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Cochrane Database of Systematic Reviews: Plain Language Summaries [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2003-.

Cochrane Database of Systematic Reviews: Plain Language Summaries [Internet].

Desferrioxamine mesylate (desferrioxamine) for managing excess iron levels in the blood of people with thalassaemia who depend on blood transfusions

This version published: 2013; Review content assessed as up-to-date: August 14, 2013.

Link to full article: [Cochrane Library]

Plain language summary

Haemoglobin carries oxygen in the blood. In thalassaemia, a genetic disease, sometimes the body cannot produce enough haemoglobin. This can be managed by receiving regular blood transfusions, but may lead to excess iron in the body which must be removed to prevent organ damage.

Iron is removed by iron chelation therapy using a substance called an iron chelator. This works by sticking to excess iron molecules in the body. When patients go to the toilet, this excess iron leaves the body.

Three iron chelators are commonly used. One (desferrioxamine) is injected and two (deferiprone and deferasirox) are taken orally. Deferasirox is licensed for use in children. Desferrioxamine is inconvenient and expensive; motivating researchers to find safe, effective oral iron chelators.

We found 22 randomised controlled trials comparing iron chelators. These do not provide enough information about death or organ damage. However, they showed all three chelators performed similarly well in removing excess iron. Several trials found combining desferrioxamine and deferiprone removed more excess iron than using just one iron chelator.

Trials showing side effects must be considered carefully. Side effects with desferrioxamine included pain or skin reactions at the injection site and joint pain. Side effects with deferiprone included joint pain, nausea, stomach upsets and low white blood cell count. Side effects with deferasirox included skin rashes, increases in liver enzymes and reduced kidney function. Low white blood cell count and reduced kidney function are important side effects and in patients receiving deferiprone or deferasirox these should be monitored regularly. Patients were three times more likely to experience a side effect when deferiprone and desferrioxamine were combined, compared with desferrioxamine alone. Three studies showed that patients using deferiprone were two and a half times more likely to have joint pain compared with using desferrioxamine alone.

We have found no evidence for changing current treatment recommendations, which state that deferiprone or deferasirox should be used to remove excess iron when desferrioxamine cannot be used or is inadequate. The Food and Drug Administration in the United States of America have approved deferiprone only as "last resort treatment of iron overload in thalassemia".

Larger randomised control trials of iron chelation therapy are needed, using standardised agreed measures of iron levels and organ damage to allow comparison of such valuable treatments.

Abstract

Background: Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through red blood cell transfusions.

Repeated transfusions result in an excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. Desferrioxamine mesylate (desferrioxamine) is one of the most widely used iron chelators. Substantial data have shown the beneficial effects of desferrioxamine, although adherence to desferrioxamine therapy is a challenge. Alternative oral iron chelators, deferiprone and deferasirox, are now commonly used. Important questions exist about whether desferrioxamine, as monotherapy or in combination with an oral iron chelator, is the best treatment for iron chelation therapy.

Objectives: To determine the effectiveness (dose and method of administration) of desferrioxamine in people with transfusion‐dependent thalassaemia.

To summarise data from trials on the clinical efficacy and safety of desferrioxamine for thalassaemia and to compare these with deferiprone and deferasirox.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, CENTRAL (The Cochrane Library), LILACS and other international medical databases, plus ongoing trials registers and the Transfusion Evidence Library (www.transfusionevidencelibrary.com). All searches were updated to 5 March 2013.

Selection criteria: Randomised controlled trials comparing desferrioxamine with placebo, with another iron chelator, or comparing two schedules or doses of desferrioxamine, in people with transfusion‐dependent thalassaemia.

Data collection and analysis: Six authors working independently were involved in trial quality assessment and data extraction. For one trial, investigators supplied additional data upon request.

Main results: A total of 22 trials involving 2187 participants (range 11 to 586 people) were included. These trials included eight comparisons between desferrioxamine alone and deferiprone alone; five comparisons between desferrioxamine combined with deferiprone and deferiprone alone; eight comparisons between desferrioxamine alone and desferrioxamine combined with deferiprone; two comparisons of desferrioxamine with deferasirox; and two comparisons of different routes of desferrioxamine administration (bolus versus continuous infusion). Overall, few trials measured the same or long‐term outcomes. Seven trials reported cardiac function or liver fibrosis as measures of end organ damage; none of these included a comparison with deferasirox.

Five trials reported a total of seven deaths; three in patients who received desferrioxamine alone, two in patients who received desferrioxamine and deferiprone. A further death occurred in a patient who received deferiprone in another who received deferasirox alone. One trial reported five further deaths in patients who withdrew from randomised treatment (deferiprone with or without desferrioxamine) and switched to desferrioxamine alone.

One trial planned five years of follow up but was stopped early due to the beneficial effects of a reduction in serum ferritin levels in those receiving combined desferrioxamine and deferiprone treatment compared with deferiprone alone. The results of this and three other trials suggest an advantage of combined therapy with desferrioxamine and deferiprone over monotherapy to reduce iron stores as measured by serum ferritin. There is, however, no evidence for the improved efficacy of combined desferrioxamine and deferiprone therapy against monotherapy from direct or indirect measures of liver iron.

Earlier trials measuring the cardiac iron load indirectly by measurement of the magnetic resonance imaging T2* signal had suggested deferiprone may reduce cardiac iron more quickly than desferrioxamine. However, meta‐analysis of two trials showed a significantly lower left ventricular ejection fraction in patients who received desferrioxamine alone compared with those who received combination therapy using desferrioxamine with deferiprone.

Adverse events were recorded by 18 trials. These occurred with all treatments, but were significantly less likely with desferrioxamine than deferiprone in one trial, relative risk 0.45 (95% confidence interval 0.24 to 0.84) and significantly less likely with desferrioxamine alone than desferrioxamine combined with deferiprone in two other trials, relative risk 0.33 (95% confidence interval 0.13 to 0.84). In particular, four studies reported permanent treatment withdrawal due to adverse events from deferiprone; only one of these reported permanent withdrawals associated with desferrioxamine. Adverse events also occurred at a higher frequency in patients who received deferasirox than desferrioxamine in one trial. Eight trials reported local adverse reactions at the site of desferrioxamine infusion including pain and swelling. Adverse events associated with deferiprone included joint pain, gastrointestinal disturbance, increases in liver enzymes and neutropenia; adverse events associated with deferasirox comprised increases in liver enzymes and renal impairment. Regular monitoring of white cell counts has been recommended for deferiprone and monitoring of liver and renal function for deferasirox.

In summary, desferrioxamine and the oral iron chelators deferiprone and deferasirox produce significant reductions in iron stores in transfusion‐dependent, iron‐overloaded people. There is no evidence from randomised clinical trials to suggest that any one of these has a greater reduction of clinically significant end organ damage, although in two trials, combination therapy with desferrioxamine and deferiprone showed a greater improvement in left ventricular ejection fraction than desferrioxamine used alone.

Authors' conclusions: Desferrioxamine is the recommended first‐line therapy for iron overload in people with thalassaemia major and deferiprone or deferasirox are indicated for treating iron overload when desferrioxamine is contraindicated or inadequate. Oral deferasirox has been licensed for use in children aged over six years who receive frequent blood transfusions and in children aged two to five years who receive infrequent blood transfusions. In the absence of randomised controlled trials with long‐term follow up, there is no compelling evidence to change this conclusion.

Worsening iron deposition in the myocardium in patients receiving desferrioxamine alone would suggest a change of therapy by intensification of desferrioxamine treatment or the use of desferrioxamine and deferiprone combination therapy.

Adverse events are increased in patients treated with deferiprone compared with desferrioxamine and in patients treated with combined deferiprone and desferrioxamine compared with desferrioxamine alone. People treated with all chelators must be kept under close medical supervision and treatment with deferiprone or deferasirox requires regular monitoring of neutrophil counts or renal function respectively. There is an urgent need for adequately‐powered, high‐quality trials comparing the overall clinical efficacy and long‐term outcomes of deferiprone, deferasirox and desferrioxamine.

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group.

Publication status: Edited (no change to conclusions).

Citation: Fisher SA, Brunskill SJ, Doree C, Gooding S, Chowdhury O, Roberts DJ. Desferrioxamine mesylate for managing transfusional iron overload in people with transfusion‐dependent thalassaemia. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD004450. DOI: 10.1002/14651858.CD004450.pub3. Link to Cochrane Library. [PubMed: 23963793]

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

PMID: 23963793

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