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1.  Evaluation of a new tablet formulation of deferasirox to reduce chronic iron overload after long-term blood transfusions 
Transfusion-dependent anemia is a common feature in a wide array of hematological disorders, including thalassemia, sickle cell disease, aplastic anemia, myelofibrosis, and myelo-dysplastic syndromes. In the absence of a physiological mechanism to excrete excess iron, chronic transfusions ultimately cause iron overload. Without correction, iron overload can lead to end-organ damage, resulting in cardiac, hepatic, and endocrine dysfunction/failure. Iron chelating agents are utilized to reduce iron overload, as they form a complex with iron, leading to its clearance. Iron chelation has been proven to decrease organ dysfunction and improve survival in certain transfusion-dependent anemias, such as β-thalassemia. Several chelating agents have been approved by the United States Food and Drug Administration for the treatment of iron overload, including deferoxamine, deferiprone, and deferasirox. A variety of factors have to be considered when choosing an iron chelator, including dosing schedule, route of administration, tolerability, and side effect profile. Deferasirox is an orally administered iron chelator with proven efficacy and safety in multiple hematological disorders. There are two formulations of deferasirox, a tablet for suspension, and a new tablet form. This paper is intended to provide an overview of iron overload, with a focus on deferasirox, and its recently approved formulation Jadenu® for the reduction of transfusional iron overload in hematological disorders.
PMCID: PMC4760653  PMID: 26929633
iron chelation therapy; transfusional iron overload; deferasirox
2.  The potential of deferasirox as a novel therapeutic modality in gastric cancer 
Iron is a crucial element for cell proliferation, growth, and metabolism. However, excess iron and altered iron metabolism are both associated with tumor initiation and tumor growth. Deferasirox is an oral iron chelator. Although some studies have indicated that deferasirox is a promising candidate for anti-cancer therapies, its effectiveness against gastric cancer has not yet been determined. This study was conducted to determine whether deferasirox exerts anti-tumor effects in gastric cancer cell lines and whether deferasirox and cisplatin act synergistically.
Four human gastric cancer cell lines (AGS, MKN-28, SNU-484, and SNU-638) were treated with various concentrations of deferasirox to determine the IC50 for each cell line. The effects of deferasirox on the cell cycle were evaluated by flow cytometry, and the effects of deferasirox on iron metabolism, the cell cycle, and apoptosis were assessed by Western blotting. To determine whether deferasirox enhances the effect of cisplatin, AGS cells were cultured in the presence and absence of cisplatin.
Deferasirox inhibited the proliferation of all gastric cancer cell lines as assessed by MTT assays. Since the IC50 of deferasirox was the lowest (below 10 μM) in AGS cells, subsequent experiments were performed in this line. Deferasirox upregulated transferrin receptor 1 expression and decreased ferroportin expression. Moreover, deferasirox induced G1 arrest; upregulated p21, p27, and p53 expression; and downregulated cyclin D1, cyclin B, and CDK4 expression. Furthermore, deferasirox induced apoptosis, upregulated N-myc downstream regulated gene 1 (NDRG1), and downregulated p-mTOR and c-myc expression. It was also found to act synergistically with cisplatin.
Our results suggest that deferasirox may exert anti-tumor effects in the context of gastric cancer. Deferasirox affects a number of different pathways and molecules; for instance, deferasirox upregulates NDRG1 expression, inhibits the cell cycle, downregulates mTOR and c-myc expression, and induces apoptosis. In addition, deferasirox appears to potentiate the anti-cancer effects of cisplatin. Although the efficacy of deferasirox remains to be tested in future studies, the results presented here indicate that deferasirox is a promising novel anti-cancer therapeutic agent.
PMCID: PMC4785730  PMID: 26965928
Deferasirox; Stomach neoplasm; Cisplatin
3.  Zygomycetes in Human Disease 
Clinical Microbiology Reviews  2000;13(2):236-301.
The Zygomycetes represent relatively uncommon isolates in the clinical laboratory, reflecting either environmental contaminants or, less commonly, a clinical disease called zygomycosis. There are two orders of Zygomycetes containing organisms that cause human disease, the Mucorales and the Entomophthorales. The majority of human illness is caused by the Mucorales. While disease is most commonly linked to Rhizopus spp., other organisms are also associated with human infection, including Mucor, Rhizomucor, Absidia, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum spp. Although Mortierella spp. do cause disease in animals, there is no longer sufficient evidence to suggest that they are true human pathogens. The spores from these molds are transmitted by inhalation, via a variety of percutaneous routes, or by ingestion of spores. Human zygomycosis caused by the Mucorales generally occurs in immunocompromised hosts as opportunistic infections. Host risk factors include diabetes mellitus, neutropenia, sustained immunosuppressive therapy, chronic prednisone use, iron chelation therapy, broad-spectrum antibiotic use, severe malnutrition, and primary breakdown in the integrity of the cutaneous barrier such as trauma, surgical wounds, needle sticks, or burns. Zygomycosis occurs only rarely in immunocompetent hosts. The disease manifestations reflect the mode of transmission, with rhinocerebral and pulmonary diseases being the most common manifestations. Cutaneous, gastrointestinal, and allergic diseases are also seen. The Mucorales are associated with angioinvasive disease, often leading to thrombosis, infarction of involved tissues, and tissue destruction mediated by a number of fungal proteases, lipases, and mycotoxins. If the diagnosis is not made early, dissemination often occurs. Therapy, if it is to be effective, must be started early and requires combinations of antifungal drugs, surgical intervention, and reversal of the underlying risk factors. The Entomophthorales are closely related to the Mucorales on the basis of sexual growth by production of zygospores and by the production of coenocytic hyphae. Despite these similarities, the Entomophthorales and Mucorales have dramatically different gross morphologies, asexual reproductive characteristics, and disease manifestations. In comparison to the floccose aerial mycelium of the Mucorales, the Entomophthorales produce a compact, glabrous mycelium. The asexually produced spores of the Entomophthorales may be passively released or actively expelled into the environment. Human disease with these organisms occurs predominantly in tropical regions, with transmission occurring by implantation of spores via minor trauma such as insect bites or by inhalation of spores into the sinuses. Conidiobolus typically infects mucocutaneous sites to produce sinusitis disease, while Basidiobolus infections occur as subcutaneous mycosis of the trunk and extremities. The Entomophthorales are true pathogens, infecting primarily immunocompetent hosts. They generally do not invade blood vessels and rarely disseminate. Occasional cases of disseminated and angioinvasive disease have recently been described, primarily in immunocompromised patients, suggesting a possible emerging role for this organism as an opportunist.
PMCID: PMC100153  PMID: 10756000
4.  The Deferasirox–AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial 
Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted.
Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, The primary analyses were for safety and exploratory efficacy.
Patients in the deferasirox arm (n = 11) were more likely than those in the placebo arm (n = 9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P = 0.1) and 90 days (82% versus 22%, P = 0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P = 0.06) and 18% (2/11) versus 56% (5/9) (P = 0.2).
Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis.
PMCID: PMC3383100  PMID: 21937481
antifungal; fungal infections; mould infections; combination therapy
5.  Deferasirox: appraisal of safety and efficacy in long-term therapy 
Journal of Blood Medicine  2013;4:101-110.
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.
PMCID: PMC3743529  PMID: 23966805
deferasirox; iron overload; thalassemia; sickle-cell disease; myelodysplastic syndrome
6.  The iron chelator deferasirox protects mice from mucormycosis through iron starvation 
The Journal of Clinical Investigation  2007;117(9):2649-2657.
Mucormycosis causes mortality in at least 50% of cases despite current first-line therapies. Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to mucormycosis. Here we demonstrate that deferasirox, an iron chelator recently approved for use in humans by the US FDA, is a highly effective treatment for mucormycosis. Deferasirox effectively chelated iron from Rhizopus oryzae and demonstrated cidal activity in vitro against 28 of 29 clinical isolates of Mucorales at concentrations well below clinically achievable serum levels. When administered to diabetic ketoacidotic or neutropenic mice with mucormycosis, deferasirox significantly improved survival and decreased tissue fungal burden, with an efficacy similar to that of liposomal amphotericin B. Deferasirox treatment also enhanced the host inflammatory response to mucormycosis. Most importantly, deferasirox synergistically improved survival and reduced tissue fungal burden when combined with liposomal amphotericin B. These data support clinical investigation of adjunctive deferasirox therapy to improve the poor outcomes of mucormycosis with current therapy. As iron availability is integral to the pathogenesis of other infections (e.g., tuberculosis, malaria), broader investigation of deferasirox as an antiinfective treatment is warranted.
PMCID: PMC1957543  PMID: 17786247
7.  Therapeutic Value of Combined Therapy with Deferasirox and Silymarin on Iron Overload in Children with Beta Thalassemia 
Beta thalassemia is an inherited hemoglobin disorder resulting in a severe, chronic anemia requiring life-long blood transfusion that induces iron overload. Silymarin is a flavonoid complex isolated from Silybin marianum with a strong antioxidant activity, inducing an hepatoprotective action, and probably, a protective effect on iron overload. The aim of this work was to determine the silymarin value in improving iron chelation in thalassemic patients with iron overload treated with Deferasirox.
Patients and Methods
This study was conducted on 40 children with beta thalassemia major under follow-up at Hematology Unit, Pediatric Department, Tanta University Hospital with serum ferritin level more than 1000 ng/ml and was divided into two groups. Group IA: Received oral Deferasirox (Exjade) and silymarin for 6 months. Group IB: Received oral Deferasirox (Exjade) and placebo for 6 months and 20 healthy children serving as a control group in the period between April 2011 and August 2012 and was performed after approval from research ethical committee center in Tanta University Hospital and obtaining an informed written parental consent from all participants in this study.
Serum ferritin levels were markedly decreased in group IA cases compared with group IB (P= 0.001).
From this study we concluded that, silymarin in combination with Exjade can be safely used in the treatment of iron-loaded thalassemic patients as it showed good iron chelation with no sign of toxicity.
We recommend extensive multicenter studies in a large number of patients with longer duration of follow-up and more advanced techniques of assessment of iron status in order to clarify the exact role of silymarin in reducing iron overload in children with beta thalassemia.
PMCID: PMC3867224  PMID: 24363880
8.  Deferasirox (ICL670A) effectively inhibits oesophageal cancer growth in vitro and in vivo 
British Journal of Pharmacology  2013;168(6):1316-1328.
Background and Purpose
Growing evidence implicates iron in the aetiology of gastrointestinal cancer. Furthermore, studies demonstrate that iron chelators possess potent anti-tumour activity, although whether iron chelators show activity against oesophageal cancer is not known.
Experimental Approach
The effect of the iron chelators, deferoxamine (DFO) and deferasirox, on cellular iron metabolism, viability and proliferation was assessed in two oesophageal adenocarcinoma cell lines, OE33 and OE19, and the squamous oesophageal cell line, OE21. A murine xenograft model was employed to assess the effect of deferasirox on oesophageal tumour burden. The ability of chelators to overcome chemoresistance and to enhance the efficacy of standard chemotherapeutic agents (cisplatin, fluorouracil and epirubicin) was also assessed.
Key Results
Deferasirox and DFO effectively inhibited cellular iron acquisition and promoted intracellular iron mobilization. The resulting reduction in cellular iron levels was reflected by increased transferrin receptor 1 expression and reduced cellular viability and proliferation. Treating oesophageal tumour cell lines with an iron chelator in addition to a standard chemotherapeutic agent resulted in a reduction in cellular viability and proliferation compared with the chemotherapeutic agent alone. Both DFO and deferasirox were able to overcome cisplatin resistance. Furthermore, in human xenograft models, deferasirox was able to significantly suppress tumour growth, which was associated with decreased tumour iron levels.
Conclusions and Implications
The clinically established iron chelators, DFO and deferasirox, effectively deplete iron from oesophageal tumour cells, resulting in growth suppression. These data provide a platform for assessing the utility of these chelators in the treatment of oesophageal cancer patients.
Linked Article
This article is commented on by Keeler and Brookes, pp. 1313–1315 of this issue. To view this commentary visit
PMCID: PMC3596639  PMID: 23126308
oesophageal cancer; iron chelation; cancer; deferasirox
9.  The iron chelator deferasirox enhances liposomal amphotericin B efficacy in treating murine invasive pulmonary aspergillosis 
Increased bone marrow iron levels in patients with haematological malignancies is an independent risk factor for developing invasive pulmonary aspergillosis (IPA), suggesting an important role for iron uptake in the pathogenesis of IPA. We sought to determine the potential for combination therapy with the iron chelator deferasirox + liposomal amphotericin B (LAmB) to improve the outcome of murine IPA compared with LAmB monotherapy.
In vitro MIC and minimum fungicidal concentration (MFC) values of the iron chelator, deferasirox, for Aspergillus fumigatus were determined by microdilution assay. In addition, we studied the efficacy of deferasirox alone or combined with LAmB in treating immunocompromised mice infected with A. fumigatus via inhalation.
Deferasirox was cidal in vitro against A. fumigatus, with an MIC and MFC of 25 and 50 mg/L, respectively. Deferasirox monotherapy modestly prolonged survival of mice with IPA. Combination deferasirox + LAmB therapy synergistically improved survival and reduced lung fungal burden compared with either monotherapy alone.
Iron chelation therapy with deferasirox alone or in combination with LAmB is effective in treating experimental IPA. Further study of deferasirox is warranted as adjunctive therapy for IPA infections.
PMCID: PMC2902852  PMID: 19942619
Aspergillus fumigatus; LAmB; IPA
10.  Iron Acquisition: A Novel Prospective on Mucormycosis Pathogenesis and Treatment 
Purpose of review
Mucormycosis is an increasingly common fungal infection with an unacceptably high mortality despite first-line antifungal therapy. Iron acquisition is a critical step in the causative organsisms’ pathogenetic mechanism. Therefore, abrogation of fungal iron acquisition is a promising therapeutic strategy to impact clinical outcomes for this deadly disease.
Recent findings
The increased risk of mucormycosis in patients in renal failure receiving deferoxamine iron chelation therapy is explained by the fact that deferoxamine actually acts as a siderophore for the agents of mucormycosis, supplying previously unavailable iron to the fungi. The iron liberated from deferoxamine is likely transported into the fungus by the high affinity iron permease. In contrast, two other iron chelators, deferiprone and deferasirox, do not supply iron to the fungus and were shown to be cidal against Zygomycetes in vitro. Further, both iron chelators were shown to effectively treat mucormycosis in animal models, and one has been successfully used as salvage therapy for a patient with rhinocerebral mucormycosis.
Further investigation and development of iron chelators is warranted as adjunctive therapy for mucormycosis.
PMCID: PMC2773686  PMID: 18978530
Mucormycosis; Rhizopus; Iron chelation; Deferasirox; deferiprone
11.  Effects of oral iron chelator deferasirox on human malignant lymphoma cells 
The Korean Journal of Hematology  2012;47(3):194-201.
Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines.
Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 µM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay.
The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups.
We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.
PMCID: PMC3464336  PMID: 23071474
Deferasirox; Malignant lymphoma; Apoptosis
12.  AB044. Update in the management of thalassemia 
Annals of Translational Medicine  2015;3(Suppl 2):AB044.
Treatment of thalassemia depends on the clinical diagnosis. Almost all severe alpha thalassemia, Hb Bart’s hydrops fetalis, die intra utero or a few minute after birth. However, pregnant woman with Hb Bart’s hydrops fetus may develop toxemia of pregnancy and antepartum and postpartum hemorrhage. Those homozygous beta thalassemias (transfusion dependent thalassemia, TDT) are severely anemic after 6 months. At birth the baby is asymptomatic because Hb F level is high. As Hb F production waning off, replaced by inefficient beta globin chain production, at the age of 6 to 12 months, the baby begins to be anemic with hepatosplenomegaly. A group of non transfusion dependent thalassemia (NTDT) includes the majority of beta thalassemia/Hb E, Hb H disease and a few cases of homozygous beta thalassemias. The thalassemia minor including both alpha and beta thalassemia carriers and some homozygous state like homozygous alpha+ thalassemia, homozygous Hb E are asymptomatic and does not need any regular treatment. All thalassemia major, TDT, patients need regular blood transfusion, every 3-4 weeks, to maintain the hemoglobin around 10-12 g/dL. For those NTDT blood is given only when necessary. Usually patients with hemoglobin level higher than 6 g/dL require no blood transfusion. In infants and children if the hemoglobin levels can be maintained at 7 g/dL or above, defective physical development and bone changes can be prevented until they reached third or fourth decades of life that osteoporosis is almost always presented in those with low hemoglobin level. Iron overload occurs in moderate and severe case without exception. This will lead to dark skin, liver cirrhosis, cardiac arrhythmia and congestive heart failure. Diabetes mellitus secondary to iron deposition in the pancreas and other endocrine dysfunction does develop if the patients live long enough. Iron chelation with 1-2 gm/day of desferrioxamine intravenously or intramuscularly every day, at least 5 days a week, is recommended for those patients who have hemochromatosis. Oral iron chelator such as deferiprone and deferasirox is recently available. This helps patients to have better compliance with the iron chelator. Stem cell transplantation has been tried with a very good result in class I cases. Because some difficulty in finding appropriated HLA matched donor lately people try to perform haploidentical stem cell transplantation with some good results. Lupstaercept (ACE-536) and Sotatarcept (ACE-011), a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemia due to ineffective erythropoiesis. Preliminary data showed that the compound could increase hemoglobin levels 1.5 g/dL after two weeks of treatment in NTDT case and decrease blood transfusion in 60% of cases with TDT. Research is in progress to find better agents to enhance Hb F production.
PMCID: PMC4563435
Thalassemia; stem cell transplantation; Hb F production
13.  Side effects of Deferasirox Iron Chelation in Patients with Beta Thalassemia Major or Intermedia 
Oman Medical Journal  2013;28(2):121-124.
Chelating agents remain the mainstay in reducing the iron burden and extending patient survival in homozygous beta-thalassemia but adverse and toxic effects may increase with the institution and long term use of this essential therapy. This study aimed to estimate the incidence of deferasirox (DFX) side effects in patients with thalassemia major or intermedia.
A retrospective study of 72 patients (mean age: 20.3±0.9 yrs; 36 male, 36 female) with thalassemia major or intermedia treated at Sultan Qaboos University Hospital, Oman, was performed to assess the incidence of side effects related to deferasirox over a mean of 16.7 month follow-up period.
Six patients experienced rashes and 6 had gastro-intestinal upset. DFX was discontinued in 18 patients for the following reasons: persistent progressive rise(s) in serum creatinine (7 patients; 40% mean serum creatinine rise from baseline), feeling unwell (2), severe diarrhea (1), pregnancy (1), death unrelated to chelator (2) and rise in serum transaminases (2). Three patients were reverted to desferoxamine and deferiprone combination therapy as DFX was no longer biochemically effective after 18 months of therapy. There was no correlation between baseline serum ferritin and serum creatinine or a rise in serum creatinine. Cardiac MRI T2* did not change with DFX therapy. However, there was an improvement in liver MRI T2* (p=0.013).
Renal side effects related to deferasirox appear to be higher than those reported in published clinical trials. Further larger studies are required to confirm these findings.
PMCID: PMC3628199  PMID: 23599881
Chelator; Kidney function; Thalassemia; Toxicity
14.  A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding 
Inorganica chimica acta  2012;393:294-303.
Iron chelating agents have the potential to minimize damage associated with oxidative stress in a range of diseases; however, this potential is countered by risks of indiscriminant metal binding or iron depletion in conditions not associated with systemic iron overload. Deferasirox is a chelator used clinically for iron overload, but also is cytotoxic to cells in culture. In order to test whether a prodrug version of deferasirox could minimize its cytotoxicity but retain its protective properties against iron-induced oxidative damage, we synthesized a prochelator that contains a self-immolative boronic ester masking group that is removed upon exposure to hydrogen peroxide to release the bis-hydroxyphenyltriazole ligand deferasirox. We present here the synthesis and characterization of this triazole-based, self-immolative prochelator: TIP (4-(5-(2-((4-boronobenzyl)oxy)phenyl)-3-(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid). TIP does not coordinate to Fe3+ and shows only weak affinity for Cu2+ or Zn2+, in stark contrast to deferasirox, which avidly binds all three metal ions. TIP converts efficiently in vitro upon reaction with hydrogen peroxide to deferasirox. In cell culture, TIP protects retinal pigment epithelial cells from death induced by hydrogen peroxide; however, TIP itself is more cytotoxic than deferasirox in unstressed cells. These results imply that the cytotoxicity of deferasirox may not derive exclusively from its iron withholding properties.
PMCID: PMC3579658  PMID: 23439614
Chelation therapy; Iron; Oxidative stress; Fenton chemistry; Reactive oxygen species; Prodrug
15.  Hypersensitivity reaction with deferasirox 
Thalassemias comprise a group of hereditary blood disorders. Thalassemia major presents with anemia within the first 2 years of life requiring frequent blood transfusions for sustaining life. Regular blood transfusions lead to iron overload-related complications. Prognosis of thalassemia has improved because of the availability of iron-chelating agents. Oral iron chelators are the mainstay of chelation therapy. Deferasirox is a new-generation oral iron chelator for once daily usage. We herein describe a patient of beta thalassemia major who developed an allergic manifestation in the form of erythematous pruritic skin rashes to the oral iron chelator deferasirox. This is a rare adverse reaction reported with deferasirox that led to a therapeutic dilemma in this particular case.
PMCID: PMC4419242  PMID: 25969661
Deferasirox; rash; thalassemia
16.  Deferasirox effectively reduces iron overload in non-transfusion-dependent thalassemia (NTDT) patients: 1-year extension results from the THALASSA study 
Annals of Hematology  2013;92(11):1485-1493.
Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was −7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of −6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-013-1808-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3790249  PMID: 23775581
Iron overload; Iron chelation; Non-transfusion-dependent thalassemia; Deferasirox
17.  Approaching low liver iron burden in chelated patients with non-transfusion-dependent thalassemia: the safety profile of deferasirox 
European Journal of Haematology  2014;92(6):521-526.
Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3.
THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2).
Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment.
The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation.
PMCID: PMC4232858  PMID: 24460655
iron chelation; iron overload; thalassemia
18.  Durable Red Blood Cell Transfusion Independence in a Patient with an MDS/MPN Overlap Syndrome Following Discontinuation of Iron Chelation Therapy 
Case Reports in Hematology  2015;2015:253294.
Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation. Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient's course in detail and review the literature on HI with chelation. Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.
PMCID: PMC4396885  PMID: 25918650
19.  A Phase 1/2, Dose-Escalation Trial of Deferasirox for the Treatment of Iron Overload in HFE-Related Hereditary Hemochromatosis 
Hepatology (Baltimore, Md.)  2010;52(5):1671-1679.
Hereditary hemochromatosis (HH) is characterized by increased intestinal iron absorption that may result in iron overload. Although phlebotomy is widely practiced, it is poorly tolerated or contraindicated in patients with anemias, severe heart disease, or poor venous access, and compliance can vary. The once-daily, oral iron chelator, deferasirox (Exjade) may provide an alternative treatment option. Patients with HH carrying the HFE gene who were homozygous for the Cys282Tyr mutation, serum ferritin levels of 300-2000 ng/mL, transferrin saturation ≥45%, and no known history of cirrhosis were enrolled in this dose-escalation study to characterize the safety and efficacy of deferasirox, comprising a core and an extension phase (each 24 weeks). Forty-nine patients were enrolled and received starting deferasirox doses of 5 (n = 11), 10 (n = 15), or 15 (n = 23) mg/kg/day. Adverse events were generally dose-dependent, the most common being diarrhea, headache, and nausea (n = 18, n = 10, and n = 8 in the core and n = 1, n = 1, and n = 0 in the extension, respectively). More patients in the 15 mg/kg/day than in the 5 or 10 mg/kg/day cohorts experienced increases in alanine aminotransferase and serum creatinine levels during the 48-week treatment period; six patients had alanine aminotransferase >3× baseline and greater than the upper limit of normal range, and eight patients had serum creatinine >33% above baseline and greater than upper limit of normal on two consecutive occasions. After receiving deferasirox for 48 weeks, median serum ferritin levels decreased by 63.5%, 74.8%, and 74.1% in the 5, 10, and 15 mg/kg/day cohorts, respectively. In all cohorts, median serum ferritin decreased to <250 ng/mL. Conclusion: Deferasirox doses of 5, 10, and 15 mg/kg/day can reduce iron burden in patients with HH. Based on the safety and efficacy results, starting deferasirox at 10 mg/kg/day appears to be most appropriate for further study in this patient population. (Hepatology 2010)
PMCID: PMC3034044  PMID: 20814896
20.  The long-term efficacy and tolerability of oral deferasirox for patients with transfusion-dependent β-thalassemia in Taiwan 
Annals of Hematology  2015;94(12):1945-1952.
Deferasirox is a novel once-daily, oral iron chelator. The aim of this study was to evaluate the long-term efficacy and tolerability of deferasirox in Taiwanese patients with transfusion-dependent β-thalassemia who have been treated with deferasirox for 7 years. Taiwanese patients aged ≥2 years with transfusion-dependent β-thalassemia whose serum ferritin levels were ≥1000 ng/mL and had started deferasirox treatment since December 2005 at the National Taiwan University Hospital were enrolled. Sixty patients were recruited for analysis, and 11 (18.3 %) patients discontinued deferasirox during the study. In the 42 patients included in the efficacy analysis, the mean serum ferritin levels decreased significantly by 2566 ng/mL after 7 years of treatment (P < 0.001). Forty-one of these patients received a cardiac T2* evaluation after 3 years of deferasirox treatment, and the mean cardiac T2* value increased significantly from 30.6 ± 16.6 to 45.9 ± 22.6 ms after 7 years of deferasirox treatment (P < 0.001). Deferasirox-related adverse events assessed by investigators were reported in 46 (76.7 %) patients. The most common adverse events related to deferasirox were skin rashes (n = 29, 48.3 %), followed by abdominal pain (n = 23, 38.3 %) and diarrhea (n = 16, 26.7 %). Most adverse events were manageable. This study demonstrated that long-term treatment with deferasirox was effective in improving iron overload, including cardiac iron overload, in patients with transfusion-dependent β-thalassemia. Deferasirox was well tolerated; however, the incidences of common adverse events related to deferasirox appeared higher in our Taiwanese patients than other studies.
Electronic supplementary material
The online version of this article (doi:10.1007/s00277-015-2476-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4604499  PMID: 26404899
β-thalassemia; Cardiac iron; Deferasirox; Iron overload
21.  New developments and controversies in iron metabolism and iron chelation therapy 
Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients’ therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.
PMCID: PMC4804243  PMID: 27019793
Iron metabolism; Iron chelation therapy; Deferiprone; Deferoxamine; Deferasirox; Iron diseases; Medical journals; Controversies
22.  The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study 
Available iron chelation regimes in thalassaemia may achieve different changes in cardiac and hepatic iron as assessed by MR. The aim of this study was to assess the efficacy of four available iron chelator regimes in 232 thalassaemia major patients by assessing the rate of change in repeated measurements of cardiac and hepatic MR.
For the heart, deferiprone and the combination of deferiprone and deferoxamine significantly reduced cardiac iron at all levels of iron loading. As patients were on deferasirox for a shorter time, a second analysis ("Initial interval analysis") assessing the change between the first two recorded MR results for both cardiac and hepatic iron (minimum interval 12 months) was made. Combination therapy achieved the most rapid fall in cardiac iron load at all levels and deferiprone alone was significantly effective with moderate and mild iron load. In the liver, deferasirox effected significant falls in iron load and combination therapy resulted in the most rapid decline.
With the knowledge of the efficacy of the different available regimes and the specific iron load in the heart and the liver, appropriate tailoring of chelation therapy should allow clearance of iron. Combination therapy is best in reducing both cardiac and hepatic iron, while monotherapy with deferiprone or deferasirox are effective in the heart and liver respectively. The outcomes of this study may be useful to physicians as to the chelation they should prescribe according to the levels of iron load found in the heart and liver by MR.
PMCID: PMC2713224  PMID: 19558722
23.  Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells 
The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies.
We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib.
Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-κB (NF-κB) and β-catenin.
We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-κB and β-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.
PMCID: PMC4773721  PMID: 26874514
Deferasirox; Iron chelator; Chronic myeloid leukemia; Imatinib; Resistance
24.  Deferasirox and Vitamin D Improves Overall Survival in Elderly Patients with Acute Myeloid Leukemia after Demethylating Agents Failure 
PLoS ONE  2013;8(6):e65998.
The prognosis of acute myeloid leukemia (AML) in elderly (≥65 years) patients is poor and treatment remains non-consensual especially for those who are not eligible for intensive therapies. Our group has shown that in vitro the iron chelator deferasirox (DFX) synergizes with vitamin D (VD) to promote monocyte differentiation in primary AML cells. Herein, we present results from a retrospective case-control study in which the association of DFX (1–2 g/d) and 25-hydroxycholecalciferol (100,000 IU/week) (DFX/VD) was proposed to patients following demethylating agents failure. Median survival of patients treated with DFX/VD combination (n = 17) was significantly increased in comparison with matched patients receiving best supportive care (BSC) alone (n = 13) (10.4 versus 4 months respectively). In addition, the only factor associated to an increased overall survival in DFX/VD-treated patients was serum VD levels. We conclude that DFX/VD treatment correlated with increased overall survival of AML patients in this retrospective cohort of elderly patients.
PMCID: PMC3688707  PMID: 23840388
25.  Hydroxyurea Could Be a Good Clinically Relevant Iron Chelator 
PLoS ONE  2013;8(12):e82928.
Our previous study showed a reduction in serum ferritin of β-thalassemia patients on hydroxyurea therapy. Here we aimed to evaluate the efficacy of hydroxyurea alone and in combination with most widely used iron chelators like deferiprone and deferasirox for reducing iron from experimentally iron overloaded mice. 70 BALB/c mice received intraperitonial injections of iron-sucrose. The mice were then divided into 8 groups and were orally given hydroxyurea, deferiprone or deferasirox alone and their combinations for 4 months. CBC, serum-ferritin, TBARS, sTfr and hepcidin were evaluated before and after iron overload and subsequently after 4 months of drug therapy. All animals were then killed. Iron staining of the heart and liver tissue was done using Perl’s Prussian Blue stain. Dry weight of iron in the heart and liver was determined by atomic absorption spectrometry. Increased serum-ferritin, TBARS, hepcidin and dry weight of iron in the liver and heart showed a significant reduction in groups treated with iron chelators with maximum reduction in the group treated with a combination of deferiprone, deferasirox and hydroxyurea. Thus hydroxyurea proves its role in reducing iron from iron overloaded mice. The iron chelating effect of these drugs can also be increased if given in combination.
PMCID: PMC3857323  PMID: 24349400

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