Deferasirox for managing transfusional iron overload in people with thalassaemia

Thalassaemia is a hereditary anaemia due to a defect in the production of haemoglobin. Regular red blood cell transfusions are needed, particularly for the severe form of the disease, thalassaemia major. This results in secondary iron overload. Since the human body has no means of actively getting rid of excessive iron, drug treatment (iron chelators) is needed. Several years ago, a new oral iron chelator, deferasirox, was introduced. However, it is not known whether deferasirox offers advantages compared to deferoxamine or deferiprone with regard to effectiveness and safety.

Four studies are included in the review. Two studies comparing deferasirox with placebo showed effectiveness of deferasirox with regard to iron excretion. Two other studies compared deferasirox with standard treatment of deferoxamine. Similar effectiveness seems to be achievable depending of the doses and ratio of the two drugs compared. It needs to be confirmed whether this results in similar improvement of patient-important outcomes in the long run.

The safety of deferasirox was acceptable; however, rarer adverse events or long-term side effects could not be adequately investigated due to the limited number of patients and the short duration of the studies. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs.

Deferasirox should be offered as an alternative to all patients who do not tolerate deferoxamine or who have poor compliance with deferoxamine. Ideally, further studies looking at patient-important, long-term outcomes as well as rarer adverse events should be conducted prior to routine recommendation of deferasirox as first line therapy in thalassaemia patients with iron overload.

Authors' conclusions: 

Deferasirox offers an important alternative line of treatment for people with thalassaemia and secondary iron overload. Based on the available data, deferasirox does not seem to be superior to deferoxamine at the usually recommended ratio of 1 mg of deferasirox to 2 mg of deferoxamine. However, similar efficacy seems to be achievable depending on the dose and ratio of deferasirox compared to deferoxamine. Whether this will result in similar efficacy in the long run and will translate to similar benefits as has been shown for deferoxamine, needs to be confirmed. Data on safety, particularly on rare toxicities and long-term safety, are still limited.

Therefore, we think that deferasirox should be offered as an alternative to all patients with thalassaemia who either show intolerance to deferoxamine or poor compliance with deferoxamine. In our opinion, data are still too limited to support the general recommendation of deferasirox as first-line treatment instead of deferoxamine. If a strong preference for deferasirox is expressed, it could be offered as first-line option to individual patients after a detailed discussion of the potential benefits and risks.

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Background: 

Thalassemia is a hereditary anaemia due to ineffective erythropoiesis. In particular, people with thalassaemia major develop secondary iron overload resulting from regular red blood cell transfusion. Iron chelation therapy is needed to prevent long-term complications.

Both deferoxamine and deferiprone have been found to be efficacious. However, a systematic review of the effectiveness and safety of the new oral chelator deferasirox in people with thalassaemia is needed.

Objectives: 

To assess the effectiveness and safety of oral deferasirox in people with thalassaemia and secondary iron overload.

Search strategy: 

We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched MEDLINE, EMBASE, EBMR, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE and three trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/. Date of the most recent searches of these databases: 24 June 2010.

Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 03 November 2011.

Selection criteria: 

Randomised controlled trials comparing deferasirox with no therapy or placebo or with another iron chelating treatment.

Data collection and analysis: 

Two authors independently assessed risk of bias and extracted data. We contacted study authors for additional information.

Main results: 

Four studies met the inclusion criteria.

Two studies compared deferasirox to placebo or standard therapy of deferoxamine (n = 47). The placebo-controlled studies, a pharmacokinetic and a dose escalation study, showed that deferasirox leads to net iron excretion in transfusion-dependent thalassaemia patients. In these studies, safety was acceptable and further investigation in phase II and phase III trials was warranted.

Two studies, one phase II study (n = 71) and one phase III study (n = 586) compared deferasirox to standard treatment with deferoxamine. Data suggest that a similar efficacy can be achieved depending on the ratio of doses of deferoxamine and deferasirox being compared; in the phase III trial, similar or superior efficacy for surrogate parameters of ferritin and liver iron concentration could only be achieved in the highly iron-overloaded subgroup at a mean ratio of 1 mg of deferasirox to 1.8 mg of deferoxamine corresponding to a mean dose of 28.2 mg/d and 51.6 mg/d respectively. Data on safety at the presumably required doses for effective chelation therapy are limited. Patient satisfaction was significantly better with deferasirox, while rate of discontinuations was similar for both drugs.

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