d. The combination of deferiprone and deferoxamine is currently the most effective means of reducing cardiac iron loading and should be initiated.6% vs 0.7.7 ms. especially with young children.7 ms vs 12. Such strategies include regularly reviewing trends in iron burden with the patient.16 Very high dosing of deferoxamine (such as 10 mg/kg/h) has been used in the past.

gastrointestinal problems and headache) noted. often lack the ability to compare changes in organ-specific iron loading with different dosing strategies. Depletion of excessive liver iron stores with desferrioxamine. solely oral therapy. 3. N Engl J Med. 2007. Prevalence of endocrine complications and short stature in patients with thalassaemia major: a multicenter study by the Thalassaemia International Federation (TIF). Wood JC. 2(suppl 2):249-255. with many assessing cardiac iron removal in moderate cardiac siderosis. Fatal agranulocytosis after deferiprone therapy in a child with Diamond Blackfan anemia. PA 19104. Harmatz PR. Huehns ER.135:574-582. 2008. direct comparisons of the efficacy of the 2 oral chelators have not been performed. Olivieri NF. 13. Such treatment could limit toxicity associated with each chelator and improve adherence. Colket Bldg. but this approach still needs to be studied. Porter JB. De Sanctis V. has undergone phase 1 study. 8. et al. Kwiatkowski. Nienhuis AW. suggesting that the chelators may simply compete for a common iron pool. as well as a reduction in serum ferritin and liver iron concentration after 12 months of treatment. Harris J. Some of these obstacles and limitations may be overcome with comparative effectiveness trials. Piga A. when available.341:99109. Piga A.51 It is unclear if this will hold true in humans. N Engl J Med. an agent that is not FDA approved. Farmaki K. including cost. Br J Haematol. Pediatr Endocrinol Rev. and single-arm treatment trials. Disclosures Conflict-of-interest disclosure: The author declares no competing financial interests.49 Retrospective analysis of the efficacy of various chelation regimens confirmed that combination therapy with deferoxamine and deferiprone was superior with regard to cardiac iron removal. 1992. Griffith PM. Furthermore. Off-label drug use: Use of deferiprone. Fax: (215) 590-3992. Randomized trials.effective. Berdoukas V. et al. Blood. to assess the proportion of subjects who respond. MD. Jaswon MS.103:1934-1936. the combination of deferiprone and deferasirox. Safety of deferasirox (Exjade) in patients with transfusion-dependent anemias and iron overload who achieve serum ferritin levels Ͻ1000 ng/mL during long-term treatment [Abstract]. A large randomized trial of deferasirox and deferoxamine was conducted. Am J Pediatr Hematol Oncol. Deferoxamine. and information about the use of chelators in combination.112:5423. and no excessive toxicity was seen. 1994. Malaventura C. Clearly. Phone: (215) 5903437. such randomized trials will be difficult. This drug is currently being investigated in phase 2 studies. randomized trials of deferiprone monotherapy compared with deferoxamine are limited. 2004. FBS0701. 2011. Eleftheriou A. Growth failure and bony changes induced by deferoxamine. Wood JC. 1989. Henter JI. Room 11024. However.148:466-475. Porter JB. and to stratify responses based on iron burden and transfusional iron intake.14:48-56. patient numbers. Schwartz E. Further research regarding the safety and efficacy of treatment with deferasirox and deferoxamine is needed before recommendations for routine clinical practice can be made. resulting in a significant improvement in cardiac T2* (5. combination treatment with deferasirox and deferoxamine did not show additive (or synergistic) iron excretion in an iron-overloaded gerbil model. Carson S. limitations to all 3 chelators exist.50 Liver iron concentration significantly improved at a median follow-up of 29 weeks. Chouliaras G. Cohen A. Philadelphia. 10. which can use large patient databases to assess the effectiveness of treatments in the “real world” setting as well as to compare costs and other factors. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. Nelson MD. Hazell JW. Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle-cell disease. Lee PD. which has not been studied. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. Moving forward. Coates T. 6. Iron chelation in thalassemia: time to reconsider our comfort zones.4:17-26. Coates TD. to conduct for a variety of reasons. Blood. 4. Martin M. et al.23 The combination of deferasirox and deferoxamine has not been extensively studied. The beta-thalassemias. 1984. Similarly. was approved for clinical use before the routine practice of performing phase 3 studies.9 ms) and left ventricular ejection fraction (51. In a pilot study. 3501 Civic Center Blvd. Blood.edu. et al. 2. Karle ´ n J. Farmaki K.107:3455-3462. One drug. Br J Haematol. and a need for additional chelator options exists.2% to 65. 9. Children’s Hospital of Philadelphia. East CA. 5. 456 American Society of Hematology . Berdoukas V. 2006. is particularly appealing. Tyszka M. Brittenham GM.58:369373. Myocardial iron loading in transfusion-dependent thalassemia and sickle cell disease.52 In 16 adults with transfusional iron overload. A phase 3 study of deferasirox (ICL670). Pappa C. Correspondence Janet L. a desazdesferrithiocin tridentate chelator modified to limit nephrotoxicity.73:403-409.331:567573. in patients with beta-thalassemia. chop. Cohen A. Koren G. nor have studies been conducted comparing deferoxamine in combination with deferiprone or deferasirox. 14 patients with thalassemia major and liver iron concentration Ͼ 15 mg/g dry wt or Ͼ 5 mg/g dry wt plus evidence of iron-related organ dysfunction were treated with deferasirox (20-30 mg/k/d) daily and deferoxamine (35-50 mg/kg/d) for 3-7 days per week (longer durations for higher liver iron concentrations). Prospective. if not impossible. MSCE. Br J Haematol. FBS0701 was administered daily for 1 week. a once-daily oral iron chelator. Br J Haematol. Olivieri NF. with limited toxicity (eg. Division of Hematology. 11. Cohen A. e-mail: kwiatkowski@email. Fung EB. Cappellini MD. 2010. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. small case series.6%). Blood. 1999. 12.109:5157-5159. et al. 2006. 7.7 to 7. but sequential rather than combination therapy would be expected to be a better strategy if the 2 chelators compete for the same iron pool. Expert Rev Hematol. 2004. Tzoumari I. the first available chelator. Future research strategies Most prior studies of chelator efficacy have consisted of retrospective analyses. but that study did not assess changes in cardiac iron and did not assess doses of deferasirox in excess of 30 mg/kg/d (an inadequate dose in a subset of patients). 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