Deferasirox for managing transfusional iron overload in people with sickle cell disease

  • Review
  • Intervention

Authors


Abstract

Background

Sickle cell disease (SCD) is a group of genetic haemoglobin disorders, that occurs in about 2.2 per 1000 births worldwide. Increasingly, some people with SCD develop secondary iron overload due to occasional red blood cell transfusions or are on long-term transfusion programmes for e.g. secondary stroke prevention. Iron chelation therapy can prevent long-term complications.

Deferoxamine and deferiprone have been found to be efficacious. However, questions exist about the effectiveness and safety of the newer oral chelator deferasirox.

Objectives

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

Search methods

We searched the Cystic Fibrosis & Genetic Disorders Group's Haemoglobinopathies Trials Register: date of most recent search:13 March 2014.

We searched MEDLINE, Embase, Biosis Previews, Web of Science, Derwent Drug File, XTOXLINE, EBMR and The Cochrane Library, respectively; date of most recent searches: 02 August 2013.

We searched four trial registries: www.controlled-trials.com; www.clinicaltrials.gov; www.who.int./ictrp/en/; www.drks.de; date of most recent searches: 03 June 2013.

Selection criteria

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

Data collection and analysis

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

Main results

Two studies (with 203 and 212 people) comparing the efficacy and safety of deferasirox and deferoxamine after 12 months and 24 weeks, respectively, were included. The overall quality, according to GRADE, for the main outcomes was moderate to low. Only limited data were available on mortality and end-organ damage, although one study did assess mortality, relative risk 1.26 (95% confidence interval 0.05 to 30.41), the 24-week follow up was too short to allow us to draw firm conclusions. One study reported a relative risk of 1.26 for the incidence of type 2 diabetes mellitus (95% confidence interval 0.05 to 30.41). Serum ferritin reduction was significantly greater with deferoxamine, mean difference of change of 440.69 µg/l (95% confidence interval 11.73 to 869.64). Liver iron concentration (reported in one study) measured by superconduction quantum interference device showed no significant difference for the overall group of patients adjusted for transfusion category, mean difference -0.20 mg Fe/g dry weight (95% confidence interval -3.15 to 2.75).

The occurrence of serious adverse events did not differ between drugs. Nausea, diarrhoea and rash occurred significantly more often in people treated with deferasirox, while adverse events of any kind were more often reported for patients treated with deferoxamine (one study). The mean increase of creatinine was also significantly higher with deferasirox, mean difference 3.24 (95% confidence interval 0.45 to 6.03). Long-term adverse events could not be measured in the included studies (follow up 52 weeks and 24 weeks). Patient satisfaction and the likelihood of continuing treatment, were significantly better with deferasirox.

Authors' conclusions

Deferasirox appears to be of similar efficacy to deferoxamine depending on depending on the appropriate ratio of doses of deferoxamine and deferasirox being compared. However, only limited evidence is available assessing the efficacy regarding patient-important outcomes. The short-term safety of deferasirox seems to be acceptable, however, follow up in the available studies was too short to assess long-term side effects. Long-term safety and efficacy data are available from a non-controlled extension phase not included in our review; however, no valid comparative conclusions can be drawn and future studies should assess comparatively long-term outcomes both for safety and efficacy.

Plain language summary

Deferasirox for managing transfusional iron overload in people with sickle cell disease

Review question

We reviewed the evidence about the effect of deferasirox on secondary iron load in people with sickle cell disease.

Background

Sickle cell disease is a genetic disorder. An increasing number of people with this disorder show secondary iron overload (an accumulation of excess iron in the body) due to repeated red blood cell transfusions. Since the human body is not able to actively get rid of excessive iron, drug treatment (known as 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 other iron chelators (deferoxamine or deferiprone) with regard to effectiveness and safety.

Study characteristics

Two randomised studies, with moderate overall quality of evidence, comparing deferasirox to deferoxamine were identified. The evidence is current to 02 August 2013. The studies with 203 and 212 participants lasted for 12 months and 24 weeks, respectively.

Key results

Only little data on patient-important outcomes such as mortality (limited by a short study follow up) and end-organ damage (incidence of diabetes mellitus) were available. Iron removal, as measured by the surrogate marker serum ferritin was significantly greater with deferoxamine. In one study, both drugs were reported to work equally well in reducing liver iron concentration.

The safety of deferasirox was acceptable; the main side effects when compared to deferoxamine were increased frequency of nausea, diarrhoea and rash as well as a mean increase of creatinine, while adverse events of any kind were observed more often in people treated with deferoxamine. Patient satisfaction and compliance with therapy was significantly greater with deferasirox.

Quality of the evidence

The overall quality of evidence rated according to the GRADE criteria was moderate due to issues with study design. For four outcomes, namely liver iron concentration, serum ferritin, creatinine increase and satisfaction with treatment, it was judged as 'moderate' quality; for one outcome (discontinuations) was judged as 'low' quality.

Summary

In summary, the evidence from the two included studies suggests that deferasirox is similarly effective as deferoxamine depending on the appropriate ratio of doses of deferoxamine and deferasirox being compared. In the short term, deferasirox appears to have an acceptable safety profile, but there are no comparative data based on randomised controlled trials available looking at long-term safety. Further data on long-term efficacy on patient-relevant outcomes and long-term adverse effects are needed to decide whether deferasirox should be used as alternative to the first-line option of deferoxamine. Currently, its use seems to be mainly warranted as a treatment option for people with sickle cell disease who cannot tolerate or comply with deferoxamine.