Calogera Gerardi

Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.

Long-term sequential deferiprone–deferoxamine versus deferiprone alone for thalassaemia major patients: a randomized clinical trial

A multicentre randomized open‐label trial was designed to assess the effectiveness of long‐term sequential deferiprone–deferoxamine (DFO–DFP) versus DFP alone to treat thalassaemia major (TM). DFP at 75 mg/kg, divided into three oral daily doses, for 4 d/week and DFO by subcutaneous infusion (8–12 h) at 50 mg/kg per day for the remaining 3 d/week was compared with DFP alone at 75 mg/kg, administered 7 d/week during a 5‐year follow‐up. The main outcome measures were differences between multiple observations of serum ferritin concentrations. Secondary outcomes were survival analysis, adverse events, and costs. Consecutive thalassaemia patients (275) were assessed for eligibility; 213 of these were randomized and underwent intention‐to‐treat analysis. The decrease of serum ferritin levels during the treatment period was statistically significant higher in sequential DFP–DFO patients compared with DFP‐alone patients (P = 0·005). Kaplan–Meier survival analysis for the two chelation treatments did not show any statistically significant differences (long‐rank test, P = 0·3145). Adverse events and costs were comparable between the groups. The trial results show that sequential DFP–DFO treatment compared with DFP alone significantly decreased serum ferritin concentration during treatment for 5 years without significant differences regarding survival, adverse events, or costs. This trial was registered at http://www.clinicaltrials.gov as # NCT00733811.

IL28B polymorphisms influence stage of fibrosis and spontaneous or interferon-induced viral clearance in thalassemia patients with hepatitis C virus infection

Background Polymorphisms in the interleukin-28B are important determinants in the spontaneous and drug-induced control of hepatitis C virus infection. Design and Methods We assessed the association of rs8099917 and rs12979860 polymorphisms with spontaneous viral clearance, severity of liver fibrosis, and response to interferon-monotherapy in 245 thalassemia major patients with hepatitis C virus infection. Results Ninety-eight patients (40%) had a spontaneous viral clearance while 147 patients (60%) developed a chronic infection. Spontaneous viral clearance was more frequent among patients with the T/T genotype of rs8099917 polymorphism (OR 2.130; P=0.008) or C/C genotype of rs12979860 polymorphism (OR 2.425; P=0.001). During observation, 131 patients with chronic infection underwent a liver biopsy; age (OR 1.058; P=0.01) G/T or G/G genotypes of rs8099917 polymorphism (OR 3.962; P=0.001), and C/T or T/T genotypes of rs12979860 polymorphism (OR 3.494; P=0.005) were associated with severe liver fibrosis, independent of liver iron concentration. Finally, T/T genotype of rs8099917 polymorphism (OR 3.014; P=0.03) or C/C genotype of rs12979860 polymorphism (OR 3.285; P=0.01), age (OR 0.902; P=0.001), female gender (OR 3.418; P=0.01) and 2 or 3 virus C genotypes (OR 4.700; P=0.007) were independently associated with sustained virological response in 114 patients treated with alpha-interferon. Conclusions Polymorphisms in the interleukin-28B are associated with the control of hepatitis C virus infection in thalassemia major patients, and understanding allelic patterns has an important role in determining prognosis and therapeutic management.

Potential myocardial iron content evaluation by magnetic resonance imaging in thalassemia major patients treated with Deferoxamine or Deferiprone during a randomized multicenter prospective clinical study.

The purpose of this study was to evaluate if the variations of heart magnetic resonance imaging in β‐thalassemia major patients treated with Deferoxamine B mesylate (DF) or Deferiprone (L1) chelation therapy is a useful tool of the indirect myocardial iron content determination. For this reason, a prospective study was carried out. Seventy‐two consecutive patients with β‐thalassemia major (35 treated with DF and 37 with L1) were studied. The main outcome results were laboratory parameters including determination of the liver iron concentration (LIC) and magnetic resonance imaging (MRI) of the heart and liver. The heart to muscle signal intensity ratios (HSIRs) were significantly increased in both the DF (t = −2.8; p < 0.01) and L1 (t = −3.1; p < 0.01) groups after one year of treatment. No statistically significant difference in the values of HSIRs was present between the two groups at the beginning of treatment (p = 0.25; t = 1.13), and after one year of treatment (p = 0.20; t = 1.28). The HSIRs were inversely correlated to the LIC (r = −0.52; p < 0.001) but not with ferritin levels (r = 0.10; p = 0.18). A positive correlation was found between the variation of the HSIRs and that of the liver signal intensity ratios (r = 0.52; p < 0.001), and a mild correlation (r = 0.40; p < 0.001) was found between the γ glutamyltransferase (γGt) levels and the HSIRs values. Our data confirm that heart MRI is sensitive enough to detect significant variations of the mean HSIR during iron chelation with DF or L1.

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.

Influence of myocardial fibrosis and blood oxygenation on heart T2* values in thalassemia patients

To determine whether T2* measurements quantifying myocardial iron overload in thalassemia patients are influenced by myocardial fibrosis and blood oxygenation.

Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients.

A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1].

Deferiprone versus deferoxamine in thalassemia intermedia: Results from a 5-year long-term Italian multicenter randomized clinical trial

In patients with thalassemia intermedia (TI), such as beta‐TI, alpha‐thalassemia (mainly HbH disease and mild/moderate forms of HbE/beta‐thalassemia), iron overload is an important challenge in terms of diagnosis, monitoring, and treatment. Moreover, to date, the only possible chelators available are deferoxamine, deferasirox, and deferiprone. Here, we report the first 5‐year long‐term randomized clinical trial comparing the effectiveness of deferiprone versus deferoxamine in patients with TI. Body iron burden, which was determined by measuring serum ferritin levels in the same patient over 5 years and analyzed according to the generalized linear mixed model (GLMM), showed a linear decrease over time in the mean serum ferritin levels in both treatment groups (P‐value = 0.035). The overall period of observation was 235.2 person‐years for the deferiprone patients compared with 214.3 person‐years for the deferoxamine patients. The results of the log‐rank test suggested that the deferiprone treatment did not affect survival compared with the deferoxamine treatment (P‐value = 0.360). The major adverse events observed included gastrointestinal symptoms and joint pain or arthralgia. Neutropenia and agranulocytosis were also detected, suggesting needing of strict hematological control. In conclusion, long‐term iron chelation therapy with deferiprone is associated with an efficacy and safety similar to that of deferoxamine, suggesting that this drug is an alternative option in cases in which deferoxamine and deferasirox are contraindicated. Am. J. Hematol. 90:634–638, 2015.

Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major.

Transfusion and iron chelation treatment have significantly reduced morbidity and improved survival of patients with thalassemia major. However, cardiac disease continues to be the most common cause of death. We report the left-ventricular ejection fraction, determined by echocardiography, in one hundred sixty-eight patients with thalassemia major followed for at least 5years who received continuous monotherapy with deferoxamine (N=108) or deferiprone (N=60). The statistical analysis, using the generalized estimating equations model, indicated that the group treated with deferiprone had a significantly better left-ventricular ejection fraction than did those treated with deferoxamine (coefficient 0.97; 95% CI 0.37; 1.6, p=0.002). The heart may be particularly sensitive to iron-induced mitochondrial damage because of the large number of mitochondria and its low level of antioxidants. Deferiprone, because of its lower molecular weight, might cross into heart mitochondria more efficiently, improving their activity and, thereby, myocardial cell function. Our findings indicate that the long-term administration of deferiprone significantly enhances left-ventricular function over time in comparison with deferoxamine treatment. However, because of limitations related to the design of this study, these findings should be confirmed in a prospective, randomized clinical trial.

SEQUENTIAL ALTERNATING DEFERIPRONE AND DEFEROXAMINE TREATMENT COMPARED TO DEFERIPRONE MONOTHERAPY: MAIN FINDINGS AND CLINICAL FOLLOW-UP OF A LARGE MULTICENTER RANDOMIZED CLINICAL TRIAL IN -THALASSEMIA MAJOR PATIENTS

In β-thalassemia major (β-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in β-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some β-TM patients who may not be able to receive other forms of chelation treatment.