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

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          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.

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          Most cited references 42

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          Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction

          Background In thalassemia major (TM), severe cardiac siderosis can be treated by continuous parenteral deferoxamine, but poor compliance, complications and deaths occur. Combined chelation therapy with deferiprone and deferoxamine is effective for moderate myocardial siderosis, but has not been prospectively examined in severe myocardial siderosis. Methods T2* cardiovascular magnetic resonance (CMR) was performed in 167 TM patients receiving standard subcutaneous deferoxamine monotherapy, and 22 had severe myocardial siderosis (T2* < 8 ms) with impaired left ventricular (LV) function. Fifteen of these patients received combination therapy with subcutaneous deferoxamine and oral deferiprone with CMR follow-up. Results At baseline, deferoxamine was prescribed at 38 ± 10.2 mg/kg for 5.3 days/week, and deferiprone at 73.9 ± 4.0 mg/kg/day. All patients continued both deferiprone and deferoxamine for 12 months. There were no deaths or new cardiovascular complications. The myocardial T2* improved (5.7 ± 0.98 ms to 7.9 ± 2.47 ms; p = 0.010), with concomitant improvement in LV ejection fraction (51.2 ± 10.9% to 65.6 ± 6.7%; p < 0.001). Serum ferritin improved from 2057 (CV 7.6%) to 666 (CV 13.2%) μg/L (p < 0.001), and liver iron improved (liver T2*: 3.7 ± 2.9 ms to 10.8 ± 7.3 ms; p = 0.006). Conclusion In patients with severe myocardial siderosis and impaired LV function, combined chelation therapy with subcutaneous deferoxamine and oral deferiprone reduces myocardial iron and improves cardiac function. This treatment is considerably less onerous for the patient than conventional high dose continuous subcutaneous or intravenous deferoxamine monotherapy, and may be considered as an alternative. Very prolonged tailored treatment with iron chelation is necessary to clear myocardial iron, and alterations in chelation must be guided by repeated myocardial T2* scans. Trial registration This trial is registered as NCT00103753
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            Financial conflicts of interest in physicians' relationships with the pharmaceutical industry--self-regulation in the shadow of federal prosecution.

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              The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores.

              We present results from a prospective, multicenter, open-label, single-arm study evaluating response of cardiac and liver iron to deferasirox therapy for 18 months. Twenty-eight patients with abnormal T2* and normal left ventricular ejection fraction were enrolled from 4 US centers. All patients initially received deferasirox doses of 30 to 40 mg/kg per day. Patients were severely iron overloaded: mean liver iron concentration (LIC) 20.3 mg Fe/g dry weight, serum ferritin 4417 ng/mL, and cardiac T2* 8.6 ms. In the intent-to-treat population, 48% reached the primary endpoint (cardiac T2* improvement at 18 months, P = not significant). There were 2 deaths: 1 from congestive heart failure and 1 from sepsis. In the 22 patients completing the trial, LIC and cardiac T2* improvements were 16% (P = .06) and 14% (P = .07), respectively. Cardiac T2* improvement (13 patients) was predicted by initial LIC, final LIC, and percentage LIC change, but not initial cardiac T2*. Cardiac iron improved 24% in patients having LIC in the lower 2 quartiles and worsened 8.7% in patients having LIC in the upper 2 quartiles. Left ventricular ejection fraction was unchanged at all time points. Monotherapy with deferasirox was effective in patients with mild to moderate iron stores but failed to remove cardiac iron in patients with severe hepatic iron burdens. This study was registered at www.clinicaltrials.gov as #NCT00447694.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                15 December 2016
                : 10
                : 4073-4078
                Affiliations
                [1 ]Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
                [2 ]Department of Haematology, University College London, London, UK
                [3 ]First Department of Pediatrics, University of Athens, Athens, Greece
                [4 ]Department of Pediatrics and Thalassemia Center, Siriraj Hospital, Mahidol University, Bangkok, Thailand
                [5 ]Department of Internal Medicine, Università di Milano, Ca Granda Foundation IRCCS, Milan, Italy
                Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol, Cyprus
                Author notes
                Correspondence: Ali T Taher, Department of Internal Medicine, American University of Beirut, Riad El Solh 1107 2020, Beirut, Lebanon, Email ataher@ 123456aub.edu.lb
                Correspondence: George J Kontoghiorghes, Postgraduate Research Institute of Science, Technology, Environment and Medicine, 3 Ammochostou Street, Limassol 3021, Cyprus, Tel +357 2627 2076, Email kontoghiorghes.g.j@ 123456pri.ac.cy
                Article
                dddt-10-4073
                10.2147/DDDT.S117080
                5170616
                © 2016 Taher et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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                Pharmacology & Pharmaceutical medicine

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