Two-Year Analysis of Efficacy and Safety of Deferasirox Treatment for Transfusional Iron Overload in Sickle Cell Anemia Patients

Cançado, Rodolfo Delfini; Olivato, Maria Cristina Albe; Bruniera, Paula; Szarf, Gilberto; Bastos, Roberto de Moraes; Melo, Murilo Rezende; Chiattone, Carlos S.

doi:10.1159/000338560

Cited by 11 publications

(11 citation statements)

References 42 publications

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“…The most common adverse effects in the study were transient and mild, with diarrhea and headaches reported in 22.6% patients each. Three patients (9.5%) were noted to have nonprogressive increase in serum creatinine 39. Taken together, these studies support the efficacy of deferasirox in iron-overloaded SCD patients and demonstrate its safety over a reasonably long time period.…”

Section: Sickle-cell Diseasesupporting

confidence: 57%

Deferasirox: appraisal of safety and efficacy in long-term therapy

Chaudhary¹,

Pullarkat²

2013

JBM

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Deferasirox is a once-daily, oral iron chelator that is widely used in the management of patients with transfusional hemosiderosis. Several Phase II trials along with their respective extension studies as well as a Phase III trial have established the efficacy and safety of this novel agent in transfusion-dependent patients with β-thalassemia, sickle-cell disease and bone marrow-failure syndromes, including myelodysplastic syndrome and aplastic anemia. Data from various clinical trials show that a deferasirox dose of 20 mg/kg/day stabilizes serum ferritin levels and liver iron concentration, while a dose of 30–40 mg/kg/day reduces these parameters and achieves negative iron balance in red cell transfusion-dependent patients with iron overload. Across various pivotal clinical trials, deferasirox was well tolerated, with the most common adverse events being gastrointestinal disturbances, skin rash, nonprogressive increases in serum creatinine, and elevations in liver enzyme levels. Longer-term extension studies have also confirmed the efficacy and safety of deferasirox. However, it is essential that patients on deferasirox therapy are monitored regularly to ensure timely management for any adverse events that may occur with long-term therapy.

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Section: Sickle-cell Diseasesupporting

confidence: 57%

Deferasirox: appraisal of safety and efficacy in long-term therapy

Chaudhary¹,

Pullarkat²

2013

JBM

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“…In 22 published, randomized clinical trials that included a total of 2,119 deferasirox-treated patients, the overall incidence of nephrotoxicity defined as an increase in sCr levels was 22% (n = 471; Figure 2a and Supplementary Table 2 online). 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Similarly, in 16 published clinical practice studies that included a total of 1,373 patients, sCr levels increased in 18% of participants (n = 242; Figure 2b and Supplementary Table 3 online). 37,38,40,60-72 However, in clinical trials and in clinical practice reports, the incidence of nephrotoxicity is higher when defined by a >33% increase in sCr levels over baseline (36% and 28.5%, respectively) than when defined by an increase in sCr levels above the ULN (7.2% and 6.3%, respectively; Figure 2).…”

Section: Epidemiologymentioning

confidence: 99%

“…42 This finding is expected because the liver metabolizes and secretes the drug. In published randomized clinical trials 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] and clinical practice studies, 37,38,40,60-72 incidence of increased sCr levels has been shown to vary by age (panels a-f) and dose of deferasirox (panels g-l). a,g | Data from randomized controlled trials that defined nephrotoxicity as sCr levels >ULN.…”

Section: Accumulation In Kidneymentioning

confidence: 99%

Deferasirox nephrotoxicity—the knowns and unknowns

et al. 2014

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In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

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“…83 Additional studies corroborate this relatively low rate of compliance due to side effects. 84,85 An ongoing multicenter, randomized, double-blind, placebo-controlled clinical trial, TELESTO, to evaluate the effect of deferasirox on low-risk MDS patients with iron overload, is underway. This trial intends to evaluate death and nonfatal events related to cardiac and liver function, 86 but, due to sustained difficulties with patient recruitment, the results may not be sufficiently powered to definitively answer these questions.…”

Section: Clinical Impact Of Iron Chelation In Mds Patientsmentioning

confidence: 99%

“…[100][101][102] In one study, 16% of patients achieved transfusion independence by 12 months with a median hemoglobin of 8 g. In this study, all patients reduced RBC transfusion frequency by 67% after 12 months of treatment. 85 Most recently, chelation with deferasirox demonstrated a 1.5-to 1.8-g/dL increase in hemoglobin despite a decrease in RBC transfusion requirements in patients with low-risk MDS. 103 Deferasirox also reduced the oxidative stress within RBCs, platelets, and neutrophils; reduced intracellular ROS and lipid peroxidation; and increased intracellular reduced glutathione stores.…”

Section: Iron Chelation and Improved Erythropoiesis In Mdsmentioning

confidence: 99%

Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome

Shenoy

Vallumsetla

Rachmilewitz

et al. 2014

Blood

107

116

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Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron’s adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism–driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.

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Two-Year Analysis of Efficacy and Safety of Deferasirox Treatment for Transfusional Iron Overload in Sickle Cell Anemia Patients

Cited by 11 publications

References 42 publications

Deferasirox: appraisal of safety and efficacy in long-term therapy

Deferasirox: appraisal of safety and efficacy in long-term therapy

Deferasirox nephrotoxicity—the knowns and unknowns

Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome

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