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      Drugs & Diseases > Hematology

      Transfusion-Induced Iron Overload Treatment & Management

      Updated: May 07, 2021
      • Author: Geneva E Guarin, MD, MBA; Chief Editor: Emmanuel C Besa, MD  more...
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      Treatment

      Medical Care

      Iron chelation therapy

      The primary goal of iron chelation therapy is to prevent the accumulation of iron reaching harmful levels by matching iron intake from blood transfusion, with iron excreted by iron chelation. [77]  Although non–transferrin-bound iron and liver deposits are chelatable to a degree, iron that is deposited in other organs such as the heart is not readily chelated, making cardiac failure a leading cause of death in patients who undergo long-term transfusions. [78]  Autopsy studies in the 1970s [79]  and MRI data [80] obtained more recently show that after receiving 75 or more units of transfused blood, more than 50% of patients have excess iron in their myocardium.

      The initiation of chelation therapy thus is a decision that has to be individualized. When to start chelation depends on the number of transfusions that were already given, the extent of iron deposition in the liver and the heart and the corresponding degree of dysfunction in these organs, and the type of transfusion regimen. [81]  

      In general, chelation therapy is started in individuals who have received regular transfusions for 1 to 2 years, whose serum ferritin levels exceed at least 1000 to 1500 mcg/L, or whose liver iron levels are > 3 to 5 mg/g dry weight. [82] This corresponds to approximately a total of 120 to 200 mL of transfused RBCs per kilogram. [82]  The American Academy of Pediatrics suggests that children receiving chelation therapy should maintain a serum ferritin level of < 1500 ng/mL or liver iron < 7 mg/g dry weight. [82]

      Three agents are approved for iron chelation therapy:

      • Deferoxamine
      • Deferiprone
      • Deferasirox

      Deferoxamine

      Deferoxamine (DFO; Desferal) has been used for more than 30 years for iron chelation. However, it is a parenteral drug that requires subcutaneous or intravenous infusions because of its short half-life and poor oral bioavailability, making compliance an issue. [83]  The only randomized trial comparing chelation with intramuscular deferoxamine to no chelation was small and involved 20 children with thalassemia. At about 6 years, the mean hepatic iron concentration in liver tissue was 42 mg/g in the untreated group and 26 mg/g in the deferoxamine group. [84] At 14 years, 6 deaths had occurred in the untreated group compared with 1 in the treated group. [85]

      The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major. [86]  Moreover, deferoxamine halts the progression to cirrhosis of hepatic fibrosis brought about by iron overload. [87]  

      The main limitations of deferoxamine as an iron chelator are its short blood circulation time, which necessitates more frequent administration, and its non-preferential distribution into non-target tissues such as the brain, kidney, muscle, and lungs. [88]  

      Current research is exploring the use of nanogel-deferoxamine conjugates to improve the performance of deferoxamine. A 2018 study found that nanogel-deferoxamine conjugates reduced the cytotoxicity of deferoxamine and significantly decreased the ferritin levels in iron-overloaded macrophages in vitro. In the same study, in an animal model, nanogel-deferoxamine had a prolonged circulation time and preferential accumulation in the liver and spleen. [89]  

      A 2019 study of nanochelators (multiple deferoxamine moieties conjugated on a backbone of polymeric nanoparticles) demonstrated that such nanochelators provide more favorable biodistribution while effectively removing excess iron exclusively via urinary elimination. [88]  These advancements in deferoxamine as an iron chelator promise to provide enhanced safety and efficacy.

      Meanwhile, deferiprone and deferasirox offer the convenience of oral iron chelation. However, those agents have significant toxicities (eg, gastrointestinal bleeding, agranulocytosis, neutropenia, thrombocytopenia, hepatic fibrosis, and kidney failure). [88]  Long-term follow-up is required before pumps and needles can be thrown away.

      Deferiprone

      Deferiprone (Ferriprox) was approved by the US Food and Drug Administration (FDA) in 2011 for transfusional iron overload caused by thalassemia syndromes. This approval was based on serum ferritin level reduction; no controlled trials demonstrated a direct treatment benefit (eg, improvement in disease-related symptoms, functioning, or increased survival). [90]  

      In April 2021, the FDA approved deferiprone for transfusional iron overload in adults and children aged 3 years and older with sickle cell disease and other anemias. Approval was based on a controlled noninferiority comparative trial of deferiprone with deferoxamine, based on evaluation of liver iron concentration (LIC). Over 12 months, estimated mean decrease from baseline in LIC was 4.13 for deferiprone and 4.38 for deferoxamine. Upon completion of the first year of therapy, 89 of the 122 patients in the deferiprone group opted to continue with treatment and 45 of the 63 patients in the deferoxamine group opted to switch to deferiprone. LIC continued to decrease over time in the patients receiving deferiprone, with the mean value dropping from 14.93 mg/g at baseline to 12.30 mg/g after 1 year, to 11.19 mg/g after 2 year, and to 10.45 mg/g after 3 years. [90]

      At least one study has reported improved cardiac outcomes with deferiprone. [91]  If true, that is a major advantage of this drug because cardiac failure remains the major cause of mortality in thalassemia. An Italian study comparing deferiprone with deferoxamine in thalassemia showed statistically significant improvement in ejection fraction in the deferiprone group at 2 years; however, the clinical significance of this finding (59% vs 62%) is unclear. [92]  In addition, concerns have been raised about bony dysplasia and impaired growth of ulnar epiphysis in Indian children treated with deferiprone. [93]

      Deferasirox

      Deferasirox (Exjade tablet for oral suspension, Jadenu oral tablet, Jadenu Sprinkles oral granules) is preferred by patients due to its convenient once-daily oral administration [94] and its cost-effectiveness. [95]  The FDA approved Exjade for chronic iron overload from blood transfusions in 2005, and approved Jadenu in 2015. Deferasirox has also been studied in non-transfusion-dependent thalassemia [96] and at both low and high iron burdens. [97] This agent has an acceptable tolerability profile and appears to have similar efficacy to deferoxamine in reducing the iron burden in transfused patients with sickle cell disease. [98]

      In a comparative study of beta-thalassemia patients, noninferiority was demonstrated in the group of patients who were allocated to the higher dose groups (deferasirox doses of 20 or 30 mg/kg) for baseline liver iron concentrations (LIC) of 7 mg/g dry weight or greater when compared with deferoxamine. [99] In another study, deferasirox 20 mg/kg showed similar efficacy to deferoxamine 40 mg/kg in terms of decreases in LIC. [100]  A comparative study of deferoxamine, deferiprone, deferoxamine + deferiprone, and deferasirox in beta-thalassemia patients found after 5 consecutive years of therapy, patients on deferasirox had the highest decrease in the prevalence of any endocrinopathy(diabetes mellitus, hypothyroidism, or hypogonadism). In addition, there was a significant decrease in osteoporosis in patients on deferasirox. [101]

      In a phase III study of 586 children with thalassemia that compared deferasirox with deferoxamine at 1 year, 53% of children in the deferasirox group had maintained or reduced hepatic iron concentrations, versus 66% in the deferoxamine group. [102]

      A phase II study of deferasirox and deferoxamine in sickle cell disease with transfusional iron overload showed comparable safety profiles. Deferasirox resulted in a median serum ferritin decrease of more than 600 mg/mL at 2 years. [103]

      A Cochrane database review by Meerpohl et al of 4 clinical trials (including 2 comparing deferasirox with deferoxamine) concluded that the drugs have similar efficacy and short-term safety profiles. However, the review fell short of recommending deferasirox as first-line treatment, despite patients preferring it over cumbersome deferoxamine administration in patients with thalassemia and transfusional iron overload. [104]

      A prospective study of 30 children on deferasirox from Iran demonstrated evidence of decreased glomerular filtration rate and renal tubular dysfunction but the mean serum creatinine level stayed less than 1 mg/dL over a 6 month follow-up. [105] Monitoring of renal function is recommended. [106] Increased hepatotoxicity in patients with MRP2 protein mutation may have some pharmacogenetic component. [107] At least one case of esophagitis has been reported. [108]

      Unlike patients with primary hemochromatosis and some other causes of secondary iron overload, patients with transfusion-induced iron overload are already anemic, and therapeutic phlebotomy is not usually an option, except in those with curable disorders such as leukemia that is in complete remission.  [109]

      Myelodysplastic syndromes are an area of increasing interest for iron chelation, in addition to traditional hemoglobinopathies such as thalassemia. [110, 111]  A 1-year, open-label study in Germany of deferasirox in low-risk and intermediate-risk myelodysplastic syndrome patients with transfusion overload showed a mean decrease from 2447 to 1685 ng/mL in serum ferritin; however, hematological improvement occurred in only 11%, with half the patients unable to complete 1 year of treatment due to adverse effects. [112]  An Italian cohort of 40 patients with myelodysplastic syndromes treated with deferasirox showed similar improvement in serum ferritin and hematological parameters and demonstrated the safety of drug when used concomitantly with azacitidine and lenalidomide. [113]

      Aplastic anemia is another area of increasing interest, because iron overload may contribute to ongoing anemia and chelation may revive the damaged marrow. [114, 115]

       

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      Surgical Care

      Liver and cardiac transplantation should be considered for appropriate patients with end-stage disease. Combined liver-heart transplants have been carried out successfully in thalassemia patients. [116]

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      Consultations

      Consultations with the following specialists should be sought in cases of transfusion-induced iron overload:

      • Hematologist
      • Cardiologist
      • Gastroenterologist/Hepatologist
      • Endocrinologist
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      Diet

      Ascorbic acid (vitamin C) increases the absorption of dietary iron 2.9-3.5 times the normal amount [117] and should probably be avoided, along with alcohol and, of course, iron supplements. However, both green and black tea inhibit absorption of iron in food. [118]

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