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Treatment with deferasirox (Exjade ® ) effectively decreases iron burden in patients with thalassaemia intermedia: results of a pilot study

2009; Wiley; Volume: 148; Issue: 2 Linguagem: Inglês

10.1111/j.1365-2141.2009.07930.x

1365-2141

Ersi Voskaridou, Eleni Plata, Maroussa Douskou, Manousos Papadakis, Eleni‐Evangelia Delaki, Dimitrios Christoulas, Evangelos Terpos,

Iron Metabolism and Disorders

Iron loading in thalassaemia intermedia (TI) occurs primarily due to increased intestinal iron absorption secondary to chronic anaemia and is further exacerbated by intermittent blood transfusion therapy. In contrast to thalassaemia major (TM) the evaluation of body iron based on serum ferritin alone may underestimate the severity of iron overload in TI (Pakbaz et al, 2007). Therefore, direct assessment of liver iron concentration (LIC) by either biopsy or non-invasive magnetic resonance imaging (MRI) is recommended (Jensen, 2004). Relatively few studies have evaluated the efficacy, safety and dosing regimen of iron chelation therapy specifically in TI (Cossu et al, 1981; Olivieri et al, 1992). Deferasirox (Exjade®) is a once-daily orally administered iron chelator approved for the treatment of transfusional iron overload in various anaemias (Cappellini et al, 2006). The aim of this preliminary, open-label, prospective, single-centre trial was to evaluate the efficacy and safety of deferasirox in sporadically transfused, iron-overloaded patients with TI. Adult male or female patients who had received sporadic red blood cell (RBC) transfusions (≤20 RBC units in their lifetime) and had confirmed liver or cardiac iron overload (serum ferritin levels of ≥1000 μg/l, liver MRI T2* of <25 ms or cardiac T2* of 500 U/l) or renal failure (creatinine clearance <60 ml/min) or had a left ventricular ejection fraction (LVEF) of 2500 μg/l without decreasing trend) and reduced for elevated levels of creatinine, urinary protein/creatinine ratio and transaminases, and in response to adverse events. Patients provided written, informed consent before entering the study. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The primary efficacy endpoint was the improvement in MRI T2* values in the liver and the heart from baseline after 12 months of deferasirox therapy. The secondary efficacy endpoints included evaluation of changes in serum ferritin, incidence, type and severity of adverse events relating to biochemical changes and patient disposition. Overall, 11 patients were enrolled and completed 12 months of deferasirox therapy. At baseline, all patients had indicators of iron overload (Table I). Serum ferritin was >1000 μg/l in all patients and liver MRI T2* was ≤6 ms in seven patients, which is indicative of moderate-to-heavy iron overload [equivalent to 7–14 mg Fe/g dry weight (dw)] and 7–12 ms in three patients indicative of mild overload (equivalent to 3–6 mg Fe/g dw). Cardiac T2* was normal in all patients (T2* of >28 ms). The majority of patients had previously received deferoxamine although its use was sporadic due to poor compliance. Two patients (Patients 3 and 9) received 10 and 12 units of packed RBCs, respectively during the study due to pulmonary hypertension, which was diagnosed after deferasirox initiation. Nine of 11 patients started on deferasirox 10 mg/kg per day; the remaining two patients (Patients 5 and 9) started on 20 mg/kg per day due to very high serum ferritin levels (>4000 μg/l) and liver T2* indicating moderate-to-heavy iron overload. By the end of the study, doses had been adjusted so that nine patients were receiving 20 mg/kg per day and two were receiving 30 mg/kg per day based on the experience and knowledge derived from TM (Thalassaemia International Federation, 2008) as there are currently no clear guidelines for the management of iron overload in TI. After 12 months of deferasirox therapy, liver MRI T2* improved from baseline in 9/10 patients from a mean value of 3·4 ± 3·0 to 4·4 ± 3·0 ms (Fig 1A, Table II); resulting in a significant mean increase from baseline of 1·0 ms (P = 0·02). Serum ferritin was reduced from baseline in 9/11 patients from a mean value of 2030 ± 1340 to 1165 ± 684 μg/l (Fig 1B, Table II). The mean reduction in serum ferritin from baseline was significant at 865 μg/l (P = 0·02). LIC was evaluated based on liver MRI T2* values according to Wood et al (2005) (Table II). A correlation with serum ferritin was observed at baseline (r = 0·63, P = 0·002), but there were no significant correlations between percentage changes of serum ferritin, LIC or liver MRI T2* after 12 months of therapy. Mean cardiac T2* and LVEF were normal at baseline and did not change significantly after 12 months of deferasirox treatment; after 12 months, mean cardiac T2* was 39·8 ± 4·5 ms (+0·9 ms; P = 0·64) and LVEF was 66·9 ± 7·9% (+0·6%; P = 0·76). These data indicate that deferasirox was effective in reducing laboratory and imaging evidence of iron overload in most of these iron-overloaded patients with TI over a period of 12 months of treatment. In contrast to TM, where cardiac iron loading is significant and heart disease is the main cause of death (Brittenham et al, 1994), myocardial iron loading has not been documented in TI (Origa et al, 2008). In agreement with these observations, myocardial iron levels were normal at baseline and remained normal during the 12-month study period. Change in liver T2* (A) and serum ferritin (B) from baseline by patient after 12 months of treatment with deferasirox. BL, baseline. Mean aspartate aminotransferase and alanine aminotransferase levels progressively decreased during the study from baseline values of 64·8 ± 29·6 and 63·5 ± 29·5 U/l, respectively to 42·5 ± 18·1 and 36·5 ± 17·6 U/l after 12 months of deferasirox therapy (P = 0·04 and P = 0·02 respectively). There were no significant changes in mean serum creatinine, cystatin-C or 24-h proteinuria. These data indicate a concomitant improvement in liver function with the reduction in body iron following deferasirox therapy for 12 months. In general, adverse events were mild and consistent with that documented throughout the registration studies of deferasirox (Vichinsky, 2008). Nausea was reported in eight patients (73%) and diarrhoea was reported in two patients (18%) within the first month of deferasirox therapy. These adverse events were treated conventionally and did not re-occur within the 12 months of this study. In conclusion, deferasirox provided effective control of iron levels in this small population of minimally transfused TI patients with no significant adverse events. Larger trials, which have been just started, will clearly define the efficacy and safety of deferasirox in TI. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Dr Rebecca Helson for medical editorial assistance with this manuscript and Mrs Marialena Konstantinidou for administrative support. All authors have nothing to disclose.