Deferasirox Research Articles

Iron-chelating therapy with deferasirox in transfusion-dependent, higher risk myelodysplastic syndromes: a retrospective, multicentre study.

Iron chelation is controversial in higher risk myelodysplastic syndromes (HR-MDS), outside the allogeneic transplant setting. We conducted a retrospective, multicentre study in 51 patients with transfusion-dependent, intermediate-to-very high risk MDS, according to the revised international prognostic scoring system, treated with the oral iron chelating agent deferasirox (DFX). Thirty-six patients (71%) received azacitidine concomitantly. DFX was given at a median dose of 1000mg/day (range 375-2500mg) for a median of 11months (range 0·4-75). Eight patients (16%) showed grade 2-3 toxicities (renal or gastrointestinal), 4 of whom (8%) required drug interruption. Median ferritin levels decreased from 1709μg/l at baseline to 1100μg/l after 12months of treatment (P=0·02). Seventeen patients showed abnormal transaminase levels at baseline, which improved or normalized under DFX treatment in eight cases. One patient showed a remarkable haematological improvement. At a median follow up of 35·3months, median overall survival was 37·5months. The results of this first survey of DFX in HR-MDS are comparable, in terms of safety and efficacy, with those observed in lower-risk MDS. Though larger, prospective studies are required to demonstrate real clinical benefits, our data suggest that DFX is feasible and might be considered in a selected cohort of HR-MDS patients.

Deferasirox-Iron Complex Formation Ratio as an Indicator of Long-term Chelation Efficacy in β-Thalassemia Major.

β-Thalassemia major patients with higher total drug levels [deferasirox (DEFR) plus its iron complex] do not yield better serum ferritin (SF) control. This study aimed to determine the concentrations of DEFR and its iron complex (Fe-[DEFR]2) in thalassemia patients to predict the chelation efficacy in terms of SF and cardiac T2* values. Patients' steady-state drug levels at trough (Ctrough) and 2 hours postdose (C2h) were determined. Because iron deposition may cause changes in the hepatic metabolism of amino acids, the concentrations of 40 amino acids in plasma were also assayed at 2 hours postdose. A total of 28 patients either dosing daily or twice daily were recruited. After a 1-month DEFR maintenance therapy, 38.8% and 30% of patients from groups of once-daily and twice-daily, respectively, had a plasma DEFR-iron complex formation ratio higher than 0.05 [High Chelation Ratio, (HCR)]. After a 6-month follow-up, those patients who had a HCR (n = 10) at C2h showed more favorable median changes in SF and cardiac T2* values (-388.0, +10.1) than those with a low DEFR-iron complex formation ratio (Low Chelation Ratio; n = 18; +10.5; +4.5) compared with the baseline. The levels of plasma L-arginine, L-alanine, L-glycine, L-norleucine, and L-serine were significantly lower in patients with the low Chelation Ratio condition than the levels in HCR patients. This therapeutic drug monitoring study revealed that a DEFR-iron complex formation ratio at C2h might be an applicable indicator of the efficacy of long-term DEFR iron chelation therapy. A better iron-control response to DEFR was observed in the patients with HCRs. The trends for the ratio might have value in dose-setting and need to be validated in a larger cohort.

Efficacy and Safety of Combined Oral Chelation With Deferiprone and Deferasirox in Children With β-Thalassemia Major: An Experience From North India.

A combination of desferrioxamine with either deferiprone (DFP) or deferasirox (DFX) for patients with β-thalassemia major who do not achieve negative iron balance with monotherapy has been studied widely. However, poor compliance resulting from the need for parentral administration of desferrioxamine and its cost necessicitates combining 2 oral chelators. A prospective study was conducted in patients with transfusion-dependent β-thalassemia major in a tertiary care center over 2 years. Patients on either DFP or DFX who were not improving on monotherapy over a long period and persistently maintaining serum ferritin >2500 µg/L were enrolled. Efficacy was assessed by serum ferritin levels assessed at 12 months and 2 years. Complete blood counts and liver and kidney function tests were monitored to assess the safety of the combination of drugs. In total, 33 patients with a mean age of 12.67 years (7.5 to 17.5 y) and a mean ferritin of 4835.2394±1443.85 µg/L formed the study cohort.In total, 28 patients completed the 1-year study period; and 12 patients completed 2 years. Mean serum ferritin reduction at 1 and 2 years was 34.99%±18.13% (range, -34.36% to 56.17%) and 44.67%±13.78% (range, 22.17% to 62.74%), respectively. The combination therapy was well tolerated. Combined oral chelation with DFP and DFX has better efficacy than either drug used alone. The combination of drugs was well tolerated and no new adverse effects were observed.

Sa1315 - Deferasirox (DFX), A Newly Oral Iron Chelator, with Gemcitabine (GEM) Inhibited Pancreatic Cancer Cell Proliferation and Induced Apoptosis in vitro and in vivo

Sa1315 - Deferasirox (DFX), A Newly Oral Iron Chelator, with Gemcitabine (GEM) Inhibited Pancreatic Cancer Cell Proliferation and Induced Apoptosis in vitro and in vivo

Synergistic inhibitory effects of deferasirox in combination with decitabine on leukemia cell lines SKM-1, THP-1, and K-562

A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.

Restoring the impaired cardiac calcium homeostasis and cardiac function in iron overload rats by the combined deferiprone and N-acetyl cysteine

Intracellular calcium [Ca2+]i dysregulation plays an important role in the pathophysiology of iron overload cardiomyopathy. Although either iron chelators or antioxidants provide cardioprotection, a comparison of the efficacy of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), N-acetyl cysteine (NAC) or a combination of DFP plus NAC on cardiac [Ca2+]i homeostasis in chronic iron overload has never been investigated. Male Wistar rats were fed with either a normal diet or a high iron (HFe) diet for 4 months. At 2 months, HFe rats were divided into 6 groups and treated with either a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day), or combined DFP plus NAC. At 4 months, the number of cardiac T-type calcium channels was increased, whereas cardiac sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) was decreased, leading to cardiac iron overload and impaired cardiac [Ca2+]i homeostasis. All pharmacological interventions restored SERCA levels. Although DFO, DFP, DFX or NAC alone shared similar efficacy in improving cardiac [Ca2+]i homeostasis, only DFP + NAC restored cardiac [Ca2+]i homeostasis, leading to restoring left ventricular function in the HFe-fed rats. Thus, the combined DFP + NAC was more effective than any monotherapy in restoring cardiac [Ca2+]i homeostasis, leading to restored myocardial contractility in iron-overloaded rats.

Cost-Utility Analysis of Three Iron Chelators Used in Monotherapy for the Treatment of Chronic Iron Overload in β-Thalassaemia Major Patients: An Italian Perspective.

Deferiprone (DFP), deferasirox (DFX) and deferoxamine (DFO) are used in thalassaemia major (TM) patients to treat chronic iron overload. We evaluated the cost-effectiveness of DFP, compared with DFX and DFO monotherapy, from an Italian healthcare system perspective. A Markov model was used over a time horizon of 5years. Italian-specific cost data were combined with Italian efficacy data. Costs and quality-adjusted life years (QALYs) were calculated for each treatment, with cost-effectiveness expressed as cost per QALY. In all scenarios modelled, DFP was the dominant treatment strategy. Sensitivity analyses showed that DFP dominated the other treatments with a >99% likelihood of being cost-effective against DFX and DFO at a willingness to pay threshold of €20,000 per QALY. DFP was the dominant and most cost-effective treatment for managing chronic iron overload in TM patients. Its use can result in substantial cost savings for the Italian healthcare system.

Safety profiles of iron chelators in young patients with haemoglobinopathies.

This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.

Combination Iron Chelation Therapy with Deferiprone and Deferasirox in Iron-Overloaded Patients with Transfusion-Dependent β-Thalassemia Major.

There are few papers on the combination therapy of deferiprone (DFP) and deferasirox (DFX) in iron-overloaded patients with transfusion-dependent β-thalassemia major (β-TM). A total of 6 patients with β-TM (5 males and 1 female) with a mean age of 23.8±5.8 years (ranging from 17 to 31) used this treatment regimen. The mean doses of DFP and DFX were 53.9±22.2 and 29.3±6.8 mg/kg/day, respectively. The duration of treatment was 11.5±4.6 months. Their serum ferritin levels were measured to be 2800±1900 and 3400±1600 ng/mL before and after treatment, respectively (p<0.6). Their cardiac magnetic resonance imaging (MRI) T2* values were 16.69±15.35 vs 17.38±5.74 millisecond (ms) before and after treatment, respectively (p < 0.9). Although there was no significant difference between their cardiac MRI T2* values before and after treatment statistically, the values improved after combination therapy with DFP and DFX in most of the patients. Liver MRI T2 * values were changed from 2.12±0.98 to 3.03±1.51 ms after treatment (p < 0.01); Further, their liver T2* values and liver iron concentration (LIC) were improved after treatment. Our study found that cardiac MRI T2* values, liver MRI T2* values, and LIC were improved after combination therapy with DFP and DFX in β-TM patients and that DFP and DFX combination therapy could be used to alleviate cardiac and liver iron loading.

Efficacy of Deferasirox as an Oral Iron Chelator in Paediatric Thalassaemia Patients.

Thalassaemia Major patients require frequent blood transfusion leading to iron overload. Excessive iron gets deposited in vital organs and leads to dysfunction of the heart, liver, anterior pituitary, pancreas, and joints. Our body has limited mechanism to excrete iron, so patients with iron overload and its complications need safe and effective iron chelation therapy. To assess the efficacy of Deferasirox (DFX) as an iron chelator, with specific reference to reduction in serum ferritin level. This is a prospective; observational study done in 45 multitransfused Thalassaemia Major Children receiving DFX therapy at registered Thalassaemia society Raipur Chhattisgarh. DFX was given in an initial dose of 20 mg/kg/day and according to response increased to a maximum of 40 mg/kg/day. Serum ferritin level was estimated at time of registration and at every three monthly intervals (four times during study period). The primary end point of the study was change in serum ferritin level after 12 months of DFX therapy. The mean serum ferritin before DFX therapy of all cases was 3727.02 ng/mL. After 12 months of mean dose of 38 mg/kg/day of DFX, the mean decline in serum ferritin was 1207.11 ng/mL (drop by 32.38%, p-value <0.001). DFX monotherapy has a good safety profile and effectively chelates total body iron in Thalassaemia major patients.

Mechanisms of Improvement of Erythropoiesis with Low Dose Deferasirox in Low Risk Myelodysplastic Syndromes

Introduction: Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal stem cell disorder characterized by dysplasia leading to ineffective hematopoiesis and evolution to acute myeloid leukemia. Anemia is the most frequent cytopenia in MDS and the majority of patients requires red blood cell (RBC) transfusion resulting in the development of iron overload (IO). Deferasirox (DFX) became a standard treatment of IO in MDS and seems to have positive effects on hematopoiesis in some MDS patients leading to reduction of RBC transfusion or even transfusion independence (Gatterman, 2012, Maurillo, 2015). In this study, our aims were to decipher the intrinsic mechanisms explaining the potential positive effects of DFX on erythroid differentiation in low risk MDS.Methods: We report our data about erythroid differentiation, cell cycle, apoptosis and cell signaling pathways concerning CD34+ hematopoietic stem progenitor cells (HSPCs) from low risk MDS samples in a 2-step erythroid differentiation liquid culture with low dose DFX.Results: We observed a higher proliferation rate at the end of the cell culture procedure with DFX 3µM versus control condition (p=0,038). We did not find these effects with DFX > 5µM. This higher proliferation rate is due to the combination of less apoptotic cells and more cycling cells. At day 10 of the culture (D10) (n=7), there were less apoptotic cells for DFX 3μM condition (DFX 3): 13,8% versus 17,5% for control condition (p=0,0325). This lower apoptosis rate was more relevant at D14 (n=9): 19,1% versus 24,7% for control condition (p=0,007). There were more cycling cells with DFX 3 at D10 (n=6): fewer cells were blocked at the beginning of the cell cycle in subG0-G0-G1 phases (68,9% versus 77,6%) (p=0,0001) and more cells (30,5% versus 21,9%) were engaged in cell cycle (S-G2-M) (p=0,0001) for DFX 3. Regarding clonogenic assays (n=10), there was an increased number of CFU-E colonies for DFX 3 versus control condition with on average 72,7 (15-261) and 46,5 (3-174,5) colonies respectively (p=0,04). We did not see any effect of DFX on erythroid differentiation. The percentages of proerythroblasts, basophilic and orthochromatic erythroblasts were similar for DFX 3 and control at D5, D10 and D14 of the cell culture regardless the techniques (flow cytometry or morphological analyses by cytospin).These functional effects were partially related to iron chelation of DFX. As expected, we saw a lower iron intracellular concentration (-12,7%) by mass spectrometry with DFX 3 (p=0,019). Nevertheless this chelation effect was not sufficient to activate iron regulation metabolism (IRP-IRE) in REMSA assay, indeed we saw no difference in IRP activity between DFX 3 and control condition. Moreover, low dose of DFX had a protector effect against mitochondrial reactive oxygen species at D14 (n=9; p=0,03). We aim to complete the Redox profile by analysis of some oxidative stress metabolites like malonaldehyde, carbonyl groups, γH2AX and oxidized form of glutathione.Then, we have investigated which signaling pathways were responsible for these functional effects by flow cytometry (FC) and immunofluorescence (IF) microscopy. By FC, PI3K/AKT, mTOR and MAPK/ERK were not over-activated in DFX 3. However,we found an increased nuclear translocation of NFκB in DFX3 (p=0,0004) by IF. Using RT-qPCR microarrays, we have analyzed the expression of 84 gene targets of NFκB. Five genes were upregulated in DFX 3 with a fold change >2 compared to control: BCL2A1, BIRC3, TNFRSF1B, EGFR, IL1B. This gene profile leads in silico to an anti-apoptotic signal (PCVIz®).To demonstrate a link between the ROS protection effects of DFX and the NFκB activation pathway, we have realized a cellular model of inhibition of thioredoxin (TRX), a ROS regulated protein, by three siRNA anti-TRX1. TRX1 in its reduced form can activate NFκB. By inhibiting TRX1, we hypothesize that NFκB pathway cannot be activated and that could impede cell proliferation. Definitive results will be presented at ASH.Conclusions: Our study described the pro-proliferative effects of low dose of DFX on erythroid progenitors in low risk MDS patients in vitro via a mechanism of mitochondrial ROS protection and NFκB activation. Those data highlight the potential interest of an early introduction of iron chelation therapy with low dose DFX (around 5mg/kg/d corresponding to a plasmatic level of 3µM) in the disease course of transfused low risk MDS patients. DisclosuresMeunier:Novartis: Research Funding. Park:Novartis: Research Funding.

Children with Thalassemia Major Display Abnormal Renal Tubular Function

Introduction. Chronic hypoxia, transfusional iron overload and chelation therapy are all contributing factors to the deterioration of renal function in thalassemia major (TM ) patients. Among chelators, deferasirox (DFX) is considered the most toxic drug for kidneys: increment of more than 30% of serum creatinine levels is used for dosage modulation or interruption. Recently tubular abnormalities have also been described. We have observed renal toxicity in nine children affected by TM and treated with DFX or deferiprone (DFP) and described the differences in glomerular or tubular function between the two oral chelators.Material and methods. Nine children, 4 males and 5 females, aged 3-17 years (median 7 y), were retrospectively evaluated. They were regularly transfused every 2-3 weeks, receiving a median of 260 g erythrocytes concentrates/kg/year. The median serum ferritin level at baseline before starting oral chelation was 1763 ug/L (range 1127-4198).Four patients (pts) received only one type of chelator (1 DFP and 3 DFX). Five pts received both DFX or DFP in different periods. Overall 8 DFX treatments (dosage 15-30 mg/kg, for 18-112 months, mean 40) and 6 DFP treatments (dosage 75-130 mg/kg for 14-54 months, mean 24) were administered. Three pts had previously received deferoxamine; 3/8 DFX pts and 1/6 DFP pts were naïf to chelation before first renal evaluation.The following renal indices were considered:− glomerular function: serum creatinine and cystatine C levels, estimated glomerular filtration rate (eGFR), according to modified Schwartz formula; urine albumin to creatinine ratio (ACR), urine protein excretion.− tubular function: glycosuria, urinary N-acetyl-beta-D-glucosamidase activity/u-creatinine (u-NAG/u-cr), (index of acute tubular damage); urine daily Beta2 microglobulin (B2MG) and Alfa1 microglobulin (A1MG) excretion (both indices of chronic tubular damage).Analyses were performed at different intervals, according to clinical conditions and patients' age, with different frequency among children.Creatinine impairment was defined as an increase over 30% of basal level. All indices were graded according to local laboratory range. Toxicity was considered significant when the tests were abnormal in at least 25% of evaluations.Results. Initial renal function was normal in all patients (median eGFR 209 ml/min/1.73 m2, range 157-295) and eGFR remained stable over time in all cases. A total of 5 pts with DFX and 3 pts with DFP showed an increase of creatinine over 30% of basal levels. Increase of ACR > 30 mg/g cr was seen in 6/8 pts (75%) in DFX and in 1/6 pts (17%) in DFP; 2 pts (1/8 in DFX and 1/6 in DFP) had macroalbuminuria (ACR >300 mg/g creatinine). No association was found between cumulative DFP dose and eGFR over time (Pearson coefficient, r = 0.06), while a moderate association was found with DFX (r = 0.5; p = 0.06).Symptomatic acute tubular toxicity was observed in 2 pts, with tubular acidosis, glycosuria and abnormal acute tubular indices (u-NAG/u-cr). A1MG and B2MG were also altered, suggesting a chronic injury substrate. Both pts were in DFX group (receiving a dose of 20 and 40 mg/kg/day, respectively) and had experienced a fast reduction in ferritin levels over a short period of time. No signs of concomitant infection were detected.u-NAG/u-cr was always abnormal in all children in both groups; mean values were 2.8 U/mmol for DFX and 2.4 U/mmol for DFP. B2MG was altered in 6/8 DFX pts and in 2/6 DFP pts (75% vs 33%). Median values were 3.0 mg/24 h for DFX and 0.5 mg/24 h for DFP, respectively. A1MG was altered in 4/8 DFX pts and 3/6 DFP pts, with median values of 164 mg/24 h for DFX and 55 mg/24 h for DFP, respectively.Conclusions. Patients withTM can experience abnormalities in renal function, especially as regards tubular damage. Acute tubular damage indices were altered in all chelated pts, whereas tests for chronic damage were abnormal more often in the DFX group than in DFP-treated pts. Albeit the significance of our findings needs further confirmation in a longer follow up, these results suggest that extensive renal evaluation is needed, in particular in children whose life expectancy is open and long-term prognosis for multiple organ function is an important issue. DisclosuresNo relevant conflicts of interest to declare.

A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

BackgroundAscorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment.ObjectivesPerform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity.Patients and MethodsEnrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched).Results22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year.At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1).In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS.A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2).Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo).ConclusionsTM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. [Display omitted] [Display omitted] DisclosuresAydinok:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

Treatment Patterns and Adherence Among Patients with Myelodysplastic Syndromes Receiving Deferasirox As Iron Chelation Therapy: A Real World Medicare Database Study

Background: Patients with myelodysplastic syndrome (MDS) may present with anemia and become red blood cell (RBC) transfusion dependent (TD), which increases the risk of iron overload (IO). Iron chelation therapy (ICT) treats IO and has been shown to be associated with improved survival and quality of life among TD MDS patients. Deferasirox (DFX) is an oral ICT used to reduce IO in TD MDS patients. This study aims to assess real-world treatment patterns and adherence among MDS patients on Medicare receiving DFX as ICT.Methods: This was a retrospective cohort study using 100% Medicare claims data from 2006-2013. Patients were diagnosed with MDS, identified using ICD-9 codes (238.72-238.76), and entered the study cohort when they met a minimum transfusion threshold of either: 10 consecutive weeks with at least 1 unit of RBC transfusion, or 20 total units of RBC transfusions. Treatment patterns, including discontinuation and treatment changes, were assessed among patients who received DFX as initial ICT and who had ≥180 days of follow-up. Discontinuation was defined as a minimum 45-day treatment gap. Adherence was defined as a medication possession ratio (MPR) ≥ 0.8. Treatment discontinuation, overall survival, acute myeloid leukemia (AML)-free survival, and cardiac event-free survival were compared between adherent and non-adherent patients using Kaplan Meier (KM) survival analysis, as well as Cox regressions controlling for time-dependent ICT use and baseline characteristics. Survivals were estimated as time from cohort entry to the event.Results: Among 6,796 MDS patients who met the minimum transfusion threshold, 591 (8.7%) received ICT. Median weeks of ICT was 15.14 (range=2.29 - 201.43 weeks). 583 (98.6%) initiated with DFX, and 374 DFX patients had a follow-up period of ≥180 days. Of these 374 patients, 213 (57.0%) discontinued DFX treatment within 180 days of initiation. Among the remaining 161 patients, one switched to deferoxamine (DFO), none augmented treatment with DFO, and 160 continued on DFX. The KM-estimated 3-month and 1-year DFX discontinuation rates were 36.5% and 77.4%, respectively, and the average time to discontinuation was 84.4 [Standard Deviation [SD]=48.6] days. Overall, the average 6-month MPR was 0.69 (SD=0.30), and 49.1% of patients were adherent (MPR≥0.8). Adherent patients had similar baseline characteristics compared with non-adherent patients, except that a lower proportion had renal disease (24.2% vs. 38.3%, P<0.01). Patients adherent to DFX had a lower risk of therapy discontinuation (Hazard Ratio=0.07, 95% Confidence Interval, 0.05-0.11) compared with non-adherent patients. Additionally, adherent patients had significantly longer cardiac event-free survival compared with non-adherent patients (1-year rate for cardiac-event/death: 66.1% vs. 76.1%, respectively, P<0.01). There were no statistically significant differences in overall survival and AML-free survival between adherent and non-adherent cohorts. Overall and AML-free survival were longer in the adherent cohort, however this did not reach statistical significance.Conclusions: DFX was the most commonly used ICT among eligible MDS patients. The majority of patients discontinued DFX within 1 year. Adherence to DFX was associated with statistically significant improved cardiac-event free survival. Further analysis on the long-term impact of the duration of chelation is warranted. DisclosuresFu:Novartis Pharmaceuticals Corporation: Consultancy. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Coe:Novartis Pharmaceuticals Corporation: Employment. Qiu:Novartis Pharmaceutical Corp: Employment, Equity Ownership. Li:Novartis Pharmaceuticals Corporation: Consultancy. Hanna:Novartis Pharmaceuticals Corporation: Consultancy. Tang:Novartis Pharmaceuticals Corporation: Consultancy. Elliott:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Paley:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

New Film-Coated Tablet Formulation of Deferasirox Is Well Tolerated in Patients with Thalassemia or MDS: Results of the Randomized, Phase II E.C.L.I.P.S.E. Study

▪Background: Patients (pts) compliant with iron chelation therapy (ICT) experience improved organ function and survival (Delea et al. Transfusion 2007;47:1919-29). Once-daily deferasirox (DFX) dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater adherence, pt satisfaction, and quality of life (Cappellini et al. Clin Ther 2007;29:909-17). However, barriers exist to pt adherence to DFX DT, including GI tolerability and palatability, leading to development of a film-coated tablet (FCT) that can be taken with or without a light meal. The FCT contains the same active substance as DT but different excipients (lactose and sodium lauryl sulfate removed). Here we present results of the randomized, open-label, Phase II ECLIPSE study that evaluated safety of DFX FCT and DT formulations in pts with transfusion-dependent thalassemia (TDT) or IPSS-R very low-, low- or intermediate-risk MDS.Methods: ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. Exclusion criteria: creatinine clearance below contraindication limit per local label (<60 mL/min or <40 mL/min), serum creatinine >1.5xULN, alanine aminotransferase >5×ULN, urine protein/urine creatinine ratio (UPCR) >0.5 mg/mg, or impaired GI function. ICT-naïve pts received DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. FCT doses are 30% lower than DT doses due to improved bioavailability, conversion factor 1.43. Dose was adjusted based on SF and investigator’s judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time. Primary endpoint was overall safety, measured by frequency and severity of AEs and changes in laboratory values from baseline (BL) over 24 wks. A secondary endpoint was evaluation of selected GI AEs.Results: 173 pts were randomized 1:1 to DT or FCT (Table 1). Mean actual daily DFX dose ± SD over 24 wks was 27.5 ± 7.7 mg/kg/day (DT) and 20.8 ± 5.4 mg/kg/day (FCT). More FCT pts were started on a dose higher than the protocol-specified dose than DT pts (26.4% vs 9.3%). Mean/median duration of exposure was 155/168 days with DT and 163/169 days with FCT. 73 (84.9%; DT) and 77 (88.5%; FCT) pts completed 24 wks. Relative consumed tablet count was high, but lower with DT (85.3%) than FCT (92.9%). Absolute median (range) change in SF at end of treatment was -85.5 (-2146 to 8250) ng/mL (from 2485 [915-8250] ng/mL at BL) with DT, and -350 (-4440 to 3572) ng/mL (from 2983 [939-8250] ng/mL at BL) with FCT, corresponding to a median relative change of -4.1% (DT) and -14.0% (FCT) at end of treatment.AEs regardless of causality were reported in similar proportions of pts for each formulation (Table 2). Fewer severe AEs were observed in FCT pts. The most common AEs with either formulation were consistent with the known DFX safety profile. Notable laboratory evaluation frequencies were similar with both formulations (Table 3).61.6% (95% CI, 50.5-71.9%) of DT pts and 58.6% (95% CI, 47.6-69.1%) of FCT pts reported ≥1 GI AEs. Similar proportions of pts had diarrhea, nausea, and abdominal pain. Fewer FCT pts had constipation and vomiting than pts receiving DT. Fewer pts had severe GI AEs with FCT than with DT. In pts receiving DT prior to study entry, fewer FCT pts had GI AEs (53.5%, FCT; 60.3%, DT), particularly diarrhea, vomiting and constipation. Increased UPCR was reported in more FCT pts (12.8%, DT; 20.7%, FCT), which could be attributed to more FCT pts receiving a higher than recommended starting dose. Renal event frequency was similar when patients were started on a correct starting dose (30.9%, DT; 33.3%, FCT). 23 pts discontinued, 10 because of AEs (n=6, DT; n=4, FCT).Conclusions: These results in pts with TDT or very low-, low- or int-risk MDS demonstrate comparable FCT and DT safety profiles, consistent with the known DFX profile. In patients with prior DT exposure, fewer GI AEs were seen with FCT than DT. Pts receiving FCT had better compliance, continued longer on treatment and experienced greater SF reduction. DFX FCT may improve pt experience with ICT resulting in greater compliance and reduced frequency and severity of iron overload-related complications. [Display omitted] [Display omitted] [Display omitted] DisclosuresTaher:Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Gilead: Consultancy; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Bluebird Bio: Consultancy.

The Impact of Autophagy on the Progression of the Myelodysplastic Syndromes

IntroductionAbout 75% of myelodysplastic syndromes (MDS) are lower risk categories with a paucity of definitive treatment and only supportive management as an option. MDS, defined by ineffective erythropoiesis produces anemia requiring frequent blood transfusions resulting in systemic iron overload. Refractory Anaemia with ring sideroblasts frequently characterised by mutations in the spliceosome machinery also contributes to cellular iron overload. Excess iron drives activation of the transcription factor NF-κB promoting pro-inflammatory cytokines production supporting tumour growth. Iron chelation is routinely used to treat transfusional iron overload. A number of observational studies have demonstrated that the iron chelator Deferasirox (DFX), improves haemoglobin levels in a subset of MDS patients (Messa, et al. 2008, Banerjee, et al. 2015). Iron metabolism is deregulated in cancer cells resulting in a net iron influx enhancing ROS production. Excess ROS promotes autophagy, a catabolic cellular recycling pathway clearing redundant and damaged organelles to sustain cellular metabolism. Autophagy is initiated by the Atg1-Atg13 protein complex and can be upregulated in cancer facilitating the propagation of the malignant clone. We have previously demonstrated that treatment with the iron chelator DFX, blocked growth of myeloid leukemia cell lines whilst sparing normal stem cells. Herein, we demonstrate that the growth inhibitory effects of DFX are mediated by its ability to inhibit autophagy. We therefore postulate that modulation of intracellular iron levels can be adopted as a viable tool to further elucidate the role of autophagy in this disease.AimsTo explore the impact of iron modulation on autophagy.To elucidate the role autophagy in myeloid cell growth and proliferation.MethodsThp-1 (myeloid cell line) expressing the autophagy reporter LC3-GFP was utilised. Autophagy results in LC3 recruitment to the autphagosomal membrane. These cells were treated with DFX in the presence/absence of chloroquine, a lysosomal enzyme inhibitor to visualise accumulated LC3-II. Cells were also treated with two other iron chelators, deferoxamine (DFO) and Dp44mT. Treated cells were then analysed using AMNIS Flow Imaging. Acute myeloid leukaemia cell lines were treated with DFX in the presence/absence of chloroquine and subjected to Western blotting using anti-LC3-II antibody. AML cell lines were also treated with 3-methyl adenine (3MA), an autophagy inhibitor. Doxycycline inducible CRISPR/Cas9 gene editing was used to delete essential autophagy genes, ATG 5 and 7 in Thp-1 cells and subjected to Western Blotting using ATG5/7 antibodies. Cell proliferation assays were done in the presence and absence of doxycycline. The impact of ATG5/7 deletion on LC3 was analysed using Western Blotting.ResultsCQ treatment of Thp-1-LC3-GFP cells demonstrated an increased number of LC3 specks, which were significantly reduced upon co-treatment with DFX. The total number of cells overall with LC3 specks was also reduced in the combination treatment of CQ and DFX. This was consistent with Western Blotting results that demonstrated lower LC3-II levels in this treatment. Cells treated with the other iron chelators, DFO and Dp44mT demonstrated no decrease in LC3 specks upon co-treatment with CQ and confirmed with Western Blotting demonstrating no change in LC3-II levels. Pharmacological inhibition of autophagy in AML cell lines using 3MA, showed dose dependent decrease in cell growth. ATG5 and ATG7 editing in Thp-1 cells using CRISPR/Cas9 resulted in significant impact on cell growth and proliferation. Loss of ATG5 and ATG7 in these cellswas confirmed using Western Blotting. LC3-II levels were significantly reduced in ATG5/7 deleted cells.ConclusionOur results demonstrate an essential role for the autophagy mediators ATG5/7 highlighting the importance of autophagy in promoting proliferation of malignant myeloid cells. The negative impact of DFX on cell growth and proliferation appears to be via its ability to inhibit autophagy. This is a unique property of DFX not observed with other iron chelators. Using DFX as a tool to modulate iron metabolism, these results have reinforced the role of deregulated iron metabolism in propagation of malignant haematopoietic cells. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treatment Outcomes in Patients with Transfusional Hemosiderosis Who Received Deferasirox for up to 3 Years: Results from Sentinel Study

Background: Adequate iron chelation therapy (ICT) and patient adherence are essential in the management of patients (pts) with chronic iron overload (IOL), which is an important cause of mortality and morbidity. Data from various clinical trials show that deferasirox (DFX), a once-daily oral iron chelator, at a recommended dose of 20 mg/kg/d stabilizes serum ferritin (SF) and liver iron concentration in transfusion-dependent pts (Chaudhary et al. J Blood Med. 2013;4:101-10). The non-interventional, SENTINEL study conducted in pts with transfusional hemosiderosis demonstrated the long-term safety and efficacy of DFX. The current analysis was performed to further evaluate the safety and efficacy of DFX in pts who completed the 3-year (yr) study, including pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d.Methods: The SENTINEL study design has been reported previously (El-Beshlawy et al. Haematologica 2016;101(s1):abst E1475). Pts aged ≥2 yrs with transfusional hemosiderosis treated with DFX in accordance with the local prescription information were enrolled. For this analysis, pts who completed the 3-yr study and/or completed the 3-yr study receiving an overall average actual dose of DFX ≥20 mg/kg/d were considered. Safety was assessed by regular monitoring and recording of adverse events (AEs) and efficacy was measured by SF levels, which were analyzed biannually, by providing summary statistics for the average SF values of each pt within that specific period.Results: Of the 120 pts enrolled, 51 (42.5%; <18 yrs, n=45; ≥18 yrs, n=6) with β thalassemia (n=30); sickle cell disease (SCD, n=18) and other anemias (n=3) completed the 3-yr study. 41/51 pts (80.4%; <18 yrs, n=37; ≥18 yrs, n=4) with β thalassemia (n=26), SCD (n=12), and other anemias (n=3) received an overall average actual dose of DFX ≥20 mg/kg/d. The most frequent reasons for study discontinuation (>10%) include pts no longer required study drug (19.2%), AEs (12.5%), and consent withdrawn (10.8%).Of the pts who completed the study, 14 (27.4%) had AEs suspected to be related to DFX, which included 10 pts receiving an overall average actual dose of DFX ≥20 mg/kg/d. The most frequent AEs (>5%) suspected to be related to DFX in pts who completed the 3-yr study were vomiting (7.8%), abdominal pain (5.9%) and lack of efficacy (5.9%). The overall incidence of AEs with suspected relationship to DFX, in pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d was consistent throughout the study without any unexpected safety findings (Figure 1).Increase in serum creatinine, >33% above baseline (BL) and the age-adjusted upper limit of normal (ULN) on at least 2 consecutive measurements (≥7 days apart), was observed in 7 (14.3%) pts who completed the study (Table 1), of whom 6 (SCD, n=5; other anemias, n=1) received an overall average actual dose of DFX ≥20 mg/kg/d.Increase in alanine aminotransferase (ALT), >5×ULN on at least 2 consecutive measurements (≥7 days apart), was observed in 1 pt with β thalassemia (BL ALT missing) during the last yr of study (Table 1). No notable increase in ALT was observed in pts, who received an overall average actual dose of DFX ≥20 mg/kg/d.In pts who completed the study, the median absolute change in SF (µg/L) values from BL to last available post BL (end of study [EOS]; n=37) was −275.0. In pts with β thalassemia and SCD, the median absolute change in SF values from BL to EOS were −284.0 (n=21) and −260.0 (n=13) respectively.In pts who completed the study and received an overall average actual dose of DFX ≥20 mg/kg/d, the median absolute change in SF values from BL to EOS (n=29) was −275.0 (Figure 2).Conclusions: Most of the pts who completed this 3-yr study had a diagnosis of β thalassemia and SCD. Overall, 42.5% of pts received DFX treatment for 3 yrs, and the majority of them were treated with an overall average actual dose of DFX ≥20 mg/kg/d. The observed safety profile of DFX was consistent with the previously published data. In pts who completed the study and received a dose of DFX ≥20 mg/kg/d, few had AEs suspected to be related to DFX. In pts who completed the study, the median change in SF values decreased from BL to EOS. The results demonstrate that an average actual dose of DFX ≥20 mg/kg/d might be required in the majority of pts, with appropriate dose adjustments based on iron intake and IOL to ensure an effective ICT, particularly in pediatric pts with transfusional hemosiderosis. [Display omitted] [Display omitted] [Display omitted] DisclosuresBruederle:Novartis Pharmaceuticals Corporation: Employment. Azmon:Novartis Pharmaceuticals Corporation: Employment. El-Beshlawy:Novartis Pharmaceuticals Corporation: Research Funding; Apo Pharma Inc.: Research Funding.

Deferasirox in the Treatment of Iron Overload during Myeloproliferative Neoplasms (MPN)

Background Deferasirox (DFX) is an oral iron chelator widely employed in the treatment of iron overload during thalassemic syndromes and myelodysplastic syndromes.Aim At present, very few data are available on the treatment with DFX in patients with Ph- Myeloproliferative Neoplasms(MPN) and transfusional requirement.Methods To address this issue, we report here on 41 patients (M 31; F 10) with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with DFX. Of them, 36 had a primary Myelofibrosis, 4 a post Essential Thrombocythemia myelofibrotic phase and 1 a post Polycythemia Vera myelofibrotic phase.Results According to IPSS classification, 8 patients (19.5%) resulted low/intermediate-1 risk, 14 (34.1%) intermediate-2 risk and 19 (46.4%) high-risk. The main features of the patients at diagnosis and at baseline of DFX treatment are reported in the Table.Treatment with DFX was started after a median interval from diagnosis of 13.3 months [interquartile range (IR) 7.3 - 41.1] and from start of transfusion dependence of 11.5 months (IR 5.8 - 20.2), with a median of 27 packed red cells units received (IR 18 - 37). The starting DFX dose was 20 mg/Kg in 16 patients (39.1%), 15 mg/Kg in 20 patients (48.8%) and 10 mg/Kg in 5 patient (12.1%). All patients were evaluable for toxicity:extra-hematological toxicity of all WHO grades was reported in 20/41 patients (48.8%) and consisted of gastro-intestinal symptoms in 7 patients, transient renal impairment in 10 patients and skin reactions in 3 patients: however, only 3 patients (7.3%) needed a permanent discontinuation for toxicity. Thirty-nine out 41 patients were evaluable for response (> 6 months of treatment). As to chelation efficacy, after a median treatment period of 15.4 months (IR 8.1 - 22.3), 4 patients achieved ferritin levels < 500 ng/ml, 10 patients ferritin levels < 1,000 ng/ml and 2 patients presented a reduction > 50% of basal ferritin but with levels > 1,000 ng/ml, with a global response rate of 16 out 39 patients (41.0%): among the remaining 23 patients, 2 discontinued for early toxicity, 20 did not have any ferritin reduction and 1 had an early unrelated death (< 6 months of treatment). As to hematological improvement, 7/39 patients (17.9%) showed an unexpected and persistent rise of Hb levels > 1.5 g/dl, with disappearance of transfusional requirement in 5 cases. The median overall survival of the whole cohort from DFX initiation was 20.7 months (95% CI 16.0 - 25.3): the median overall survival from DFX initiation in patients with chelation response was 46.9 months (95% CI 10.7 - 83.0) compared to 14.0 months (95% CI 5.6 - 22.3) in patients without chelation efficacy (p=0.002).Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, also in this setting an hematological improvement can occur in a sizeable rate of patients. [Display omitted] DisclosuresBreccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Impact of Age and Type of Underlying Disease on Long-Term Safety and Efficacy in Patients with Transfusional Hemosiderosis Treated with Deferasirox: Results from a 3-Year Non-Interventional Study (SENTINEL)

Background: Hemosiderosis, due to frequent blood transfusions, is associated with liver, heart and endocrine dysfunction. Deferasirox (DFX), a once-daily oral iron chelator is used in the management of these patients (pts). The results of the 3-year (yr), non-interventional SENTINEL study demonstrated long-term safety and efficacy of DFX in a large cohort of pts with transfusional hemosiderosis. The current analysis was performed to further evaluate the long-term efficacy and safety of DFX by age and underlying disease.Methods: The SENTINEL study design was previously reported (El-Beshlawy et al. Haematologica 2016;101(s1):abst E1475). In this study, data were collected for 3 yrs from the initiation of treatment with DFX. Pts aged ≥2 yrs treated with DFX for transfusional hemosiderosis, enrolled according to the local prescription information, were included in the study. Safety was evaluated by regular monitoring and recording of adverse events (AEs) and is reported in all pts who received ≥1 dose of DFX and had ≥1 post baseline (BL) safety assessment (safety set). During each bi-annual time period, summary statistics are provided for the average SF values taken for each pt within that specific time period.Results: Of the120 pts enrolled, 49 (40.8%) were diagnosed with β thalassemia, 31 (25.8%) with sickle cell disease (SCD), 21 (17.5%) with myelodysplastic syndrome (MDS), and 19 (15.8%) with other anemias. The mean±SD age was 28.9±29.0 (range, 1-88) yrs (<18 yrs, n=69 [7.5±4.2]; ≥18 yrs, n=51 [57.9±22.1]).Overall, 42.5% (n=51; <18 yrs, n=45; ≥18 yrs, n=6) of pts completed the 3-yr study. Most common reasons for discontinuation (>10%) include pts no longer requiring study drug (19.2%), AEs (12.5%), and withdrawal of consent (10.8%).Median duration of DFX exposure was 29.9 months (mos), (<18 yrs, 36.0; ≥18 yrs, 10.0). Mean average actual dose was 23.2±8.2 mg/kg/d (<18 yrs, 25.7±6.6; ≥18 yrs, 17.7±8.9).Overall, 54.7% (n=64) of pts did not receive prior iron chelation therapy (ICT) and 45.3% (n=53) received prior ICT. Of the pts evaluable for average actual dose, 56.5% (26/46) of pts without prior ICT and 82.2% (37/45) of pts with prior ICT received treatment with an average actual dose of DFX ≥20 mg/kg/d. Pts without prior ICT received a lower average actual dose (mg/kg/d, mean±SD) of DFX compared to pts receiving prior ICT (<18 yrs, 23.8±5.2 vs 27.6±7.4; ≥18 yrs, 15.4±7.7 vs 20.3±9.7) (Table 1).Of the 117 pts evaluated for safety, increase in serum creatinine, >33% above BL and the age-adjusted upper limit of normal (ULN) on at least 2 consecutive measurements (≥7 days apart) were observed in 14 pts (12%; 95% confidence interval [CI], 7.1-19.2; MDS [n=3], SCD [n=7] and other anemias [n=4]).Increase in alanine aminotransferase (ALT), >5×ULN on at least 2 consecutive measurements (≥7 days apart) was observed in 1 pt (0.9%; 95% CI, 0.0-5.2) with β thalassemia (BL ALT missing).DFX-related AEs gradually decreased over time (Figure 1A). Overall incidence of AEs regardless of relationship with DFX also decreased over time (Figure 1B).In the overall pt population, the median absolute change in SF values (µg/L) from BL to last available post BL (end of study, EOS) was −359.8. In pts with β thalassemia, the median absolute change in SF values from BL to EOS was −491.0 (n=27) in pts <18 yrs and −79.0 (n=6) in pts ≥18 yrs (Figure 2).Conclusions: Nearly, 40% of the pts received treatment with DFX for 36 mos during the study, indicating good tolerance of DFX treatment, and 45% of the pts received prior ICT. Pts with prior ICT received a higher average actual dose of DFX compared to pts without prior ICT. Pediatric pts received a higher average actual daily dose compared to adult pts, irrespective of the chelation group. The majority of pts with prior ICT received an average actual dose of DFX ≥20 mg/kg/d. Long-term treatment with DFX demonstrated a gradual decrease in SF values in the overall pt population, though this was not immediate, likely because of delayed increases in dose based on weight gain and ongoing iron intake. DFX-related AEs gradually decreased over 3 yrs and demonstrated an acceptable safety profile. This reinforces that an average actual dose of DFX ≥20 mg/kg/d might be required in majority of pts for appropriate management of transfusional hemosiderosis in actual practice. [Display omitted] [Display omitted] [Display omitted] DisclosuresBruederle:Novartis Pharmaceuticals Corporation: Employment. Azmon:Novartis Pharmaceuticals Corporation: Employment. El-Beshlawy:Novartis Pharmaceuticals Corporation: Research Funding; Apo Pharma Inc.: Research Funding.

Improved Patient-Reported Outcomes with a Film-Coated Versus Dispersible Tablet Formulation of Deferasirox: Results from the Randomized, Phase II E.C.L.I.P.S.E. Study

▪Background: Patients (pts) with hematological disorders such as transfusion-dependent thalassemia (TDT) and myelodysplastic syndromes (MDS) require long-term supportive therapy with iron chelation therapy (ICT) to remove excess iron and prevent organ failure. Adherence to ICT can affect survival, so a well-tolerated and effective chelation regimen is required. The once-daily dispersible tablet (DT) formulation of the iron chelator deferasirox (DFX) has been available since 2005, offering an alternative to parenteral deferoxamine, yet barriers remain to pt adherence including the need to take the drug in a fasting state, palatability and GI tolerability. A DFX film-coated tablet (FCT) was developed that can be taken orally, once-daily with or after a light meal, and is potentially less burdensome to pts than the DT formulation. Here we report pt-reported outcomes, during the 24-week (wk) study.Methods:ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. ICT-naïve pts received either DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. Dose was adjusted based on SF and investigator’s judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (±5-10 mg/kg/day, maximum 40 mg/kg/day [DT]; ±3.5-7 mg/kg/day, maximum 28 mg/kg/day [FCT]); dose adjustments for safety reasons permitted at any time. The modified satisfaction with iron chelation therapy (modified SICT; 5-point response scales to assess adherence (six questions), satisfaction/preference (two questions), and concern (three questions) domain scores) and palatability (taste, aftertaste, ability to consume medicine, perception of medicine) questionnaires were completed at wks 2, 3, 13, and end of treatment. The GI symptom diary consisted of five items (pain in your belly, nausea, vomiting, constipation, diarrhea) rated on an 11-point scale and was completed daily.Results: In total, 173 pts were enrolled; 87 were treated with FCT and 86 were treated with DT. Completion rates for questionnaires (~80% at the start reducing to ~70% by wk 24) and GI daily diary (~70% at the start reducing to ~35% by wk 24) were similar for each formulation. Throughout the 24-wk study period, FCT pts consistently reported greater adherence (attributable to: easier to remember to take medication, thinking less about stopping medication, instructions from doctor followed more closely, medication easier to take, less bothered by time taken to prepare medication and waiting time before eating), greater satisfaction/preference (in general and with administration of medicine), and fewer concerns (attributable to: less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects), than DT pts (Figure 1). Pts assessed which medication for iron overload they would like best, choosing between: FCT, DT, powder to sprinkle on food, and ’I don’t know’. At end of treatment, 53/60 (88.3%) evaluable pts receiving FCT indicated that they preferred the FCT and 41/63 (65.1%) evaluable pts receiving DT indicated they would prefer FCT. FCT pts reported higher satisfaction on palatability scores than DT pts (Figure 1), reporting no taste or aftertaste and that they are able to swallow the full amount of medicine with the right amount of liquid. The difference in score between DT and FCT was >1 point (minimal important difference) for all domains and palatability at most visits, indicating a clinically meaningful difference between formulations. Overall GI summary scores were low for both formulations indicating pts experience very little trouble/concern associated with GI symptoms; DT pts reported more trouble/concern than those receiving FCT (Figure 2).Conclusions: These results show a clear preference in favor of DFX FCT in all domains for the modified SICT. Pts were satisfied with their medicine during the study period and more pts were satisfied with DFX FCT compared with DT at all visits. DFX FCT offers pts an improved formulation that does not require administration in a fasting state, has better palatability, and very little concern associated with GI tolerability. Enhanced pt satisfaction with the new DFX FCT formulation may improve adherence, thereby, reducing iron overload-related complications. [Display omitted] [Display omitted] DisclosuresTaher:Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Gilead: Consultancy; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Bluebird Bio: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Celegene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.