Iron chelation therapy in thalassemia major: A systematic review with meta-analyses of 1520 patients included on randomized clinical trials

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Abstract

The effectiveness of deferoxamine (DFO), deferiprone (DFP), or deferasirox (DFX) in thalassemia major was assessed. Outcomes were reported as means ± SD, mean differences with 95% CI, or standardized mean differences. Statistical heterogeneity was tested using χ2 (Q) and I2. Sources of bias and Grading of Recommendations Assessment, Development and Evaluation system (GRADE) were considered. Overall, 1520 patients were included. Only 7.4% of trials were free of bias. Overall measurements suggest low trial quality (GRADE). The meta-analysis suggests lower final liver iron concentrations during associated versus monotherapy treatment (p < 0.0001), increases in serum ferritin levels during DFX 5, 10, and 20 mg/kg versus DFO-treated groups (p < 0.00001, p < 0.00001, and p = 0.002, respectively), but no statistically significant difference during DFX 30 mg/kg versus DFO (p = 0.70), no statistically significant variations in heart T2* signal during associated or sequential versus mono-therapy treatment (p = 0.46 and p = 0.14, respectively), increases in urinary iron excretion during associated or sequential versus monotherapy treatment (p = 0.008 and p = 0.02, respectively), and improved ejection fraction during associated or sequential versus monotherapy treatment (p = 0.01 and p < 0.00001, respectively). These findings do not support any specific chelation treatment. The literature shows risks of bias, and additional larger and longer trials are needed.

Introduction

Thalassemia and hemoglobin disorders are an emerging global health burden, [1] accounting for about 3.4% of deaths in children less than 5 years of age [2]. The current therapeutic management of thalassemia is based on regular blood transfusions and iron chelation therapy [3]. Chelation aims to reduce iron stores or correct iron imbalance, and constitutes a major improvement for all people with thalassemia major [3]. Therefore, standards for the treatment of children and adults with thalassemia have been developed [4], [5].

The three main chelators used in current clinical practice are deferoxamine (DFO) (Desferal®; Novartis), deferiprone (DFP) (Ferriprox®; Apotex), and deferasirox (DFX) (Exjade®; Novartis) [6]. The main findings concerning the effectiveness and safety profiles of DFO, DFP, and DFX have been described extensively elsewhere [7], [8], [9], [10], [11]. Moreover, there is also growing off-license usage of DFP in associated with (administration of the two drugs during the same day) or in sequential with (administration of the two drugs on different days) DFO following recent reports of their synergistic effect, particularly with regard to the iron burden in the heart [12], [13]. We identified eight published reviews on iron chelators with our search strategy [14], [15], [16], [17], [18], [19], [20], [21]. However, only four of these included meta-analyses, [19] none included sequential chelation treatment, and none reported GRADE. Moreover, none was conducted systematically, i.e. based on a previously public protocol guiding the review process. Furthermore, none assessed the risks of systematic errors (‘bias’), random errors (‘play of chance’), and design errors [22], [23], [24].

Because these questions remain unanswered, the main objective of our study was to conduct a systematic review of the clinical effectiveness profile of iron chelators for patients with transfusion-dependent thalassemia major, according to previously published criteria[25].

Section snippets

Literature searches

The following electronic databases were utilized (AG and FA) to search for relevant published literature: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, ISI Web of Knowledge, the ClinicalTrials.gov register, Current Controlled Trials, World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the reference lists of articles. The date of the last search was June 2010. Two authors (AG and FA) independently scanned all titles and abstracts

Search results

The results of our research strategies are summarized in Fig. 1. Sixteen RCTs were included in this review with a total of 1520 patients aged from 5 to 50 years. Five RCTs were long-term follow-ups of the trials already included in the analysis. Within these 16 trials, 11 different comparisons were detected. In these, the chelators were compared with each other as monotherapies, in combination with each other, or as sequentially administered chelators. Table 2 reports the main findings of the

Discussion

The aim of this systematic review was to evaluate the effectiveness of DFO, DFP, and DFX alone or in associated or as sequential therapies in transfusion-dependent patients with thalassemia major. This meta-analysis suggests that ejection fraction at the end of the intervention was statistically significantly higher after combined (Fig. 4a) or sequential DFP and DFO treatments (Fig. 4b). Liver iron concentration at the end of the intervention was statistically significantly decreased after

Support and sponsorships

Nine trials reported the source of funding [11], [13], [29], [31], [41], [44], [45], [46], [47].

The trials that received funding from a governmental agency included co-funding from the Sicilian Thalassaemic Association and European Community [47].

The trials that documented support from industry included Novartis Pharma [11] and Lipomed, Switzerland, for DFP, [29], [44] and Novartis Pharmaceuticals Corporation, [46] Apotex, Novartis, Apopharma [45].

One trial received funding from both non

Authorship contributions

AF, AV, GA, AM, and CG designed the research, performed the research, and prepared an initial draft of the paper.

AK, AC, MDC, SF, PC, RWG, LP, JBP, FB, and FC analyzed the data and discussed the draft issue by issue.

AF and AM wrote the final draft of the paper.

PH and JW addressed scientific and language issues as international external reviewers.

AI was a representative of the patients who examined the document.

Declarations of interest

Conflict of interest disclosure: AF, AM, AV, GA, CG, FB, LP, FC, AI, RWG, AC, and SF declare no competing financial interests; MDC, PC, and JBP report having received consulting fees from Novartis Pharmaceuticals. PH received research grants from Novartis, and support from Novartis and Ferrokin, and participated in medical advisory boards for Apotex; JW received research grants from Novartis and is a consultant for Ferrokin Biosciences. AK reports participating in study monitor committees for

Acknowledgments

The research leading to these results has received funding by the Italian Ministry of Health and the Italian Foundation for the Cure of Thalassaemia “Leonardo Giambrone”, under the project “Inter-regional Network for Thalassaemia: HTA for the diagnostic and therapeutic intervention for iron overload”, coordinated by the Basilicata Region. Prof. David Nathan provided valuable advice that was greatly appreciated. We thank Foundation Franco and Piera Cutino for their continuous encouragement.

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