Long-Term Use of Deferiprone Enhances Significantly the Left Ventricular Ejection Function in Thalassemia Major
Authors: Maggio Aurelio , Capra Marcello , Cuccia Liana , Gagliardotto Francesco , Rigano Paolo , Calvaruso Giusi , Pitrolo Lorella , Prossomariti Luciano , Filosa Aldo , Romeo Maria Antonietta , Caruso Vincenzo , Argento Crocetta , Gerardi Calogera , Campisi Saveria , Violi Pietro , Cianciulli Paolo , Rizzo Michele , D'Ascola Domenico Giuseppe , Perrotta Ketty , Fidone Carmelo , Roccamo Gaetano , Carollo Antonella , Rigoli Luciana , Commendatore Francesca Valeria , Giugno Roberto , Rosso Rossellina , Cingari Rocca , Galati Maria Concetta , Quarta Antonella , Ciancio Angela , Vitrano Angela 
Published: October 2019

Abstract
Abstract 5302

Background:
A multicentre randomized controlled trial (RCT) was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM) (Maggio et al.,2009). Effectviness, survival, adverse events and costs were comparable between the groups. These findings were confirmed in a further 21-month follow-up (Pantalone et al., 2011). Moreover, deferiprone-alone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular ejection function (LVEF). However, little is known of its relative effect on LVEF after long-term treatment. Therefore, data from this prospective RCT were retrospectively analyzed to assess the LVEF responses to these treatments.

Methods:
In this retrospective survey of RCT, 99 patients with TM received, from September 30, 2000 to December 31, 2007, LVEF study consecutively (Table I). Generalized Estimating Equations (GEE) model was used to show the possible change of the mean of LVEF over the time between the Sequential DFP-DFO versus the DFP (Hedeker & Gibbons, 2006). This approach was implemented in the 'xtgee' procedure of Stata 11 software (StataCorp, College Station, TX, USA). All of the statistical analyses were performed under code at the Department for Mathematical and Statistical Sciences 'S. Vianelli', University of Palermo (Italy) by A.V.

Results:
Baseline findings are shown on Table I. Figure 1 shows the proÞles of the GEE model for the change in the mean LVEF between the two groups. The regression coefficient of treatment suggests as, the DFP-group shows statistically significant increase of mean ejection fraction over time (Coeff. 0,97, 95% CI (0,51; 1,44), p-value<0,0001, Fig. I). Actually, while the Sequential DFP-DFO treatment shows a slight advantage in terms of difference in the mean of LVEF (Coeff. 2,36, 95% CI (0,02; 4,71), p-value=0,047,Fig. I), it does not increase significantly LVEF over the time (Coeff. −0,34, 95% CI (−1,09; 0,39), p-value=0,359).

Discussion:
Previous retrospective studies suggested as deferiprone –treated patients had higher LVEF in comparison with Deferoxamine (DFO) or Deferasirox (DFX) treated groups (Anderson et al., 2002; Pepe et al., 2011). Moreover, survival analysis suggested a substantial decline in cardiac deaths in recent years, related to switching high-risk patients from subcutaneous desferrioxamine to chelation regimes which include the oral chelator deferiprone (Borgna-Pignatti et al., 2006; Telfer et al., 2009). Finally, Pennell et al. 2006 suggested, during a RCT over 1 year comparing DFO versus DFP, as LVEF increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P =.003). This retrospective survey of long-term prospective RCT, shows as the effect of deferiprone-alone treatment increases significantly during the years (Coeff. 0,97, 95% CI (0,51; 1,44), p-value<0,0001, Fig. 1). Cardioprotective effect of deferiprone on mitochondrial function in cultured, iron-loaded heart cells has been suggested (Link et al., 1999;Glickstein et al., 2006;Xu et al.,2006), even at concentrations below the iron-mobilizing effect (Link et al.,1999). These findings clincally support as long-term treatment with DFP-alone enhances LVEF over the years and may prevent death due to heart failure in patients with thalassemia major.

Disclosures:
Off Label Use: Deferiprone on sequencial way with Deferoxamine.