Case of presymptomatic aceruloplasminemia treated with deferasirox

Aceruloplasminemia is an autosomal recessive disease characterized by an abnormal iron metabolism. The absence of ferroxidase activity caused by mutation of ceruloplasmin leads to iron overload in the brain, liver and other organs. We report a 35‐year‐old man who was diagnosed with aceruloplasminemia without neurological manifestation despite the accumulation of iron in the brain and liver. To prevent the development of neurodegenerative disorder related to iron toxicity, iron depletion therapy was performed. Iron chelator deferasirox was effective in reducing serum ferritin level and to prevent the progression of the disease.     

Deferasirox: uncertain future following renal failure fatalities,agranulocytosis and other toxicities

Cases of fatal, acute, irreversible renal failure and cytopenias, including agranulocytosis and thrombocytopenia, have been disclosed in a postmarketing report on deferasirox, a few months after the European Union authorities and about a year after the FDA proceeded to its accelerated approval. No details on the incidence rate or the cause of these toxicities have yet been reported. Other toxic side effects include skin, gastric, auditory and ocular abnormalities, and hepatitis. Regular serum creatinine, blood counts and other toxicity monitoring as well as withdrawal of deferasirox from the patients affected and those with serum ferritin < 0.5 mg/l was recommended. Toxicity, inability to clear cardiac iron and high cost (€60/g) question the future universal role of deferasirox, by comparison with the safety and efficacy records of deferiprone, deferoxamine and their combination in the treatment of transfusional iron overload. Also questioned are the procedures adopted by regulatory authorities and the marketing methods of pharmaceutical companies on orphan drugs, which are of no benefit to thalassaemia patients in developing countries.     

Studies on a Family with HB J Calabria (α2 β2 64 (E8 GLY → ASP)

Hb J Calabria is a fast moving hemoglobin variant which was found in an Italian family by Vecchio et al. (1), and in a French family by Blouquit et al.who studied its functional properties (2). The original family described by Vecchio et al. in which both Hb J Calabria and β-thal-assemia were present has been reexamined and is the subject of the present study. Hematological and clinical features of the carriers are described. The heterozygous carriers of Hb J Calabria showed only mild variable sub-clinical anemia and levels of the abnormal hemoglobin ranging from about 33 to 42%. The Hb J Calabria/β-thal-assemia double heterozygote showed a moderate chronic hemolytic anemia with alterations of the RBC indices and morphology in addition to splenomegaly. The relationship between structural abnormality, functional properties and clinical expression of Hb J Calabria is discussed.     

Five Years of Deferasirox Therapy for Cardiac Iron in β-Thalassemia Major

Abstract

Myocardial siderosis in β-thalassemia major (β-TM) remains the leading cause of death. Deferasirox (DFX), a new iron chelation treatment, has proved to be effective in reducing or preventing cardiac iron burden in thalassemic patients according to clinical trials with maximum duration of up to 3 years except one that was recently published and lasted 5 years. The aim of this study was to evaluate the efficacy of DFX in reducing or preventing cardiac iron burden in 23 patients with β-TM after 5 years of therapy. All patients had a magnetic resonance imaging (MRI) T2* evaluation of their cardiac iron load before starting DFX therapy and after a period of 5 years. Ferritin levels and left ventricular ejection fraction (LVEF) were also evaluated at the same time. Deferasirox was administered in a starting dose of 30?mg/kg/day and never increased to more than 40?mg/kg/day. The MRI T2* cardiac iron load mean values before DFX was 32.82?±?10.86?ms, and after 32.13?±?7.74?ms, showing a stability in MRI T2* myocardial value but a significant improvement in two patients with an intermediate iron load (12 vs. 23?ms). The mean LVEF value was 68.43?±?7.08% before treatment with DFX and 67.95?±?5.94% after DFX therapy without significant change. Our results confirm previous studies that DFX is considered an effective chelating agent used as monotherapy for at least 5 years and is more efficacious in moderate to severe cardiac iron loaded thalassemic patients.     

Deferasirox in patients with iron overload secondary to hereditary hemochromatosis: results of a 1‐yr Phase 2 study

This open‐label, prospective, phase 2 study evaluated the safety and efficacy of deferasirox (10 ± 5 mg/kg/d) in patients with hereditary hemochromatosis (HH) and iron overload refractory to or intolerant of phlebotomy. Ten patients were enrolled and all completed the 12‐month treatment period. There were significant decreases from baseline to end of study (i.e., 12 months) in median serum ferritin (P < 0.001), mean transferrin saturation (P < 0.05), median liver iron concentration (P < 0.001), and mean alanine aminotransferase (P < 0.05). The median time to achieve serum ferritin reduction ≥50% compared to baseline was 7.53 months. The most common adverse events were mild, transient diarrhea (n = 5) and nausea (n = 2). No patient experienced an increase in serum creatinine that exceeded the upper limit of normal. These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients.     

Deferasirox effect on renal haemodynamic parameters in patients with transfusion‐dependent β thalassaemia

Some patients with β thalassaemia experience non‐progressive creatinine increases with deferasirox, mostly within normal limits; the mechanisms involved are not fully elucidated. The effects of deferasirox on renal haemodynamics, including glomerular filtration rate (GFR) and renal plasma flow (RPF), were investigated in a Phase I, open‐label study in β thalassaemia major patients with iron overload. Patients received deferasirox 30 mg/kg/d up to Week 8, followed by a 2‐week washout period, and extended treatment up to Week 104 with a 4‐week washout period. In the short‐term study (n = 11), mean GFR and RPF declined from baseline to Week 8 (mean [%] change:?9·2 [?9·5%] and ?105·7 ml/min [?17·8%], respectively). A similar pattern was observed during the long‐term study (n = 5); mean GFR and RPF decreased up to Week 52 (?19·1 [?17·7%] and ?155·6 ml/min [?26·1%]), with similar change at Week 104 (?18·4 [?17·2%] and ?115·9 ml/min [?19·6%]). Measures returned to baseline values after each washout. Serum creatinine and creatinine clearance followed a similar pattern. Effects of deferasirox on renal haemodynamics were mild and reversible for up to 2 years of treatment, with no progressive worsening of renal function over time. www.clinicaltrials.gov : NCT00560820.     

Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload

Background

The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with β-thalassemia major in the cardiac sub-study of the EPIC trial.

Design and Methods

Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years.

Results

Baseline myocardial T2* was severe (>5 to <10 ms) in 39 patients, and moderate-to-mild (10 to <20 ms) in 62 patients. Mean deferasirox dose was 33.1±3.7 mg/kg/d in the one-year core study increasing to 36.1±7.7 mg/kg/d during the second year of treatment. Geometric mean myocardial T2* increased from a baseline of 11.2 to 14.8 ms at two years (P<0.001). In patients with moderate-to-mild baseline T2*, an increase was seen from 14.7 to 20.1 ms, with normalization (≥20 ms) in 56.7% of patients. In those with severe cardiac iron overload at baseline, 42.9% improved to the moderate-to-mild group. The incidence of drug-related adverse events did not increase during the extension relative to the core study and included (≥5%) increased serum creatinine, rash and increased alanine aminotransferase.

Conclusions

Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with β-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT 00171821","term_id":"NCT00171821"}}NCT 00171821)     

Optimising management of deferasirox therapy for patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes

Effective iron chelation therapy is an important part of treatment in patients with transfusion‐dependent thalassaemia and lower‐risk myelodysplastic syndromes (MDS). Key strategies for optimising iron chelation therapy include ensuring good adherence and preventing and managing adverse events (AEs). Good adherence to iron chelation therapy with deferoxamine and deferasirox has been linked to improved survival and/or reductions in complications related to iron overload; however, maintaining good adherence to iron chelators can be challenging. Patients with transfusion‐dependent thalassaemia or lower‐risk MDS showed better adherence to the deferasirox film‐coated tablet (FCT) formulation than to the deferasirox dispersible tablet formulation in the ECLIPSE trial, reflecting in part the improved palatability and convenience of deferasirox FCT. As well as affecting adherence, AEs may lead to dose reduction, interruption or discontinuation, resulting in suboptimal iron chelation therapy. Preventing and successfully managing AEs may help limit their impact on adherence, and following dosage and administration recommendations for iron chelators such as deferasirox may help minimise AEs and optimise treatment in patients with transfusion‐dependent thalassaemia and lower‐risk MDS.