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Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias.
Taher, AT, Origa, R, Perrotta, S, Kouraklis, A, Ruffo, GB, Kattamis, A, Goh, AS, Huang, V, Zia, A, Herranz, RM, et al
Health and quality of life outcomes. 2018;(1):216
Abstract
BACKGROUND Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients ≥2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. METHODS The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. RESULTS One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. CONCLUSIONS These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014.
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Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease.
Martin-Bastida, A, Ward, RJ, Newbould, R, Piccini, P, Sharp, D, Kabba, C, Patel, MC, Spino, M, Connelly, J, Tricta, F, et al
Scientific reports. 2017;(1):1398
Abstract
Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.
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Limitations of serum ferritin to predict liver iron concentration responses to deferasirox therapy in patients with transfusion-dependent thalassaemia.
Porter, JB, Elalfy, M, Taher, A, Aydinok, Y, Lee, SH, Sutcharitchan, P, El-Ali, A, Han, J, El-Beshlawy, A
European journal of haematology. 2017;(3):280-288
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Abstract
BACKGROUND In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable. OBJECTIVES AND METHODS This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox. RESULTS Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively. CONCLUSIONS As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone.
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Defining serum ferritin thresholds to predict clinically relevant liver iron concentrations for guiding deferasirox therapy when MRI is unavailable in patients with non-transfusion-dependent thalassaemia.
Taher, AT, Porter, JB, Viprakasit, V, Kattamis, A, Chuncharunee, S, Sutcharitchan, P, Siritanaratkul, N, Origa, R, Karakas, Z, Habr, D, et al
British journal of haematology. 2015;(2):284-90
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Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 μg/l), as well as thresholds to guide chelator dose interruption (<300 μg/l) and dose escalation (>2000 μg/l). (clinicaltrials.gov identifier: NCT00873041).
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R2 and R2* are equally effective in evaluating chronic response to iron chelation.
Wood, JC, Zhang, P, Rienhoff, H, Abi-Saab, W, Neufeld, E
American journal of hematology. 2014;(5):505-8
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MRI relaxometry (R2, R2*) has generally replaced liver biopsy for estimation of liver iron stores in response to iron chelation, but there have been no longitudinal studies comparing R2 and R2* techniques. We use R2 and R2* liver iron concentration (LIC) estimates, transfusional iron burdens, and drug compliance data to calculate iron chelation efficiency (ICE) in patients undergoing a Phase II trial of SPD602. Fifty-one patients underwent a baseline examination, 39 patients completed 1 year, and 26 patients completed 2 years. Baseline LICR2 and LICR2* estimates were unbiased, but had limits of agreement exceeding 50%, suggesting that these techniques cannot be interchanged with one another in the same patient. However, ICE estimates across the two techniques compared more favorably, with r(2) values reaching 0.89 at 2 years. 95 confidence intervals for efficiency estimates were 0.0 ± 4.1%. These data indicate that clinical trial and clinical effectiveness data calculated using LICR2 and LICR2* estimates can be compared to one another, even though LIC estimates may be disparate on cross-sectional analysis. While the choice of MRI assessment technique for clinical trials and for clinical management depends on many logistical considerations, one can have confidence comparing conclusions on clinical effectiveness.
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Endocrine function and bone disease during long-term chelation therapy with deferasirox in patients with β-thalassemia major.
Casale, M, Citarella, S, Filosa, A, De Michele, E, Palmieri, F, Ragozzino, A, Amendola, G, Pugliese, U, Tartaglione, I, Della Rocca, F, et al
American journal of hematology. 2014;(12):1102-6
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Iron overload in β-thalassemia major (TM) typically results in iron-induced cardiomyopathy, liver disease, and endocrine complications. We examined the incidence and progression of endocrine disorders (hypothyroidism, diabetes, hypoparathyroidism, hypogonadism), growth and pubertal delay, and bone metabolism disease during long-term deferasirox chelation therapy in a real clinical practice setting. We report a multicenter retrospective cohort study of 86 transfusion-dependent patients with TM treated with once daily deferasirox for a median duration of 6.5 years, up to 10 years. No deaths or new cases of hypothyroidism or diabetes occurred. The incidence of new endocrine complications was 7% (P = 0.338, for change of prevalence from baseline to end of study) and included hypogonadism (n = 5) and hypoparathyroidism (n = 1). Among patients with hypothyroidism or diabetes at baseline, no significant change in thyroid parameters or insulin requirements were observed, respectively. Mean lumbar spine bone mineral density increased significantly (P < 0.001) and the number of patients with lumbar spine osteoporosis significantly decreased (P = 0.022) irrespective of bisphosphonate therapy, hormonal replacement therapy, and calcium or vitamin D supplementation. There were no significant differences in the number of pediatric patients below the 5th centile for height between baseline and study completion. Six pregnancies occurred successfully, and four of them were spontaneous without ovarian stimulation. This is the first study evaluating endocrine function during the newest oral chelation therapy with deferasirox. A low rate of new endocrine disorders and a stabilization of those pre-exisisting was observed in a real clinical practice setting.
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The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial.
van Eijk, LT, Heemskerk, S, van der Pluijm, RW, van Wijk, SM, Peters, WH, van der Hoeven, JG, Kox, M, Swinkels, DW, Pickkers, P
Haematologica. 2014;(3):579-87
Abstract
In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699).
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Geographical variations in current clinical practice on transfusions and iron chelation therapy across various transfusion-dependent anaemias.
Viprakasit, V, Gattermann, N, Lee, JW, Porter, JB, Taher, AT, Habr, D, Martin, N, Domokos, G, Cappellini, MD
Blood transfusion = Trasfusione del sangue. 2013;(1):108-22
Abstract
BACKGROUND AND OBJECTIVES Many patients with chronic anaemia require blood transfusions as part of their treatment regimen. As a result, iron overload will inevitably develop if not adequately managed by iron chelation therapy. There are many guidelines relating to transfusion and chelation practices for patients with transfusion-dependent anaemia; however, there is a lack of information on how treatment practices differ around the world. The objective of this manuscript is to highlight key features of current transfusion and chelation management, including similarities and differences across various anaemias and between geographical regions worldwide. MATERIALS AND METHODS Data collected at study entry to the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study, which recruited 1,744 patients with a variety of transfusion-dependent anaemias across 23 countries from three geographic regions, were assessed. These analyses compared transfusion and chelation treatment prior to the start of study treatment, together with iron burden assessed at study entry by serum ferritin, liver iron concentration and labile plasma iron levels. RESULTS AND CONCLUSIONS Data show that transfusion and iron chelation practices differ between anaemias and between geographical regions; this may be linked to availability and accessibility of transfusion and chelation therapy, patients' compliance, physicians' attitudes, costs and use of treatment guidelines. Approximately 60% of these transfusion-dependent patients were severely iron overloaded with a serum ferritin level over 2,500 ng/mL, indicating that the risks of iron burden may have been underestimated and current iron chelation therapy, if considered, may not have been adequate to control iron burden.
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Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study.
Lee, JW, Yoon, SS, Shen, ZX, Ganser, A, Hsu, HC, El-Ali, A, Habr, D, Martin, N, Porter, JB
Haematologica. 2013;(7):1045-8
Abstract
Reports are emerging of hematologic responses associated with iron chelation therapy; however, studies are limited in aplastic anemia patients. Deferasirox reduced iron overload in aplastic anemia patients enrolled in the EPIC (Evaluation of Patients' Iron Chelation with Exjade(®)) study (n=116). A post hoc analysis of hematologic responses was conducted on 72 patients with evaluable hematologic parameters (according to UK guideline criteria), 24 of whom received deferasirox without concomitant immunosuppressive treatment. Partial hematologic responses were observed in 11 of 24 (45.8%) patients; all became transfusion-independent. One patient had an additional platelet response and one patient had an additional platelet and hemoglobin response. Mean serum ferritin levels at end of study were significantly reduced in partial hematologic responders (n=11; -3948 ± 4998 ng/mL; baseline 6693 ± 7014 ng/mL; percentage change from baseline -45.7%; P=0.0029). In non-responders, the reduction in serum ferritin was less pronounced (n=13; -2021 ± 3242 ng/mL; baseline 4365 ± 3063 ng/mL; % change from baseline -27.6%; P=0.0171). Alongside reduction in iron overload, deferasirox may, therefore, improve hematologic parameters in a subset of aplastic anemia patients. Further investigation is required to elucidate the mechanisms involved.
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Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone.
Porter, JB, Wood, J, Olivieri, N, Vichinsky, EP, Taher, A, Neufeld, E, Giardina, P, Thompson, A, Moore, B, Evans, P, et al
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2013;(1):38
Abstract
BACKGROUND Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear. METHODS A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50-60 mg/kg 12-24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR. RESULTS Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 ± 1.6 ms p = 0.04; and DFO monotherapy +1.9 ± 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group. CONCLUSIONS Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients.