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Transfusion-Induced Iron Overload Treatment & Management

  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Mar 10, 2014

Medical Care

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, with the exception of curable disorders such as leukemia that is in complete remission.[75]

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.[76] Although NTBI 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 amongst those who undergo long-term transfusions.[77]

The initiation of chelation therapy is a decision that has to be individualized. In general, transfusions exceeding 100 mL/kg of body weight are reasonable enough to merit thorough evaluation and probable initiation. Autopsy studies in the 1970s[78] and MRI data[79] obtained in recent years show that after 75 or more units of transfused blood, more than 50% of patients have excess iron in their myocardium.

Myelodysplastic syndromes are an area of increasing interest for iron chelation, in addition to traditional hemoglobinopathies such as thalassemia.[80, 81] A 1-year, open label study in Germany of deferasirox in low-risk and intermediate-risk patients who have myelodysplastic syndromes 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.[82] 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.[83]

Aplastic anemia is another area of increasing interest where iron-overload may contribute to ongoing anemia and chelation may revive the damaged marrow.[84, 85]

Deferoxamine (DFO) 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.[86]

The only randomized trial comparing chelation with intramuscular deferoxamine to no chelation was small and presented 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.[87] At 14 years, 6 deaths occurred in the untreated group compared with 1 in the treated group.[88]

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.[89] In the United States, the mean total medical costs have been estimated to be $59,233 per year, including $10,899 for deferoxamine and $8,722 for the administration of chelation therapy.[90]

Two novel oral iron chelators, deferiprone and deferasirox (EXJADE; Novartis Pharma Stein AG, Stein, Switzerland), provide potentially useful treatments for iron overload. A new enthusiastic era for iron chelation with less burdensome oral treatments is dawning, but long-term follow-up is required before pumps and needles can be thrown away.[91]

Deferiprone (Ferriprox) has been at the center stage of a huge controversy between the major investigator (Dr. Nancy Olivieri, the Hospital for Sick Children and the University of Toronto) and the drug manufacturer ApoPharma .[92] The original study, after 7 years of research, concluded that deferiprone was less effective and resulted in an increased incidence of hepatic fibrosis.[93] Although some conflicting data exist from larger studies,[94] the drug did not gain approval in Canada, but it was approved in Europe and is also being manufactured in India.

Deferiprone was approved the US Food and Drug Administration (FDA) in October 2011. 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). At least one study has reported improved cardiac outcomes with deferiprone;[95] if true, this is a major advantage of this drug because cardiac failure remains the major cause of mortality in thalassemia. An Italian study comparing deferiprone to deferoxamine in thalassemia showed statistically significant improved ejection fraction in the deferiprone group at 2 years; however, the clinical significance of this finding (59% vs 62%) is unclear.[96]

Concerns about bony dysplasia and impaired growth of ulnar epiphysis in Indian children on treatment with deferiprone were recently raised.[97]

Deferasirox (EXJADE) is preferred by patients due to its convenient once-daily oral administration[98] and its cost-effectiveness.[99] Deferasirox has been approved by the FDA. Its use has also been studied in no-transfusion dependent thalassemia[100] and both at low and high iron burdens.[101] 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.[102]

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.[103] In another study, deferasirox 20 mg/kg showed similar efficacy to deferoxamine 40 mg/kg in terms of decreases in LIC.[104]

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.[105]

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.[106]

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.[107]

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.[108] Monitoring of renal function is recommended.[109] Increased hepatotoxicity in patients with MRP2 protein mutation may have some pharmacogenetic component.[110] At least one case of esophagitis has been reported.[111]


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.[112]



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

  • Hematologist
  • Cardiologist
  • Gastroenterologist/Hepatologist
  • Endocrinologist


Ascorbic acid (vitamin C) increases the absorption of iron 2.9-3.5 times the normal amount[113] and should probably be avoided, along with alcohol and, of course, iron supplements.



Activity in patients with transfusion-induced iron overload is as tolerated.

Contributor Information and Disclosures

Muhammad A Mir, MD, FACP Assistant Professor of Medicine (Hematology, Blood/Marrow Transplant) Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

Muhammad A Mir, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Hematology, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology

Disclosure: Nothing to disclose.


Gerald L Logue, MD Professor of Medicine, Head of the Division of Hematology, Vice Chairman for Education, Department of Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Gerald L Logue, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American College of Physicians, American Society of Hematology, American Federation for Clinical Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MB, BCh, FRCPC, DTM&H Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MB, BCh, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada, American Clinical and Climatological Association, International Society of Blood Transfusion

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: GSK Pharmaceuticals,Alexion,Johnson & Johnson Talecris,,Grifols<br/>Received honoraria from all the above companies for speaking and teaching.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Pradyumna D Phatak, MBBS, MD Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute

Pradyumna D Phatak, MBBS, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching.

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Iron status in iron deficiency and overload. NTBI = non–transferrin-bound iron; TIBC = total iron-binding capacity.
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