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Background Oral P2Y12 receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y12 receptor antagonist with a rapid onset and short duration of action. Objectives This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI. Methods Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y12 reaction units Results Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y12 reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications. Conclusions Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445 , 2018-000765-36 [EudraCT])

Objective: Many patients with transfusional iron overload are at risk for progressive organ dysfunction and early death and poor compliance with older chelation therapies is believed to be a major contributing factor. Phase II/III studies have shown that oral deferasirox 20–30 mg/kg/d reduces iron burden, depending on transfusional iron intake. Methods: The prospective, open-label, 1-yr ESCALATOR study in the Middle East was designed to evaluate once-daily deferasirox in patients ≥2 yr with β-thalassaemia major and iron overload who were previously chelated with deferoxamine and/or deferiprone. Most patients began treatment with deferasirox 20 mg/kg/d; doses were adjusted in response to markers of over- or under-chelation. The primary endpoint was treatment success, defined as a reduction in liver iron concentration (LIC) of ≥3 mg Fe/g dry weight (dw) if baseline LIC was ≥10 mg Fe/g dw, or final LIC of 1–7 mg Fe/g dw for patients with baseline LIC of 2 to

This subgroup analysis evaluated the effect of once-daily oral deferasirox on labile plasma iron (LPI) levels in patients from the prospective, 1-yr, multicentre ESCALATOR study. Mean baseline liver iron concentration and median serum ferritin levels were 28.6 +/- 10.3 mg Fe/g dry weight and 6334 ng/mL respectively, indicating high iron burden despite prior chelation therapy. Baseline LPI levels (0.98 +/- 0.82 micromol/L) decreased significantly to 0.12 +/- 0.16 micromol/L, 2 h after first deferasirox dose (P = 0.0006). Reductions from pre- to post-deferasirox administration were also observed at all other time points. Compared to baseline, there was a significant reduction in preadministration LPI that reached the normal range at week 4 and throughout the remainder of the study (Por = 0.02). Pharmacokinetic analysis demonstrated an inverse relationship between preadministration LPI levels and trough deferasirox plasma concentrations. Once-daily dosing with deferasiroxor =20 mg/kg/d provided sustained reduction in LPI levels in these heavily iron-overloaded patients, suggesting 24-h protection from LPI. Deferasirox may therefore reduce unregulated tissue iron loading and prevent further end-organ damage.

Background FTY720 is a novel immunomodulator that was developed to produce optimal graft protection with improved safety and tolerability. Phase II studies have demonstrated the efficacy of FTY720 up to the doses of 2.5 mg with full-dose cyclosporine (FDC). Methods This multicenter, double-blind, Phase IIb, randomized study evaluated the safety and efficacy of 5 mg FTY720 (n=87; Group 1) vs. 2.5 mg FTY720 (n=90; Group 2) vs. mycophenolate mofetil (MMF; n=94; Group 3) in de novo renal transplant patients receiving FDC and prednisone. Results The primary efficacy endpoint was the occurrence of treated biopsy-proven acute rejection, graft loss, death, or premature study discontinuation (composite endpoint) within 6 months. The primary endpoint was superior in Group 1 (24%) and statistically noninferior in Group 2 compared to Group 3 (24.1% vs. 29.2% vs. 39.4%; P=0.025 and 0.0039, respectively). FTY720 plus FDC was generally well tolerated, with a similar incidence of adverse events across all groups. FTY720 was associated with higher incidence of bradycardia (Group 1: 26.4%, P=0.0002 and Group 2: 15.6%, P=0.046, vs. Group 3: 6.4%), respiratory disorders (Group 1: 40.2%, not significant [P=NS] and Group 2: 34.4%, P=NS vs. Group 3: 28.7%). One macular edema occurred in Group 2. Lower creatinine clearances were observed with FTY720 versus MMF (Group 1: 52.4 ml/min, P=NS and Group 2: 51.7 ml/min, P=0.039 vs. Group 3: 62.5 ml/min). Conclusions Although FTY720 with FDC provided adequate protection from acute rejection the safety profile was less favorable for adverse events than current standard immunosuppression in de novo renal transplant patients.

Background: Labile plasma iron (LPI) is a toxic, directly chelatable form of non-transferrin- bound iron that is produced continually in conditions of iron overload and, due to rapid uptake into hepatocytes, myocardium and endocrine tissues, leads to secondary expansion of the cellular iron pool. The sustained presence of an iron chelator in the plasma may help avoid accumulation of LPI, thereby minimizing iron-related morbidity and mortality. This analysis evaluates the effect of deferasirox on LPI levels in patients (pts) with transfusion-dependent anemias enrolled in the large-scale, prospective, 1-yr multicenter EPIC trial. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusion episodes or >100 mL/kg of RBCs) and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw). Deferasirox starting dose was determined based on blood transfusion frequency. Dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) were based on SF trends and safety markers. Blood samples to measure LPI and assess the deferasirox pharmacokinetic profile were taken pre-administration and 2 hrs post administration at baseline and wks 12, 28 and 52. Results: LPI data are available from 1602 pts (825 M, 777 F; mean 30.4±23.0 yrs). Underlying anemias were: β-thalassemia (n=1029), myelodysplastic syndromes (MDS; n=305), aplastic anemia (AA; n=104), sickle cell disease (SCD; n=79), rare anemias (mostly hemolytic in nature) (n=42), and other conditions associated with anemias requiring transfusion (n=43). Mean LPI, pre and post deferasirox administration, at baseline and wks 12, 28 and 52 are shown in Table 1. Table 1. Mean LPI, pre and post deferasirox administration, at baseline and after repeat doses Baseline Week 12 Week 28 Week 52 Pre Post Pre Post Pre Post Pre Post NOTE: Data are mean LPI±SD (μmol/L); normal levels are 0–0.40 μmol/L All pts 0.89 ±1.84 0.33 ±1.59 0.30 ±0.90 0.11 ±0.56 0.27 ±0.87 0.11 ±0.62 0.47 ±1.35 0.30 ±1.33 β-thalassemia 1.25 ±2.34 0.58 ±2.10 0.40 ±1.07 0.15 ±0.67 0.34 ±0.94 0.13 ±0.72 0.60 ±1.55 0.39 ±1.52 MDS 0.53 ±0.63 0.02 ±0.11 0.08 ±0.28 0.02 ±0.10 0.15 ±0.88 0.03 ±0.18 0.14 ±0.32 0.02 ±0.07 AA 0.23 ±0.34 0.01 ±0.02 0.08 ±0.20 0.01 ±0.04 0.06 ±0.20 0.01 ±0.03 0.04 ±0.10 0.03 ±0.10 SCD 0.11 ±0.54 0.04 ±0.29 0.09 ±0.42 0.06 ±0.31 0.11 ±0.28 0.14 ±0.46 0.10 ±0.21 0.07 ±0.19 Rare anemias 0.50 ±0.55 0.01 ±0.04 0.05 ±0.13 0.01 ±0.03 0.06 ±0.18 0.01 ±0.03 0.29 ±0.52 0.02 ±0.03 Overall mean deferasirox dose during the 1-yr treatment period was 22.4±6.0 mg/kg/day (β-thalassemia, MDS, AA, SCD and rare anemias: 24.3±5.5, 19.3±5.7, 17.8±4.7, 20.2±3.8 and 18.6±5.6 mg/kg/day, respectively). At each time point, peak LPI levels observed just before deferasirox dosing were decreased compared with baseline and were mostly within the normal range from week 12 onwards in each underlying anemia. A small rebound at 52 wks was seen in the thalassemia sub-group: this could be associated with decreased compliance or other reasons, to be investigated further. In all pts, mean steady-state plasma concentration (ie pre-administration value) of deferasirox at wks 12, 28 and 52 was 32.9, 35.9 and 39.4 μmol/L, respectively. At each time point this was approximately half of the concentration value observed at 2 hrs post administration (84.4, 89.3 and 97.0 μmol/L, respectively). Conclusions: The results from this 1-yr study confirm the ability of once-daily deferasirox to provide sustained reduction in toxic LPI levels across various transfusion-dependent anemias, supporting previous data in pts with β-thalassemia. This is likely due to trough levels of deferasirox being within the therapeutic range, thereby preventing LPI levels rebounding between doses. Deferasirox therapy may therefore reduce unregulated tissue iron loading and prevent further end-organ damage in these pts.

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 Table 1. Median change from BL in SF (ng/mL) by average actual dose received BL End of study Average actual dose categories Mean iron intake, mg/kg/day n Median SF n Median change from BL in SF P -value versus BL Only 9.5% of pts (n=89) discontinued therapy. Reasons for withdrawal were AEs (n=31, 3.3%), consent withdrawal (n=24, 2.6%), unsatisfactory therapeutic effect (n=12, 1.3%), lost to follow-up (n=5, 0.5%), death (n=4, 0.4%, three due to cardiac failure and one to septicemia following surgery, none treatment related by investigators’ assessment) and other (n=13, 1.4%). The most common investigator-assessed drug-related AEs were rash (n=115, 12.3%), diarrhea (n=76, 8.1%) and abdominal pain (n=50, 5.3%). The majority of AEs were mild-to-moderate (>95%). Thirty-seven pts (3.9%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Five (0.5%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in four pts. Conclusions: These data confirm that in heavily iron-loaded pts with β-thalassemia major, higher deferasirox doses are needed to achieve significant reductions in SF, while lower doses are able to maintain iron balance. The starting dose guided by the rate of iron intake from blood transfusions and current iron burden should be titrated individually and promptly (at 3 months) according to SF trends and safety markers. Deferasirox treatment in this subgroup was generally well tolerated (including doses ≥30 mg/kg/day) with a low discontinuation rate.

Background: Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. In registration trials, the starting dose was based on baseline liver iron concentration (LIC). The prospective multicenter EPIC trial, the largest ever conducted for an iron chelator, included patients (pts) with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. One-year results are presented. Methods: Pts (aged ≥2 yrs) had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and R2 MRI-confirmed LIC of >2 mg Fe/g dry weight (dw). Deferasirox starting dose was 20 mg/kg/d for pts receiving 2–4 blood units/mth. An initial dose of 10 or 30mg/kg/d was considered for pts receiving less or more frequent blood transfusions, respectively. Protocol-specified dose adjustments of 5–10 mg/kg/d (range 0–40 mg/kg/d) were done every 3 months based on SF trends and safety markers. Primary efficacy endpoint was SF change from baseline (BL) at 1 year. Results: 1744 pts (901 M, 843 F; mean age 30.6±23.3 yrs) were enrolled; 33.1% (n=577) aged 20 mg/kg/d. 39% of pts had dose increases at a median of 24 weeks after treatment initiation (range 2–53). Overall, median SF was significantly decreased from BL by 264 ng/mL after 1 year (P Table 1. Median change from BL in SF (ng/mL) and mean iron intake (mg/kg/day) by average actual dose BL End of study Over the study Average actual dose categories N Median SF (ng/mL) N Median change from BL in SF (ng/mL) P -value vs BL N Mean iron intake (mg/kg/day) 1389 pts (79.6%) completed 1 year; reasons for discontinuation were adverse events (AEs; n=153; 8.8%), consent withdrawal (n=77; 4.4%), unsatisfactory therapeutic effect (n=20; 1.1%) and various other reasons (n=62; 3.6%); there were 31 (1.8%) drug related SAEs and 42 deaths, none assessed by investigators as treatment related. The most common drug-related (investigator-assessed) AEs were diarrhea (n=251; 14.4%), rash (n=174; 10.0%), nausea (n=135; 7.7%) and abdominal pain (n=97; 5.6%). 175 pts (10.0%) had serum creatinine value >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. 13 (0.7%) had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in 11 pts. Conclusions: This large study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated with a safety profile consistent with data from previous clinical trials.

Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naive (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias | | All (n=1744) | TM (n=937) | TI (n=84) | MDS (n=341) | AA (n=116) | SCD (n=80) | Rare (n=43) | DBA (n=14) | |:-----------------------------------:| ------------ | ---------- | --------- | ----------- | ---------- | ---------- | ----------- | ---------- | | *Mean ± SD; **Median | | Age, yrs* | 30.6±23.3 | 18.4±10.8 | 19.2±14.4 | 67.9±11.4 | 33.3±17.1 | 23.9±13.2 | 39.5±22.7 | 17.3±13.2 | | Transfusions in last yr* | 17.8±12.5 | 17.5±8.8 | 13.5±7.1 | 24.3±17.7 | 12.5±13.0 | 10.7±8.2 | 21.0±18.7 | 19.0±18.7 | | Total transfused in last yr, mL/kg* | 159±136 | 190±139 | 155±87 | 116±123 | 116±179 | 84±57 | 153±142 | 185±148 | | Total yrs on transfusions* | 12.3±10.4 | 16.8±10.4 | 10.2±7.8 | 3.6±4.6 | 6.1±5.7 | 13.0±9.6 | 10.9±11.8 | 13.3±10.0 | | % of lifetime on transfusions* | 62.9±39.4 | 89.8±15.2 | 61.2±28.8 | 5.7±8.4 | 27.1±29.3 | 59.5±30.1 | 44.3±41.5 | 87.5±23.2 | | LIC in last yr, mg Fe/g dw* | 10.7±9.0 | 9.5±7.8 | 9.7±5.5 | 14.4±8.5 | 12.0±4.3 | 11.8±8.4 | – | 8.8±4.2 | | SF, ng/mL** | 3135 | 3157 | 3493 | 2730 | 3254 | 3163 | 3161 | 2289 | | Prior chelation, % | | | | | | | | | | DFO | 58.6 | 66.7 | 78.6 | 40.2 | 26.7 | 62.5 | 55.8 | 71.4 | | Deferiprone | 1.6 | 1.3 | – | 4.1 | – | 1.3 | 2.3 | – | | DFO/deferiprone | 16.7 | 25.0 | 4.8 | 7.0 | 5.2 | 12.5 | 11.6 | 14.3 | | Other | 0.3 | 0.4 | – | 0.3 | – | – | – | – | | None | 23.0 | 7.0 | 16.7 | 48.4 | 68.1 | 23.8 | 30.2 | 14.3 | Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naive despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis. Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr. Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was 4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts. Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.

Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Background: Steroid-resistant patients with Diamond-Blackfan anemia (DBA) require life-long transfusion therapy, which ultimately results in toxic iron overload. Efficacy and safety of a once-daily, oral iron chelator, deferasirox (Exjade®), in patients with DBA have been demonstrated in one trial in which patients were dosed based on liver iron concentration (LIC) at enrollment. More recently, patients with various transfusion dependant anemias have been enrolled as part of a large, prospective, multicenter trial, the EPIC study, to evaluate whether fixed starting doses of deferasirox, based on transfusion history and subsequent dose titration, can provide clinically acceptable chelation, as measured by serum ferritin (SF). Data for the DBA sub-group are presented. Methods: Fourteen patients with transfusion-dependent DBA and SF levels of ≥1000 ng/mL, or 20 transfusions or 100 mL/kg of blood) and a R2 MRI confirmed LIC >2 mg Fe/g dry weight, were enrolled. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of 3-month SF trends and safety markers. SF was assessed every 4 weeks; the primary efficacy endpoint was change in SF from baseline at 52 weeks. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: Male (n=7) and female (n=7) patients with DBA (mean age 17.3 years), had a median baseline SF of 2288.8 ng/mL, and received a mean of 185.0 mL/kg of blood in the year prior to enrollment. Most patients had received previous chelation therapy with deferoxamine (DFO; 71.4%); two patients (14.3%) had received combination DFO/deferiprone and two (14.3%) had received no prior chelation therapy. All patients completed 12 months of treatment with no discontinuation. At 12 months, a significant reduction in SF from baseline was observed in the total population at an average actual dose of 21.0±4.8 mg/kg/day (−789.5 ng/mL; 2288.8 ng/mL [baseline]; P=0.0121). A similar reduction was seen in patients receiving an average actual dose of deferasirox ≥20–80%). There were no clinically relevant changes in markers of renal function. Two (14.3%) patients had an increase in alanine aminotransferase (ALT) that exceeded >10xULN (upper limit of normal) on two consecutive visits; all had elevated ALT levels at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent DBA patients with iron overload. Efficacy was demonstrated in patients receiving doses above and below 20 mg/kg/day, suggesting the need to individually titrate the dose according to the rate of iron intake from ongoing blood transfusions, as well as current iron burden and target SF levels. Deferasirox was well tolerated, with an AE profile similar to that observed in other patient groups.

Background: As iron overload can cause serious clinical sequelae in pediatric patients with β-thalassemia, it is important to assess the long-term efficacy and safety profile of any iron chelator used in children. The ESCALATOR study evaluated deferasirox (Exjade®) in β-thalassemia patients, during a 1-year core trial and an extension trial of at least 1 year’s duration. This analysis evaluates the efficacy and safety of deferasirox in a subgroup of pediatric patients enrolled in the ESCALATOR trial. Methods: β-thalassemia patients included in this analysis were aged 2– Results: In total, 166 pediatric patients entered, and 158 (95%) completed, the extension study; 149 (89.8%), 1 (0.6%) and 16 (9.6%) patients had received prior chelation with DFO, deferiprone and DFO/deferiprone combination, respectively. The median duration of exposure to deferasirox was 144 weeks (2.8 years). 101/166 patients (61%) had dose increases in the extension study; dose was increased above 30 mg/kg/day in most patients (n=75). Dose decreases due to AEs or abnormal lab values were required in only 4 (2%) patients. Three (2%) and 10 (6%) patients, respectively, had dose decreases and temporary treatment interruptions because target ferritin level (≤500 ng/mL ×2 consecutive occasions) had been achieved. At EOS, the final deferasirox dose exceeded 30 mg/kg/day in 114 patients (69%). Data for mean LIC and median SF at baseline, 1 year and end of study are presented in Table 1. Table 1. LIC and SF at baseline, 1 year following treatment initiation and end of study. Baseline 1 year End of study Overall change P -value LIC, mg Fe/g dw, mean ± SD 18.7±8.5 17.1±12.0 11.4±9.3 −7.9±8.7 Of eight discontinuations during the extension study, six patients were lost to follow-up, one was due to AEs and one patient died due to respiratory failure, considered by the investigator to be non-treatment related. Despite dose increases and longer exposure in the extension phase, there was no increase in drug-related AEs in the extension compared with the core phase. There were no significant changes in markers of liver or renal function during the extension phase. Mean left ventricular ejection fraction increased significantly from 65.3% at core baseline to 69.4% at study end (P Conclusions: Following a median of 2.8 years, adequate dose adjustments with deferasirox significantly reduced LIC and SF in heavily iron-overloaded children who were previously unsuccessfully chelated. Doses ≥30 mg/kg/day were achieved in 69% of patients in the extension phase and deferasirox was generally well tolerated, with no increase in drug-related AEs compared with the 1-year assessment, and a low discontinuation rate.