SummaryIn the last few decades, the life expectancy of regularly transfused b-thalassaemia major (TM) patients has dramatically improved following the introduction of safe transfusion practices, iron chelation therapy, aggressive treatment of infections and improved management of cardiac complications. How such changes, especially those attributed to the introduction of iron chelation therapy, improved the survival of TM patients to approach those with b-thalassaemia intermedia (TI) remains unknown. Three hundred and seventy-nine patients with TM (n = 284, dead 40) and TI (n = 95, dead 13) were followed retrospectively since birth until 30 June 2015 or death. Kaplan-Meir curves showed statistically significant differences in TM and TI survival (P < 0Á0001) before the introduction of iron chelation in 1965, which were no longer apparent after that date (P = 0Á086), reducing the Hazard Ratio of death in TM compared to TI from 6Á8 [95% confidence interval (CI) 2Á6-17Á5] before 1965 to 2Á8 (95% CI 0Á8-9Á2). These findings suggest that, in the era of iron chelation therapy and improved survival for TM, the major-intermedia dichotomy needs to be revisited alongside future directions in general management and prevention for both conditions.
SummaryA 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 = 0AE005). KaplanMeier survival analysis for the two chelation treatments did not show any statistically significant differences (long-rank test, P = 0AE3145). 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.
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 5 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 5 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.
Sickle cell disease (SCD) is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin (HbS). Clinical manifestations of SCD are mainly characterized by chronic hemolysis and acute vaso-occlusive crisis, which are responsible for severe acute and chronic organ damage. SCD is widespread in sub-Saharan Africa, in the Middle East, Indian subcontinent, and some Mediterranean regions. With voluntary population migrations, people harboring the HbS gene have spread globally. In 2006, the World Health Organization recognized hemoglobinopathies, including SCD, as a global public health problem and urged national health systems worldwide to design and establish programs for the prevention and management of SCD. Herein we describe the historical experience of the network of hemoglobinopathy centers and their approach to SCD in Italy, a country where hemoglobinopathies have a high prevalence and where SCD, associated with different genotypes including ß-thalassemia, is present in the native population.
Thalassemia is a group of genetically inherited hemoglobin (Hb) disorders characterized by reduced synthesis of the b-globin chain and a sub-sequent imbalance in the a/b-globin chain ratio that results in chronic hemolytic anemia. The severity of clinical phenotype is used to distinguish this heterogeneous disease in two main subtypes: Thalassemia Major (TM) and Thalassemia Intermedia (TI). Iron overload is mostly due to increased intestinal absorption because of chronic anemia. Transfusions, in contrast with what happens in TM, have a minor role in the development of iron overload. However, although 1-year data from the phase 2, prospective, randomized, double-blind, placebo-controlled trial and 1-year extension results from the THALASSA study assessing the efficacy and safety of deferasirox in TI patients with iron overload have been reported, no data, during randomized trials, have been so far published on Deferiprone (DFP) treatment (Taher et al Blood 2012 and Ann Hematol 2013) Adult patients with TI were randomly assigned in permuted blocks of 10 with a ratio 1:1 to DFP at 75 mg/kg/day for 7 d/week divided into three oral daily doses (DFP-group) or DFO by sc infusion (8–10 h) at 50 mg/kg per day for 5 d/week (DFO-group). The study was designed to detect an improvement in decreasing mean serum ferritin levels in each of the treated-groups from the initiation of therapy to each year (from year 1 to year 5) with a significance level of 5% and 80% power. The planned number of subjects was between 40 and 100 (Rochon Biometrics 1991). The primary endpoint was the treatment efficacy evaluated as change from the baseline value in serum ferritin levels during the 5 years assessed using a linear mixed-effects model (LMM, Laird-Ware Biometrics 1982) where we assumed the patient effect (given by the intercept terms for each patient) as random effect, while the treatment effect (treat), the time effect (time), the treatment-by-time interaction effect (treat×time), and the total transfusions in ml (tot TX) as fixed effects. Secondary endpoints were safety and survival analysis at 5-years evaluated considering the number of advers events and Kaplan-Meir curves respectively. Overall 88 patients, observed at 12 SoSTE centers in Italy between January 2001 and May 2011, were randomized (47 DFP-group and 41 DFO-group). There were no differences observed at baseline between the two randomized groups in clinical and haematological findings. The regression coefficient of time suggested that there was a linear decrease over time in the mean serum ferritin levels in both treatment-groups even if the p-value was very close to the statistical significance (Coeff. -88.4, 95% CI (-182.4; 5.6), p-value =0.065). However, the mean serum ferritin levels did not seem to be significantly different between the two treatment-groups over time (Coeff. -77.4, 95% CI (-231.7; 77.1), p-value=0.326 ). The effect of total blood transfusion on serum ferritin levels was not statistically significant (Coeff. 0.06, 95% CI (-0.01; 0.1), p-value=0.100). The estimated profiles of serum ferritin levels in the two groups were represented in Figure I. Agranulocytosis was reported in 4 case of DFP versus no cases of DFO group, respectively (p-value=0.118). Neutropenia was statistically significant different between the two groups DFP (6 (12.5%) versus no cases in DFO , p-value=0.027). Kaplan-Meier survival probability curves for the two treatment groups are shown in Figure II, and the log-rank test did not show any statistically significant difference in the survival between the two groups (p-value=0.36). In conclusion, these findings suggest as DFP shows same effectiveness and survival probability versus DFO with controlled safety profile. Therefore, these results support the possibility of using this drug in TI patients in which DFO and Deferasiorx is contraindicated. Figure I: Estimated profiles of the mean serum ferritin in the two treatment-groups from the fitted linear mixed-effects model. Figure I:. Estimated profiles of the mean serum ferritin in the two treatment-groups from the fitted linear mixed-effects model. Figure II. Kaplan–Meier survival probability curves in the two treatment groups during multi-center TI clinical trial (DFP: continous line; DFO: dashed line), (p-value=0.36). Figure II. Kaplan–Meier survival probability curves in the two treatment groups during multi-center TI clinical trial (DFP: continous line; DFO: dashed line), (p-value=0.36). Disclosures No relevant conflicts of interest to declare.
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