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.
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.
This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia 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].Serial observations of LVEF over 3 years, in the same patient, were retrospectively assessed in 99 patients with TM during the sequential DFP-DFO multicenter randomized open-label trial [1]. A generalized estimating equation (GEE) model was used to demonstrate changes in mean LVEF over time [2].The regression coefficient of treatment suggested that the DFP-alone group showed a statistically significant increase in mean LVEF over time (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).These findings suggest that long-term treatment with DFP-alone can significantly enhance LVEF over time. These findings agree with a survival analysis reporting a substantial decline in cardiac deaths during recent years, related to the switching of high-risk patients from DFO to chelation regimens that include the oral chelator DFP [3][4][5].Oral chelation treatment has improved greatly adherence and management of patients with TM [6,7].The improvement of the LVEF after 1-year DFP treatment has been reported [8][9][10][11].However, the effects of DFP on LVEF after long-term treatment have not been fully investigated.This letter reports a retrospective survey performed on patients with TM, previously enrolled in a long-term randomized open-label trial carrying ahead in Italy on the behalf of the Italian Society for the Study of Thalassaemia and Haemoglobinopathies (SoSTE) [1]. Ninety-nine out of 213 patients enrolled in the sequential DFP-DFO trial underwent longterm echocardiographic study of LVEF measured at baseline and every 12 months over three consecutive years (Fig. 1). Among these, 39 and 60 received sequential DFP (75 mg/kg for 4 days/week)-DFO (50 mg/kg for 3 days/week) or DFP-alone (75 mg/kg for 7 days/week) treatment, respectively (Table I).The hematological and clinical findings at enrollment are shown in Table I. No differences were observed at baseline between the two randomized groups. Particularly, the main findings of body iron overloading, expressed as serum ferritin at baseline, liver iron concentration (LIC), baseline LVEF <55%, and total number of blood transfusions were not statistically significantly different (Table I). Moreover, although baseline LVEF appears unlike between the two groups ( Fig. 1), this was not statistically significantly different (P-value 5 0.10, Table I).The DFP-alone group showed statistically significant increase over time in mean LVEF in comparison with sequential DFO-FP treatment (coefficient 0.97, 95% CI (0.51; 1.44), P-value <0.0001).Furthermore, the regression coefficient of treatment suggested that there was a statistically significant difference in mean LVEF between the two treated groups favoring the sequential group (coefficient 2.36, 95% CI (0.02; 4.71), P-value 5 0.047, but this ...
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