Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with nontransfusion-dependent thalassemia syndromes

Abstract

Dear editor As the scientific steering committee for THALASSA (an assessment of Exjade in nontransfusion-dependent thalassemia [NTDT]), we read with interest the review by Kontoghiorghe and Kontoghiorghes entitled “Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes” published in January 2016.1 While this review provides a detailed overview of available iron chelators for the treatment of NTDT patients, there remain some factual inaccuracies and misrepresentations of data related to deferasirox. Therefore, we believe that the current article may be misleading to readers of Drug Design, Development and Therapy. Foremost, there is no mention that to date deferasirox is the only oral iron chelator approved for the treatment of chronic iron overload in NTDT patients. Approval was granted following the successful THALASSA trial (n=166), the first randomized, controlled study showing that deferasirox significantly reduces iron overload in NTDT patients with a manageable safety profile.2,3 As such, we feel that the recommendation by Kontoghiorghe and Kontoghiorghes for deferiprone as the first-line treatment of NTDT patients is concerning given the absence of robust clinical evidence and regulatory approval. Indeed, deferiprone is recommended as a second-line treatment in most clinical practice guidelines worldwide. Furthermore, the authors draw many of their conclusions regarding deferasirox tolerability from postmarketing surveillance information, yet neglect to mention premarketing clinical trial experience from ~700 adult/pediatric patients supporting a clinically manageable safety profile for deferasirox with appropriate patient monitoring.4 Both sources of data should be considered for a balanced analysis of drug-related tolerability issues. There are also several specific claims regarding deferasirox that we would like to highlight as inaccurate and provide further supportive evidence to the contrary: “DFX appears to increase iron and other toxic metal absorption.” Concerns about the increased iron uptake were addressed during the development of deferasirox and were shown not to occur.5 Given the structural similarities between iron–deferasirox and aluminum–deferasirox complexes,6 increased gastrointestinal uptake of aluminum would not be anticipated in vivo. These data were neither discussed nor cited. “[…] excess iron removal from the heart by DFX is not effective and in most cases very slow, with no improvement in LVEF, especially in heavily iron-loaded TM patients.” Clinical evidence for deferasirox in the removal of cardiac iron has been demonstrated in the large, prospective EPIC cardiac substudy and the randomized CORDELIA study.7,8 Deferasirox was effective in removing cardiac iron and maintaining cardiac function in thalassemia patients with mild, moderate, and severe cardiac siderosis. Furthermore, in CORDELIA, although the enrolled patients had left ventricular ejection fraction ≥56% at baseline, small improvements were noted in some patients.8,9 This is important because even small improvements can reduce the risk of heart failure.10 “The use of DFX is not recommended for iron-loaded patients with serum ferritin lower than 500 ng/mL.” The authors cite deferasirox-labeling information from 2010, prior to updates in 2015 that include the indication of deferasirox for NTDT patients. In the 2015 version, treatment interruptions are indicated when serum ferritin is <300 ng/mL, the safety of which was established in THALASSA.4,11 “Lower efficacy and higher toxicity was reported for DFX in TI […] by investigators not related or funded by the manufacturers of DFX.” This statement is based on one retrospective, single-center study of a combined population of β-thalassemia major and intermedia patients.12 The cited study by Karimi et al13 was an independent study, and there are additional investigator-initiated studies14,15 that were not cited. Together with the outcomes of THALASSA, results from these studies provide credible evidence supporting the efficacy and safety of deferasirox in NTDT patients. “DFX is also very expensive and cannot be afforded by the vast majority of patients.” Here, there is no mention of cost-effectiveness analyses by Karnon et al16 who have demonstrated that the higher drug cost of deferasirox may be offset by savings due to the cost of DFO administration (eg, pumps and needles) or the reduced need to treat iron overload-related complications that can develop when patients are not compliant with DFO. Finally, we feel it necessary to inform readers that Dr Kontoghiorghes has a conflict of interest in deferiprone, which has not been declared. Dr Kontoghiorghes was a member of the team who first synthesized deferiprone and has subsequently been described as the discoverer (eg, http://www.pri.ac.cy/research.htm). We hope this letter clarifies some of the misconceptions presented by Kontoghiorghe and Kontoghiorghes and will provide physicians with additional information for consideration when deciding upon the most appropriate treatment for their patients.