A Systematic Review of the Effect of Iron Chelation Therapy on Survival in Patients with Sickle Cell Disease and β-Thalassemia

Background: Patients with sickle cell disease (SCD) and beta (β)-thalassemia often require regular blood transfusions; however, each unit of blood contains approximately 200 mg of iron, which can rapidly lead to iron overload (IO). This can result in iron deposition in the heart, liver, and endocrine organs, ultimately leading to organ failure, including cardiac disease, liver fibrosis, and metabolic disorders. The introduction of iron chelation therapy (ICT) with deferoxamine (DFO) and more recently deferiprone (DFP) and deferasirox (DFX) has had a significant impact on IO, demonstrating reductions in serum ferritin level and liver iron content. Although ICT has become the standard of care over the past few decades, there are limited data on the effects of these agents on overall survival. The objective of this systematic review is to evaluate the impact of ICT on survival in patients with transfusion-dependent SCD or β-thalassemia.

Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols(PRISMA-P) guidelines. Electronic databases, including Embase, PubMed, Cochrane Library, and the World Health Organization (WHO) Clinical Trials Search Portal, along with American Society of Hematology annual meeting abstracts from 2010-2015 were searched to identify English language articles that were relevant to the topic. Search terms included "sickle cell anemia" or "SCA," "sickle cell disease" or "SCD," "beta thalassemia" or "thalassemia," "iron chelation," "iron overload," "survival," "death," "study," and "trial." Abstracts identified by the literature were independently reviewed and only articles with unanimous support were included; when the eligibility of an abstract was disputed, a full copy of the article was retrieved for review. References were excluded for lack of evidence of survival analysis, comparison between regimens, or if trials had fewer than 25 patients. Details of the included studies were collected for categorization. Although a meta-analysis of the data was initially planned, there were too few studies with similar study parameters to complete the analysis.

Results: For SCD, the literature search yielded 203 articles of which 6 were deemed relevant (Figure 1). Of these, 3 were excluded and 3 (published between 2001 and 2014) were included. Reasons for exclusion included small patient number, no comparator, and being a theoretical paper. Only 1 of the 3 was a randomized clinical trial (RCT). For β-thalassemia, theliterature analyses yielded 398 articles of which 40 were deemed relevant (Figure 2). After reviewing the articles, 22 were excluded while 18 (published between 1991 and 2015) were included. Reasons for exclusion included small patient number, no comparator, no survival data, no chelation data, or a focus on hematopoietic stem cell or bone marrow transplantation. Only 3 of the 18 were RCTs; the remainder were retrospective and/or longitudinal studies. Most data on effectiveness of ICT were from longitudinal studies that suggest treatment outcomes have improved significantly over time mainly due to the introduction of new and improved iron chelation agents, including oral treatments and combination therapy. Effectiveness was also investigated in studies evaluating treatment compliance that suggest survival is improved in patients compliant to ICT. Compliance has been enhanced with the introduction of oral agents such as DFP and DFX compared with DFO, which requires daily subcutaneous injections.

Conclusions: This systematic review identified few RCTs of ICT reporting survival in SCD and β-thalassemia. Despite limited data, the available literature suggests that ICT improves overall survival in SCD and β-thalassemia. Survival may also have been affected by factors such as hydroxyurea usage and the number of blood transfusions. Newer oral treatments have improved compliance, shown to be an important factor in survival, although there have not been any prospective long-term RCTs adequately powered to compare the efficacy among available iron chelation agents in either SCD or β-thalassemia.

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