Gian Luca Forni

A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease

Deferasirox is a once‐daily, oral iron chelator developed for treating transfusional iron overload. Preclinical studies indicated that the kidney was a potential target organ of toxicity. As patients with sickle cell disease often have abnormal baseline renal function, the primary objective of this randomised, open‐label, phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population. Assessment of efficacy, as measured by change in liver iron concentration (LIC) using biosusceptometry, was a secondary objective. A total of 195 adult and paediatric patients received deferasirox (n = 132) or deferoxamine (n = 63). Adverse events most commonly associated with deferasirox were mild, including transient nausea, vomiting, diarrhoea, abdominal pain and skin rash. Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests. Discontinuation rates from deferasirox (11·4%) and deferoxamine (11·1%) were similar. Over 1 year, similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine. Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy to deferoxamine in reducing iron burden in transfused patients with sickle cell disease.

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

Objectives/methods:  This 1‐yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or β‐thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC).

Pregnancy and β-thalassemia: an Italian multicenter experience

Background Recent advances in the management of thalassemia have significantly improved life expectancy and quality of life of patients with this hemoglobinopathy, with a consequent increase in their reproductive potential and desire to have children. Design and Methods We describe the methods of conception and delivery, as well as the course and outcome of pregnancy including transfusions, iron overload and chelation in 46 women with thalassemia major (58 pregnancies) and in 11 women with thalassemia intermedia (17 pregnancies). Conception was achieved after gonadotrophin-induced ovulation in 33 of the women with thalassemia major and spontaneously in all of those with thalassemia intermedia. Results Among the women with thalassemia major, 91% of the pregnancies resulted in successful delivery of 45 singleton live-born neonates, five sets of twins and one set of triplets. No secondary complications of iron overload developed or worsened during pregnancy. When considering only the singleton pregnancies, the proportion of babies with intrauterine growth retardation did not differ from that reported in the general Italian population. The high prevalence of pre-term births (32.7%) was mostly related to multiple pregnancies and precautionary reasons. Pregnancy was safe in most women with thalassemia major or intermedia. However, women with thalassemia intermedia who had never previously been transfused or who had received only minimal transfusion therapy were at risk of severe alloimmune anemia if blood transfusions were required during pregnancy. Conclusions Provided that a multidisciplinary team is available, pregnancy is possible, safe and usually has a favorable outcome in patients with thalassemia. In women with hypogonadotropic hypogonadism, gonadal function is usually intact and fertility is usually retrievable.

Genetic and clinical heterogeneity of ferroportin disease

Ferroportin is encoded by the SLC40A1 gene and mediates iron export from cells by interacting with hepcidin. SLC40A1 gene mutations are associated with an autosomal type of genetic iron overload described as haemochromatosis type 4, or HFE4 (Online Mendelian Inheritance in Man number 606069), or ferroportin disease. We report three families with this condition caused by novel SLC40A1 mutations. Denaturing high‐performance liquid chromatography was employed to scan for the SLC40A1 gene. A D181V (A846T) mutation in exon 6 of the ferroportin gene was detected in the affected members of an Italian family and shown to have a de novo origin in a maternal germinal line. This mutation was associated with both parenchymal and reticuloendothelial iron overload in the liver, and with reduced urinary hepcidin excretion. A G80V (G543T) mutation in exon 3 was found in the affected members of an Italian family with autosomal hyperferritinaemia,. Finally, a G267D (G1104A) mutation was identified in exon 7 in a family of Chinese descent whose members presented with isolated hyperferritinaemia. Ferroportin disease represents a protean genetic condition in which the different SLC40A1 mutations appear to be responsible for phenotypic variability. This condition should be considered not only in families with autosomal iron overload or hyperferritinaemia, but also in cases of unexplained hyperferritinaemia.

A pilot trial of deferiprone for neurodegeneration with brain iron accumulation

Deferiprone was shown to reverse iron deposition in Friedreich’s ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation.

Long-term safety and efficacy of deferasirox (Exjade®) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease

To date, there is a lack of long‐term safety and efficacy data for iron chelation therapy in transfusion‐dependent patients with sickle cell disease (SCD). To evaluate the long‐term safety and efficacy of deferasirox (a once‐daily oral iron chelator), patients with SCD completing a 1‐year, Phase II, randomized, deferoxamine (DFO)‐controlled study entered a 4‐year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5‐year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow‐up (9·2%) and adverse events (AEs) (7·6%). Investigator‐assessed drug‐related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild‐to‐moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥4 years deferasirox exposure significantly decreased by −591 μg/l (95% confidence intervals, −1411, −280 μg/l; P = 0·027; n = 67). Long‐term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

Regression of symptoms after selective iron chelation therapy in a case of neurodegeneration with brain iron accumulation.

We report the results of iron chelating treatment with deferiprone in a 61‐year‐old woman with signs and symptoms of neurodegeneration with brain iron accumulation (NBIA). After 6 months of therapy the patients gait had improved and a reduction in the incidence of choreic dyskinesias was observed. Her gait returned to normal after an additional 2 months of therapy, at which time there was a further reduction in involuntary movements and a partial resolution of the blepharospasm.

Patient-Reported Outcomes of Deferasirox (Exjade®, ICL670) versus Deferoxamine in Sickle Cell Disease Patients with Transfusional Hemosiderosis

Background/Aims: There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment. Methods: As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5–30 mg/kg/day) or deferoxamine (20–50 mg/kg, 5 days per week); 121 had previously received deferoxamine. Results: At each time point, significantly more patients who had previously received deferoxamine were ‘satisfied/very satisfied’ with deferasirox, or found treatment to be ‘convenient/very convenient’ compared with deferoxamine (p < 0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively). Conclusions: Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes.

A phase 2 study of the safety, tolerability and pharmacodynamics of FBS0701, a novel oral iron chelator, in transfusional iron overload

This was a 24-week, multicenter phase-2 study designed to assess safety, tolerability, and pharmacodynamics of FBS0701, a novel oral chelator, in adults with transfusional iron overload. Fifty-one patients, stratified by transfusional iron intake, were randomized to FBS0701 at either 14.5 or 29 mg/kg/d (16 and 32 mg/kg/d salt form). FBS0701 was generally well tolerated at both doses. Forty-nine patients (96%) completed the study. There were no drug-related serious adverse events. No adverse events (AEs) showed dose-dependency in frequency or severity. Treatment-related nausea, vomiting, abdominal pain, and diarrhea were each noted in < 5% of patients. Mean serum creatinine did not change significantly from Baseline or between dose groups. Transaminases wer increased in 8 (16%), three of whom acquired HCV on-study from a single blood bank while five had an abnormal baseline ALT. The 24 week mean change in liver iron concentration (ΔLIC) at 14.5 mg/kg/d was +3.1 mg/g (dw); 29% achieved a decrease in LIC. Mean ΔLIC at 29 mg/kg/d was -0.3 mg/g (dw); 44% achieved a decrease in LIC (P < .03 for ΔLIC between doses). The safety and tolerability profile at therapeutic doses compare favorably to other oral chelators.

Prevalence and Risk Factors for Pulmonary Arterial Hypertension in a Large Group of β-Thalassemia Patients Using Right Heart Catheterization A Webthal Study

Background— Pulmonary arterial hypertension (PAH) remains a concern in patients with &bgr;-thalassemia major (TM) and intermedia (TI); however, studies evaluating its prevalence and risk factors using systematic confirmation on right heart catheterization are lacking. Methods and Results— This was a multicenter cross-sectional study of 1309 Italian &bgr;-thalassemia patients (mean age 36.4±9.3 years; 46% men; 74.6% TM, 25.4% TI). Patients with a tricuspid-valve regurgitant jet velocity ≥3.2 m/s (3.6%) on transthoracic echocardiography further underwent right heart catheterization to confirm the diagnosis of PAH (mean pulmonary arterial pressure ≥25 mm Hg and pulmonary capillary wedge pressure ⩽15mm Hg). The confirmed PAH prevalence on right heart catheterization was 2.1% (95% confidence interval [CI], 1.4–3.0) and was higher in TI (4.8%; 95% CI, 3.0–7.7) than TM (1.1%; 95% CI, 0.6–2.0). The positive predictive value for the tricuspid-valve regurgitant jet velocity ≥3.2 m/s threshold for the diagnosis of pulmonary hypertension was 93.9%. Considerable functional limitation and decrease in the 6-minute walk distance were noted in patients with confirmed PAH. On multivariate logistic regression analysis, independent risk factors for confirmed PAH were age (odds ratio, 1.102 per 1-year increase; 95% CI, 1.06–1.15) and splenectomy (odds ratio, 9.31; 95% CI, 2.57–33.7). Conclusions— The prevalence of PAH in &bgr;-thalassemia patients as confirmed on right heart catheterization was 2.1%, with an ≈5-fold higher prevalence in TI than TM. Advanced age and splenectomy are risk factors for PAH in this patient population. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01496963.