Longitudinal prospective comparison of pancreatic iron by magnetic resonance in thalassemia patients transfusion-dependent since early childhood treated with combination deferiprone-desferrioxamine vs deferiprone or deferasirox monotherapy.

BACKGROUND: In transfusion-dependent thalassemia patients who started regular transfusions in early childhood, we prospectively and longitudinally evaluated the efficacy on pancreatic iron of a combined deferiprone (DFP) + desferrioxamine (DFO) regimen versus either oral iron chelator as monotherapy over a follow-up of 18 months. MATERIALS AND METHODS: We selected patients consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia network who received a combined regimen of DFO+DFP (No.=28) or DFP (No.=61) or deferasirox (DFX) (No.=159) monotherapy between the two magnetic resonance imaging scans. Pancreatic iron overload was quantified by the T2* technique. RESULTS: At baseline no patient in the combined treatment group had a normal global pancreas T2* (≥26 ms). At follow-up the percentage of patients who maintained a normal pancreas T2* was comparable between the DFP and DFX groups (57.1 vs 70%; p=0.517).Among the patients with pancreatic iron overload at baseline, global pancreatic T2* values were significantly lower in the combined DFO+DFP group than in the DFP or DFX groups. Since changes in global pancreas T2* values were negatively correlated with baseline pancreas T2* values, the percent changes in global pancreas T2* values, normalized for the baseline values, were considered. The percent changes in global pancreas T2* values were significantly higher in the combined DFO+DFP group than in either the DFP (p=0.036) or DFX (p=0.030) groups. DISCUSSION: In transfusion-dependent patients who started regular transfusions in early childhood, combined DFP+DFO was significantly more effective in reducing pancreatic iron than was either DFP or DFX.

MRI multicentre prospective survey in thalassaemia major patients treated with deferasirox versus deferiprone and desferrioxamine.

We prospectively assessed the efficacy of deferasirox versus deferiprone or desferrioxamine as monotherapy in thalassaemia major (TM) patients by magnetic resonance imaging (MRI). We selected the patients enrolled in the Myocardial Iron Overload in Thalassaemia network who received only one chelator between two MRIs (deferasirox = 235, deferiprone = 142, desferrioxamine = 162). Iron overload was measured by T2* technique and biventricular function by cine images. Among the patients with baseline myocardial iron, in all three groups there was a significant improvement in global heart T2* values. The deferiprone and desferrioxamine groups showed a significant improvement in left ventricular ejection fraction (LVEF). Only the deferiprone group showed a significant improvement in right ventricular ejection fraction (RVEF). The improvement in global heart T2* was significantly lower in the deferasirox versus the deferiprone group. The improvement in the LVEF was significantly higher in the deferiprone and desferrioxamine groups than in the deferasirox group and the improvement in the RVEF was significantly higher in the deferiprone than in deferasirox group. Among the patients with baseline hepatic iron, the changes in hepatic iron were comparable in deferasirox versus the other groups. Deferasirox monotherapy was less effective than deferiprone in improving myocardial siderosis and biventricular function and less effective than desferrioxamine in improving the LVEF.

Gender differences in the development of cardiac complications: a multicentre study in a large cohort of thalassaemia major patients to optimize the timing of cardiac follow-up.

We assessed whether male gender was associated with a higher risk of cardiac iron accumulation and fibrosis, heart dysfunction and complications in a large, multicentre cohort of thalassaemia major (TM) patients, in order to optimize the timing in cardiac follow-up. We considered 1711 TM patients (899 females, 31·09 ± 9·08 years), enrolled in the Myocardial Iron Overload in Thalassaemia Network. Clinical/instrumental data are recorded from birth to the first Cardiovascular Magnetic Resonance Imaging scan. Although having a similar risk of accumulating iron, males showed a significantly higher risk of developing cardiac dysfunction, heart failure, arrhythmias and cardiac complications overall, when compared to females (P < 0·0001). Up to 20-30 years of follow-up, the Kaplan-Meier curves for the outcomes for which the male sex was a significant prognosticator almost overlapped, whereas they clearly diverged after this period. In patients with follow-up longer than 20 years, males exhibited a significantly higher risk of ventricular dysfunction, heart failure, arrhythmias, and cardiac complications. Female patients may have an intrinsically better tolerance for iron toxicity. International guidelines suggest annual cardiac evaluation for thalassaemia patients. It is possible that female patients can be evaluated at longer intervals, thus reducing health costs.

Cardiac complications and diabetes in thalassaemia major: a large historical multicentre study.

The relationship between diabetes mellitus (DM) and cardiac complications has never been systematically studied in thalassaemia major (TM). We evaluated a large retrospective historical cohort of TM to determine whether DM is associated with a higher risk of heart complications. We compared 86 TM patients affected by DM with 709 TM patients without DM consecutively included in the Myocardial Iron Overload in Thalassaemia database where clinical/instrumental data are recorded from birth to the first cardiovascular magnetic resonance (CMR) exam. All of the cardiac events considered were developed after the DM diagnosis. In DM patients versus non-DM patients we found a significantly higher frequency of cardiac complications (46.5% vs. 16.9%, P < 0.0001), heart failure (HF) (30.2% vs. 11.7%, P < 0.0001), hyperkinetic arrhythmias (18.6% vs. 5.5%, P < 0.0001) and myocardial fibrosis assessed by late gadolinium enhancement (29.9% vs. 18.4%, P = 0.008). TM patients with DM had a significantly higher risk of cardiac complications [odds ratio (OR) 2.84, P < 0.0001], HF (OR 2.32, P = 0.003), hyperkinetic arrhythmias (OR 2.21, P = 0.023) and myocardial fibrosis (OR 1.91, P = 0.021), also adjusting for the absence of myocardial iron overload assessed by T2* CMR and for the covariates (age and/or endocrine co-morbidity). In conclusion, DM significantly increases the risk for cardiac complications, HF, hyperkinetic arrhythmias and myocardial fibrosis in TM patients.

Paraplegia due to spinal cord compression by extramedullary erythropoietic tissue in a thalassaemia intermedia patient with gynecomastia secondary to cirrhosis: successful treatment with hydroxyurea.

We report a 24 years old patient with thalassaemia intermedia and gynecomastia, complicated by paraplegia and urinary/fecal incontinence due to spinal cord compression by an extramedullary erythropoiesis (EE) mass, treated with long-term hydroxyurea (HU). Neurological improvement occurred during the first 6 weeks of HU therapy (1,000 mg/day) and magnetic resonance imaging showed a reduction in EE mass. HU dosage was reduced to 500 mg/day after 5 months, and treatment was discontinued after 25 months. Five months later there was a partial recurrence of neurological symptoms, which responded to radiotherapy. HU may have a role in the symptomatic treatment of spinal cord compression due to EE, particularly when radiotherapy is unavailable.

Healing of leg ulcers with hydroxyurea in thalassaemia intermedia patients with associated endocrine complications.

We report a preliminary clinical experience in the use of hydroxyurea (HU) for the treatment of leg ulcers in thalassaemia intermedia patients with associated endocrine complications. We administered HU 1 g/day to 6 adult patients with thalassaemia intermedia for 90 days. We observed an improvement (3 patients) or healing (3 patients) of chronic leg ulcers. Recurrence was observed in the absence of maintenance therapy (2 patients). Two patients discontinued HU because of adverse effects (stomach pain and fever). No significant increase in total Hb or HbF levels occurred. In conclusion, HU appears suitable for the treatment of leg ulcers unresponsive to conventional treatment in patients with thalassaemia intermedia.

Left ventricular remodeling, systolic function, and diastolic function in young adults with beta-thalassemia intermedia: a Doppler echocardiography study.

BACKGROUND: The aim of this study was to investigate the left ventricular (LV) remodeling and function in 24 asymptomatic young adults affected by beta-thalassemia intermedia (TI), in order to compare the obtained data with that of 80 patients affected by beta-thalassemia major (TM) and 65 healthy subjects. METHODS: LV volumes and shapes, mass index, mass/volume ratio, systolic and diastolic function, stroke volume, and cardiac index were determined by two-dimensional and M-mode echocardiography. RESULTS: In the TM and TI groups, LV volumes, diastolic and systolic shapes were significantly different from the control subjects, but the ejection fraction was slightly reduced only in the TM group. The TI group had larger LV volumes than did the TM group (mean [+/- SD] end-diastolic volume index, 99.4 +/- 21.9 vs 82.7 +/- 21.5 mL/m(2), respectively [p < 0.005]; mean end-systolic volume index, 42.8 +/- 12.2 vs 36.1 +/- 12.9 mL/m(2), respectively [p < 0.05]). Both groups showed an increase of the LV mass index, but the mass/volume ratio did not differ from the control subjects. The systolic volume index and the cardiac index were increased in both groups, but the increase was more pronounced in the TI group. Fractional shortening (FS) and the mean velocity of circumferential shortening (mVCFc) were decreased in the TM group (FS, 33.6 +/- 5.5% vs 36.9 +/- 4.1, respectively [p < 0.001]; mVCFc, 1.06 +/- 0.18 vs 1.17 +/- 0.12 circumference per second, respectively [p < 0.0001]). The LV contractile state was depressed only in the TM group, and the preload index was normal in both. LV filling showed an increase in the total flow velocity integral due to increases in the peak E wave (E) and peak A wave (A) velocities and integrals, with an increase of the E/A ratio in the TM group and a slight decrease in the TI group. The isovolumic relaxation time was prolonged in both groups. There was no major derangement in the pulmonary venous flow. CONCLUSIONS: Asymptomatic young adults with TI show significant increases in LV volumes, LV mass, and cardiac index that are more pronounced than those in TM patients. LV systolic function is preserved in the TI group but is slightly depressed in the TM group due to the increase of afterload and to reduced contractility. The hemodynamic and hematologic factors involved in the etiopathogenesis of these findings are discussed, such as the treatment strategy.