No abstract

Introduction: Since HU has been FDA-approved for patients with SCD, it is not clear what proportion are taking a therapeutic dose (≥15mg/kg/day). There is also inadequate reporting of the frequency of HU dose modification during follow-up, or whether those who were treated with subtherapeutic doses (<15mg/kg/day) benefit from HU. We conducted this analysis to answer these important questions in a single center in Palermo, Italy. Methods: Patients were enrolled at the Haematology Department of Ospedale V. Cervello between January 2000 and April 2014. Laboratory parameters and frequency of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) were recorded. Blood counts, fetal hemoglobin (HbF) response, and changes in SCD complications were compared between the first and last visits to the clinic and across these 3 groups: patients who never took HU were combined with those who suspended HU before the last visit (no HU group, n=50, 36%); HU <15mg/kg (n=30, 21%); or HU ≥15mg/kg (n=60, 43%). Results: There were a total of 140 patients: 25 HbSS, 54 HbSβ0thal, and 61 HbSβ+thal. Median follow-up was 6.6 years. The median age was 35 years (range 0.4-61 years). 28% of patients never took HU, and 8% suspended HU treatment during the follow-up. Among patients taking <15mg/kg HU at first visit, about half stayed in the same dose range (<15mg/Kg/day) and half increased to the ≥15mg/kg dose range. Among patient taking ≥15 mg/kg, 17% decreased to <15mg/Kg/day due to cytopenia; 83% stayed on the ≥15 mg/kg. White blood cell (WBC) counts were lower in both HU groups, but comparing first and last visits, the change in WBC within each group was insignificant (P all >0.05, Table 1). Similarly, the change in total hemoglobin levels within each group was also insignificant (P all >0.05). HbF decreased in the no HU group, likely due to maturing age of 2 young children included in this group. Both HU treatment groups had modest increases in HbF (P=0.004, 0.001). With respect to SCD complications, the no HU group had less severe disease at the first visit, with lower percent of subjects with and fewer episodes of VOC and ACS (Table 2). While there was an increase in both VOC and ACS with time, this increase was not statistically significant. Both HU treatment groups had a significant reduction in both complications (p<0.0001 in both), and the magnitude of reduction was similar. The pattern of reduction appeared to be similar in all SCD phenotypes, but the small sample size precluded subtype analysis. Comparing changes in laboratory markers of liver and kidney function as well as TRV and ejection fraction between the first and last visit showed no significant differences. Conclusions: About one third of patients with SCD never took or discontinued HU. While these patients may have less severe disease initially, their rates of complications increased during follow-up. Among those taking HU, dose adjustment was common. HU increased HbF and is associated with reducing VOC and ACS. Since the increase in HbF and changes in HU dosing parameters were only modest in patients even on the highest HU doses, titrating HU to the maximum HbF response should be explored in order to improve markers of organ function. Table 1: Hematologic parameters based on HU status First Visit Last Visit NO HU HU <15mg/kg HU >15mg/kg NO HU HU <15mg/kg HU >15mg/kg WBC (k/uL) 11.2 8.74* 10.9 10.7 7.8* 8.3* Hgb (g/dL) 10.0 10.2 10.0 10.2 9.7 9.9 HbF (%) 11.9** 9.4* 10.7* 7.7 11.7* 12.8* *P<0.05 compared to no HU group **includes 4 subjects with hereditary persistent of HbF and 2 children aged 3 months. Table 2: SCD complications based on HU status VOC ACS % of subjects Crisis per patient per year % of subjects Mean episodes per patient F V L V F V L V F V L V F V L V No HU 60 70 2 2.5 22 28 0.2 0.28 HU<15mg/kg 90 56.6 4.3* 1.2* 50 20 0.7* 0.23 HU>15mg/kg 96.6 60 4.1* 1.1* 51 25 1.1* 0.32 FV, first visit; LV, last visit *P<0.05 compared to no HU group Disclosures No relevant conflicts of interest to declare.

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.