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      Efficacy and safety of deferasirox, an oral iron chelator, in heavily iron-overloaded patients with β-thalassaemia: the ESCALATOR study

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          Abstract

          Objective:

          Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake.

          Methods:

          The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to <10 mg Fe/g dw.

          Results:

          Overall, 233/237 enrolled patients completed 1 yr’s treatment. Mean baseline LIC was 18.0 ± 9.1 mg Fe/g dw, while median serum ferritin was 3356 ng/mL. After 1 yr’s deferasirox treatment, the intent-to-treat population experienced a significant treatment success rate of 57.0% ( P = 0.016) and a mean reduction in LIC of 3.4 mg Fe/g dw. Changes in serum ferritin appeared to parallel dose increases at around 24 wk. Most patients (78.1%) underwent dose increases above 20 mg/kg/d, primarily to 30 mg/kg/d. Drug-related adverse events were mostly mild to moderate and resolved without discontinuing treatment.

          Conclusions:

          The results of the ESCALATOR study in primarily heavily iron-overloaded patients confirm previous observations in patients with β-thalassaemia, highlighting the importance of timely deferasirox dose adjustments based on serum ferritin levels and transfusional iron intake to ensure patients achieve their therapeutic goal of maintenance or reduction in iron burden.

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          Most cited references 17

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           V Desmet,  F CALLEA,  F Gudat (1995)
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            Iron-chelating therapy and the treatment of thalassemia.

            Iron-chelating therapy with deferoxamine in patients with thalassemia major has dramatically altered the prognosis of this previously fatal disease. The successes achieved with deferoxamine, as well as the limitations of this treatment, have stimulated the design of alternative strategies of iron-chelating therapy, including orally active iron chelators. The development of the most promising of these, deferiprone, has progressed rapidly over the last 5 years; data from several trials have provided direct and supportive evidence for its short-term efficacy. At the same time, the toxicity of this agent mandates a careful evaluation of the balance between risk and benefit of deferiprone in patients with thalassemia, in most of whom long-term deferoxamine is safe and efficacious therapy.
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              Survival in medically treated patients with homozygous beta-thalassemia.

              The prognosis of patients with homozygous beta-thalassemia (thalassemia major) has been improved by transfusion and iron-chelation therapy. We analyzed outcome and prognostic factors among patients receiving transfusions and chelation therapy who had reached the age at which iron-induced cardiac disease, the most common cause of death, usually occurs. Using the duration of life without the need for either inotropic or antiarrhythmic drugs as a measure of survival without cardiac disease, we studied 97 patients born before 1976 who were treated with regular transfusions and chelation therapy. We used Cox proportional-hazards analysis to assess the effect of prognostic factors and life-table analysis to estimate freedom from cardiac disease over time. Of the 97 patients, 59 (61 percent) had no cardiac disease; 36 (37 percent) had cardiac disease, and 18 of them had died. Univariate analysis demonstrated that factors affecting cardiac disease-free survival were age at the start of chelation therapy (P < 0.001), the natural log of the serum ferritin concentration before chelation therapy began (P = 0.01), the mean ferritin concentration (P < 0.001), and the proportion of ferritin measurements exceeding 2500 ng per milliliter (P < 0.001). With stepwise Cox modeling, only the proportion of ferritin measurements exceeding 2500 ng per milliliter affected cardiac disease-free survival (P < 0.001). Patients in whom less than 33 percent of the serum ferritin values exceeded 2500 ng per milliliter had estimated rates of survival without cardiac disease of 100 percent after 10 years of chelation therapy and 91 percent after 15 years. The prognosis for survival without cardiac disease is excellent for patients with thalassemia major who receive regular transfusions and whose serum ferritin concentrations remain below 2500 ng per milliliter with chelation therapy.
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                Author and article information

                Journal
                Eur J Haematol
                ejh
                European Journal of Haematology
                Blackwell Publishing Ltd
                0902-4441
                1600-0609
                June 2009
                : 82
                : 6
                : 458-465
                Affiliations
                [1 ]American University Beirut, Lebanon
                [2 ]Cairo University Cairo, Egypt
                [3 ]Ain Shams University Cairo, Egypt
                [4 ]National Thalassemia Center Damascus, Syrian Arab Republic
                [5 ]Sultan Qaboos University Muscat, Oman
                [6 ]Novartis Pharmaceuticals Corporation NJ, USA
                [7 ]Novartis Pharma AG Basel, Switzerland
                [8 ]King Faisal Specialist Hospital and Research Center Riyadh, Saudi Arabia
                Author notes
                Correspondence Ali Taher, Department of Internal Medicine, Hematology, Oncology Division, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon. Tel: +961 1 749 230/1 extn 5811, 5987; Fax: +961 1 365 612; e-mail: ataher@ 123456aub.edu.lb
                Article
                10.1111/j.1600-0609.2009.01228.x
                2730551
                19187278
                © 2009 John Wiley & Sons A/S

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Categories
                Original Articles

                Hematology

                transfusional iron overload, deferasirox, iron chelation, β-thalassaemia

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