ALBERT

Description: Introduction: Oxidative stress plays a central role in the pathogenesis of morbidities in β-thalassemia. Peroxiredoxin-2 (PRDX2) is the third most abundant cytoplasmic protein in red cells and is able to reduce and detoxify a vast range of organic peroxides, H2O2, and peroxynitrite. PRDX2 has been demonstrated to be induced by oxidative stress and that cells overexpressing PRDX2 are more resistant to the oxidative stress. Vitamin E is a fat-soluble vitamin and an anti-oxidant which is often depleted in thalassemia patients as a result of iron overload. Aim: This randomized prospective trial aimed to investigate the efficacy and safety of vitamin E as an adjuvant therapy to the three used iron chelators in moderately iron overloaded young vitamin E-deficient β-thalassemia major (β-TM) patients in relation to tissue iron overload and examine its potential corrective value to markers of oxidative stress and to the level of PRDX2 as a novel protective marker of oxidative stress. Methods: Inclusion criteria were β-TM patients aged 6-18 years, vitamin E deficient, serum ferritin (SF) 〉1000-2500 μg/L and cardiac T2* 〉 10 ms and ejection fraction 〉 56 %. A total of 245 β-TM patients were screened for eligibility, 180 were enrolled while 35 did not meet inclusion criteria and 30 were excluded. The 180 β-TM vitamin E-deficient patients were equally enrolled into 3 groups (each; n=60) and received desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX). Patients in each group were further randomized either to receive vitamin E supplementation (400 IU daily) or not (n=30). All patients received vitamin E (group A) or no vitamin E (group B) were followed-up for one year with assessment of transfusion index, hemoglobin, serum ferritin (SF), liver iron content (LIC) and cardiac magnetic resonance imaging (MRI) T2*. Malondialdehyde (MDA), as an index for lipid peroxidation, and antioxidants including reduced glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase and PRXD2 were assessed. Results: Baseline vitamin E was negatively correlated to SF, LIC and MDA while it was positively correlated to GSH, GPX, catalase and PRXD2. No significant difference was found as regards the studied variables at baseline and study end in patients who did not receive vitamin E (group B). After vitamin E therapy, transfusion index, SF, and LIC were significantly decreased in group A patients while hemoglobin and cardiac MRI T2* were elevated compared with baseline levels or those in group B without vitamin E. MDA levels were decreased while all the studied antioxidants were increased post-vitamin E supplementation compared with baseline levels or those in group B without vitamin E. The same improvement was found among DFP-treated patients post-vitamin E compared with baseline data. DFP-treated patients had the highest hemoglobin and antioxidant levels with the lowest SF and LIC compared with DFO or DFX subgroups. Conclusions: Vitamin E as an adjuvant therapy possibly potentiates the efficacy of DFP more than DFO and DFX in reducing iron burden and reduces oxidative stress in the moderately iron overloaded vitamin E-deficient β-TM patients, with no adverse events. Disclosures No relevant conflicts of interest to declare.

Description: Background Cardiac iron removal is relatively slow and patients with cardiac siderosis can take years to normalize cardiac T2* to 〉20 ms. Prospective comparison of iron chelators are mostly limited to studies of 1-yr duration. CORDELIA is a large randomized trial comparing deferasirox (DFX) with deferoxamine (DFO) in patients with β-thalassemia major (TM), which demonstrated the non-inferiority of DFX vs DFO for cardiac iron removal at 1 yr, with a trend for superiority of DFX (P=0.057). This 1-yr extension was planned to collect additional data on efficacy and safety of DFX and DFO in patients with cardiac siderosis when treated for up to 2 yr. Methods Study design has been reported previously (Pennell Blood 2012; abst 2124). Patients enrolled had cardiovascular magnetic resonance-measured cardiac T2* 6–20 ms, left ventricular ejection fraction (LVEF) ≥56%, and R2-magnetic resonance imaging liver iron concentration (LIC) ≥3 mg Fe/g dw. Patients completing 1 yr were eligible to continue on DFX or DFO as assigned, or to switch treatment on entering the extension if judged by the investigator to be of therapeutic benefit. Target doses were an intensified DFO regimen of 50–60 mg/kg/d sc for 8–12 h, 5–7 d/wk, or DFX at 40 mg/kg/d. Efficacy is reported for changes from core baseline (BL). Safety was monitored continuously. Results for patients continuing with DFX or DFO are reported here. Results In total, 160/197 patients completed 1 yr; 74 patients continued into the extension on DFX (mean age 20.1 ± 6.9 yr; 59.5% male) and 29 patients on DFO (17.0 ± 5.4 yr; 58.6%). At core BL, 29.7% DFX patients had cardiac T2* 33% from BL and 〉 upper limit of normal (ULN) at 2 consecutive values occurred in 2.7% of DFX and 3.4% of DFO patients. Frequency of ALT elevations 〉5 x ULN and 2 x BL were comparable between groups. Discussion Cardiac T2* increased substantially during 2-yr treatment with DFX or DFO. Improvement with DFX was comparable with DFO, although DFO patient numbers were low. The magnitude of cardiac T2* improvement with DFX was consistent with previous long-term studies (Pennell Blood 2010). Mean LVEF was stable and remained within normal limits in both groups. LIC continued to decrease from very high BL levels with DFX and DFO. The reduction in CIC in the extension was similar or possibly greater than in the core, which might relate to the falling LIC. Long-term safety profiles of DFX and DFO were consistent with previous reports. Disclosures: Pennell: Shire: Consultancy, Honoraria; ApoPharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Porter:Celgene: Consultancy; Shire: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Piga:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Wegener:Novartis: Employment. Habr:Novartis: Employment. Shen:Novartis: Employment. Aydinok:Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background Transfusion-dependent patients with severe cardiac siderosis often require intensive iron chelation therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move from a high-risk (cardiac T2*

Description: Background We conducted an investigator-driven, multicenter, open label, randomized study to establish whether the source of factor VIII (FVIII) replacement (plasma-derived, pd; or recombinant, r) affects the rate of inhibitory alloantibodies in previously untreated patients (PUPs) with severe hemophilia A. Methods Between 2010 and 2014, 303 PUPs who provided consent through their tutors were screened at 42 participating sites in 14 countries from Africa, the Americas, Asia and Europe. The original aim was to screen 300 patients, randomize 270 (10% screening failure) and follow them for 50 exposure days (ED) or 3 years. Once the intended numbers were included, follow-up was terminated due to logistic and budgetary reasons. Screening criteria were age 5 treatments with blood components and 10 were not infused after randomization. The remaining 251 patients were analysed and 35 had truncated follow-up (25 dropout, 10 study termination). Patients were aged 0-81 months at randomization (median 14 months) and received between 1 and 50 infusions of FVIII concentrates (median 22). Of those who did not develop an inhibitor, over 70% had 〉20 ED. 76 patients developed an inhibitor, of which 50 were high-titred. The cumulative inhibitor incidence was 35.4% (95% confidence interval (CI95) 28.9-41.9%). 90% of inhibitors developed within 20 EDs, both for all and high-titre inhibitors. After randomization 125 patients received pdFVIII and 126 rFVIII. The putative confounders were equally divided between the two product class arms. There were 29 inhibitors (20 high-titred) in the group treated with the class of pdFVIII and 47 (30 high-titred) in those treated with rFVIII. The cumulative inhibitor incidence was 26.7% (CI95 18.3-35.1%) for pdFVIII and 44.5% (CI95 34.7-54.3%) for rFVIII (Figure). For high-titre inhibitors the cumulative incidence was 18.5% (CI95 12.1-26.9%) for pdFVIII and 28.4% (CI95 19.6-37.2%) for rFVIII. By univariate Cox regression analysis rFVIII was associated with an 87% higher incidence of inhibitors than pdFVIII (hazard ratio (HR) 1.87, CI95 1.18-2.97). For high-titre inhibitors the rate was 70% increased (HR 1.70, CI95 0.96-2.99). The associations did not materially change after adjustment for putative confounders: in adjusted models the rate remained 70-90% elevated for rFVIII vs pdFVIII. When analysis was restricted to sites that had not randomized patients to a second generation full length rFVIII or pdFVIII (n=131 patients, 25 inhibitors), the risk of other rFVIII concentrates vs pdFVIII was still twofold increased (HR 1.99, CI95 1.00-3.99). Conclusions The rFVIII product class was associated with a 1.87-fold higher incidence of inhibitors than the pdFVIII class. This difference remained even when second generation full length rFVIII concentrate was excluded from the analyses. The results of this randomized study have implications in the choice of product for management of PUPs, as inhibitor development remains a major challenge in the management of haemophilia A. (Funded by the Angelo Bianchi Bonomi Foundation, Italian Ministry of Health, Grifols, Kedrion and LFB - Registed at EudraCT 2009-001186-88). Figure 1. Figure 1. Disclosures Peyvandi: Octapharma: Other: Investigator; LFB, Kedrion, Novonordisk, Bayer, Roche, CSL Behring.: Consultancy, Honoraria, Research Funding. Mannucci:Novonordisk, Grifols, Kedrion, Bayer, Biotest, Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Karimi:Octapharma: Other: Investigator. Young:Baxter, Grifols: Consultancy, Honoraria. Santagostino:Roche: Speakers Bureau; Bayer: Speakers Bureau; Baxter/Baxalta: Speakers Bureau; Octapharma: Speakers Bureau; Biotest: Speakers Bureau; Novo Nordisk: Speakers Bureau; Kedrion: Speakers Bureau; Biogen/Sobi: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Mancuso:Baxter, Pfizer, CSL Behring, Baxter, Sobi/Biotest: Consultancy; Novo Nordisk, Bayer: Speakers Bureau. Mahlangu:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bonanad:Baxalta: Research Funding. Ewing:Baxter, Novo Nordisk, Grifols, Bayer, Kedrion: Honoraria. Owaidah:King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Kavakli:Baxter: Other: advisory board member and received educational and investigational support; Bayer: Other: advisory board member and received educational and investigational support; Novo Nordisk: Other: advisory board member and received educational and investigational support; Pfizer: Other: advisory board member and received educational and investigational support; Bio Products Laboratory: Other: received educational and investigational support; CSL Behring: Other: received educational and investigational support; Octapharma: Other: received educational and investigational support. Manco-Johnson:Baxter, bayer, biogen, CSL Behring, NovoNordish: Honoraria. Neme:Novo Nordisk and Pfizer: Other: fees for speaking. Wicklund:NovoNordisk, Bayer, Baxter (now Baxalta), Biogen-Idec, CSL-Behring, National Hemophilia Foundation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zulfikar:Eczacýbaþý-Baxter, Pfizer, Novo Nordisk: Consultancy, Honoraria, Research Funding.

Description: Background: The ESCALATOR study evaluated once-daily deferasirox in β-thal pts unsuccessfully chelated with DFO and/or deferiprone (L1). Phase II/III studies have shown that deferasirox 20–30 mg/kg/d maintains/reduces iron burden, depending on transfusional iron intake. However, PK evaluation indicated that exposure to deferasirox was lower in children than adults. To examine the relationship between dose and efficacy in heavily transfused children, a subanalysis of ESCALATOR pts (2–5 × ULN on ≥2 consecutive visits were noted in 21 children; baseline values were high in 16/21 pts. Mean (SD) LVEF increased by 2.5% (8.2). Physical and sexual development progressed normally. At EOS, most pts reported greater satisfaction, convenience and less time lost compared with prior therapy. In total, 94.6% of pts preferred deferasirox. Conclusions: These data suggest that with appropriate dosing, deferasirox can effectively control iron burden with a clinically manageable safety profile in heavily iron-overloaded children who were previously unsuccessfully chelated. Dose increases to ≥25 mg/kg/d were required to reach target reductions in iron burden, with no safety concerns. This highlights the importance of timely dose adjustments to achieve therapeutic goals. Pts preferred deferasirox to previous chelation therapy, which may improve long-term compliance. Mean (SD) change from baseline 95% CI LIC, mg/g (n=163) −3.0 (6.1) – Baseline LIC ≥7 mg/g (n=143) −3.5 (6.2) −4.5, −2.5 Baseline LIC

Description: Cardiac iron overload causes most deaths in β-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with β-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ± coefficient of variation) improved from a baseline of 11.2 ms (± 40.5%) to 12.9 ms (± 49.5%) (+16%; P 〈 .001). LVEF (mean ± SD) was unchanged: 67.4 (± 5.7%) to 67.0 (± 6.0%) (−0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (± 25.6%) to 32.5 ms (± 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (± 4.7%) to 69.6 (± 4.5%) (+1.8%; P 〈 .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

Description: Key Points DFX-DFO combination followed by DFX monotherapy led to a meaningful decrease in myocardial and liver iron in severe siderosis patients. Substantial liver iron reduction may be helpful in patients needing rapid control of liver iron (eg, pretransplant or planned pregnancy).

Description: Background: The 1-year, prospective, multicenter EPIC trial, the largest ever conducted for an iron-chelating agent, evaluated the efficacy and safety of the once-daily, oral chelator deferasirox (Exjade®) in patients (pts) with transfusion-dependent anemias. 54% of 1744 pts had β-thalassemia major, providing one of the largest data sets assessing the use of deferasirox in this group. Data from this subgroup are presented. Methods: Pts (≥2 years old) with transfusional iron overload due to β-thalassemia and serum ferritin (SF) levels of ≥1000 ng/mL or 20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration 〉2 mg Fe/g dry weight, received an initial deferasirox dose of 10–30 mg/kg/day dependent on transfusion requirements. Protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 months based on SF trends and safety markers. The change at week 52 from baseline (BL) was the primary efficacy endpoint. Results: 937 pts with β-thalassemia major, 450 males and 487 females (mean age 18.4±10.8 years), were enrolled. Median BL SF was 3157 ng/mL (range 462–22320). In the year prior to enrollment, pts received a mean of 189.8 mL/kg of blood (range 0–1768). Most pts (n=625; 66.7%) had received deferoxamine (DFO); 234 (25.0%) DFO/deferiprone combination, 12 (1.3%) deferiprone alone and four (0.4%) other therapy; 66 (7.0%) were chelation naive. 798 pts (85%) started on ≤20 mg/kg/day and 139 (15%) on 〉20 mg/kg/day. 51% required a dose increase at a median of 24 weeks after treatment initiation (range 2–53). After 1 year, median SF significantly decreased from BL by 129 ng/mL (P=0.0007) at an average actual dose of 24.2±5.6 mg/kg/day. Pts receiving an average actual dose of ≥30 mg/kg/day achieved a significant reduction in SF at 1 year. Pts receiving an average actual dose of

Description: Background: The ESCALATOR trial evaluated deferasirox (Exjade®) in heavily iron-overloaded β-thalassemia patients (pts) previously treated with DFO and/or deferiprone. In the 1-year core study, 76% of pts required dose increases from 20 to 25/30 mg/kg/day at a median of 24 weeks, therefore the effect of deferasirox on liver iron concentration (LIC) and serum ferritin (SF) at 52 weeks may not reflect the effect of optimal dosing. An extension phase has assessed efficacy and safety after at least 1 additional year’s treatment at more optimal dose levels. Methods: All pts initially received deferasirox 20 mg/kg/day (except three receiving 10 mg/kg/day). Deferasirox dose at the start of extension depended on the last dose received in the core trial. Dose adjustments, performed in steps of 5–10 mg/kg/day were based on SF levels and safety markers; dose increases above 30 mg/kg were permitted due to a protocol amendment in the extension phase. Efficacy was assessed yearly by LIC and monthly by SF. Adverse events (AEs) and lab parameters were monitored. Results: 247 pts (166 pediatric [≥2–

Description: The liver is the main body site for iron storage. Iron chelators as DFo and L1 had problems of compliance and intolerance respectively. This prospective study enrolled 76 BTM patients aged from 9–33 years, mean of 14±4.4 to evaluate the effectiveness of both chelators judged by serum ferritin (sf) and liver iron content (LIC) using repeated liver biopsies. Fifty patients were on DFo 35 mg/kg/day 5 days per week and twenty-six were on L1 75 mg/kg/day on daily bases. Mean baseline sf values were 3678±1922 and 3573±1879 ng/ml while mean baseline LIC was 19.2±7.9 and 18.9±8.1 mg fe/g dw, while 12% and 14% showed evidence of liver fibrosis (score ≥ 3) respectively. Twenty-four months later; a decline in sf by 287±837 in Dfo (In Dfo compliant group [number = 30]who had received ≥ 75% of planned dose; sf dropped by 890±437 while increased in DFo non compliant by 621±513). While falling by 729±633 in L1 group. A decrease in LIC by 3.9±2.8 mg fe/g dw (−5.8±3.1 in Dfo compliant,+2.6±3.3 in Dfo non compliant) and falling by 2.2±3.4 mg fe/g dw in L1 group, the difference was statistically significant P〈 0.05 between compliant and non compliant DFo and insignificant difference between Dfo and L1.The mean iron excretion: intake was 1.61,0.86 and 1.48 in Dfo compliant, non compliant and L1 respectively. A positive correlation was found between sf and LIC in both groups. Fibrosis was improved in Dfo compliant group better than L1 but no statistically significant difference was observed, while progressive fibrosis in 10% of Dfo non compliant group. All Dfo compliant group completed study, 18 out of 20 Dfo non compliant while six L1 patients discontinued the drug prematurely (3 severe gastrointestinal disturbances, 2 severe arthralgia and one repeated neutropenia). Conclusion: Both Dfo and L1 are effective iron chelators evident by drop in sf, LIC and improved fibrosis, however compliance and intolerance are still troublesome.