Deferasirox Treatment Research Articles

Deferasirox exerts anti-epileptic effects by improving brain iron homeostasis via regulation of ITPRIP

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.

Electroacupuncture improves cognitive function in APP/PS1 mice by inhibiting oxidative stress related hippocampal neuronal ferroptosis

BackgroundElectroacupuncture, recognized as a crucial non-pharmacological therapeutic approach, has demonstrated notable efficacy in enhancing cognitive function among Alzheimer's disease (AD) patients. This study aimed to investigate the neuroprotective properties of electroacupuncture in APP/PS1 mice with AD. MethodsA total of thirty APP/PS1 mice were randomly assigned to three groups: the Alzheimer's disease group (AD), the electroacupuncture treatment group (EA), and the ferroptosis inhibitor deferasirox treatment group (DFX). Additionally, ten C57BL/6 mice were included as a control group (Control). In the EA group, mice underwent flat needling at Baihui and Yintang, as well as point needling at Renzhong, once daily for 15 min each time. In the DFX group, mice received intraperitoneal injections of deferasirox at a dosage of 100 mg/kg/day. Following the 28-day treatment period, behavioral evaluation, morphological observation of neurons, and detection of neuronal ferroptosis were conducted. ResultsThe electroacupuncture treatment demonstrated a significant improvement in spatial learning, memory ability, and neuronal damage in mice with AD. Analysis of neuronal ferroptosis markers indicated that electroacupuncture interventions reduced the elevated levels of malondialdehyde, iron, and ptgs2 expression, while also increasing superoxide dismutase activity, Ferroportin 1 and glutathione peroxidase 4 expression. Moreover, the regulatory impact of electroacupuncture on ferroptosis may be attributed to its ability to enhance the expression and nuclear translocation of Nrf2. ConclusionsThis study suggested that electroacupuncture could inhibit the neuronal ferroptosis by activating the antioxidant function in neurons through p62/Keap1/Nrf2 signal pathway, thereby improve the cognitive function of AD mice by the neuronal protection effect.

Deferasirox Targeting Ferroptosis Synergistically Ameliorates Myocardial Ischemia Reperfusion Injury in Conjunction With Cyclosporine A.

Ferroptosis, an iron-dependent form of regulated cell death, is a major cell death mode in myocardial ischemia reperfusion (I/R) injury, along with mitochondrial permeability transition-driven necrosis, which is inhibited by cyclosporine A (CsA). However, therapeutics targeting ferroptosis during myocardial I/R injury have not yet been developed. Hence, we aimed to investigate the therapeutic efficacy of deferasirox, an iron chelator, against hypoxia/reoxygenation-induced ferroptosis in cultured cardiomyocytes and myocardial I/R injury. The effects of deferasirox on hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis were examined in cultured cardiomyocytes. In a mouse model of I/R injury, the infarct size and adverse cardiac remodeling were examined after treatment with deferasirox, CsA, or both in combination. Deferasirox suppressed hypoxia- or hypoxia/reoxygenation-induced iron overload in the endoplasmic reticulum, lipid peroxidation, and ferroptosis in cultured cardiomyocytes. Deferasirox treatment reduced iron levels in the endoplasmic reticulum and prevented increases in lipid peroxidation and ferroptosis in the I/R-injured myocardium 24 hours after I/R. Deferasirox and CsA independently reduced the infarct size after I/R injury to a similar degree, and combination therapy with deferasirox and CsA synergistically reduced the infarct size (infarct area/area at risk; control treatment: 64±2%; deferasirox treatment: 48±3%; CsA treatment: 48±4%; deferasirox+CsA treatment: 37±3%), thereby ameliorating adverse cardiac remodeling on day 14 after I/R. Combination therapy with deferasirox and CsA may be a clinically feasible and effective therapeutic approach for limiting I/R injury and ameliorating adverse cardiac remodeling after myocardial infarction.

Patient preference for deferasirox film-coated versus dispersible tablet formulation: a sequential-design phase 2 study in patients with thalassemia.

Iron chelation therapy (ICT) is the mainstay of treatment in patients with thalassemia requiring blood transfusions. This phase 2 JUPITER study evaluated patient preference betweenfilm-coated tablet (FCT) and dispersible tablet (DT) in transfusion-dependent thalassemia (TDT) or non-TDT (NTDT) patients treated with both formulations in a sequential manner. The primary endpoint waspatient-reported preference for FCT over DT, while secondary outcomes included patient reported outcomes (PROs) evaluated by overall preference, and by age, thalassemia transfusion status, and previous ICT status. Out of183 patients screened, 140 and 136 patients completed the treatment periods 1 and 2 of the core study, respectively. At week48, themajority of patients preferred FCT over DT (90.3 vs. 7.5%; difference of percentage: 0.83 [95% confidence interval (CI), 0.75-0.89; P < 0.0001]). FCT scored better on secondary PROs and showed less severe gastrointestinal symptoms than DT, except in the change of modified Satisfaction with Iron Chelation Therapy (mSICT) preference scores, which were similar for both the formulations. Patients with TDT had stable ferritin levels, while it showed adownward trend up to week 48 in patients with NTDT on deferasirox treatment. Overall, 89.9% ofpatients reported ≥ 1 adverse event (AE), of which 20.3% experienced ≥ 1 serious AE. The most common treatment-emergent AEs were proteinuria, pyrexia, urine protein/creatinine ratio increase, diarrhea, upper respiratory tract infections, transaminase increase, and pharyngitis. Overall, this study reinforced the observations from theprevious study by showing a distinct patient preference for FCT over DT formulation and further supported the potential benefits oflife-long compliance with ICT.

TO STUDY EFFECTIVENESS OF DEFERASIROX, AN ORAL IRON CHELATOR IN BLOOD TRANSFUSION DEPENDENT PEDIATRIC THALASSEMIA PATIENTS

Background: Inblood transfusion related thalassemia patients, high iron state is observed because of regular blood transfusion. Our body has limited mechanism to excrete iron, excess of iron gets deposited in various organs causing their dysfunction. To prevent the complication associated with this iron overload use of iron chelators becomes important in management of such patients. Aims /Objectives: 1.To determine effectiveness of deferasirox, an oral iron chelator to decrease iron overload in reference to serum ferritin level in blood transfusion dependent pediatric thalassemia patients. 2.To determine effectiveness of deferasirox in reducing iron deposition induced organ damage. Methods: This is a hospital based retrospective observationalstudy conducted on 80 blood transfusion dependent thalassemia patients admitted in tertiary care hospital. Data was collected in pre-designed case record sheets after taking consent from parents. Results:in the present study the mean age was 7.12 years for females and 10.93 years for males. The mean of pre and post blood transfusion hemoglobin was significantly higher (7.07 and 10.76 respectively). The mean blood transfusion days are 26.33. Mean annual blood requirement is 198.99. Mean drop rate is 1.02. On comparing mean ferritin levels, there was a significant difference between baseline (711.81), start of deferasirox treatment (1271.71) and the end of 2nd dose increment of deferasirox (2076.11). The mean ferritin decreased significantly after starting deferasirox (from 1360.03 to 1271.71) by the end of1stdose increment (from 1832.41 to 1696.75) by the end of 2nd dose increment (from 2097.32 to 2076.11) , but when we compare mean ferritin after end of 2nddose increment of deferasirox (2076.11) with6 month back mean ferritin (2506) or current mean ferritin (2514.90) there is increase in ferritin.Mean blood transfusions at start of deferasirox is (11.025), at 1st dose increment is (26.13), at 2nd dose increment is (42.12).There were no organ complications seen with the present population at the end of the study Conclusion: from the results of our study, we state that using deferasirox as oral iron chelator in blood transfusion dependent pediatric thalassemia patients helps in reducing iron overload till we reach maximum dose of oral deferasirox but beyond that there is significant increase in serum ferritin level,thereby necessitating use of another iron chelator along with oral deferasirox(either deferoxamine, deferiprone or some new iron chelator),. Also in this study it is observed that there is no iron deposition related significant organ damage.

The Effect of Deferasirox Dose and Treatment Duration on Frequency of Proteinuria and Renal Functions in Patients with Thalassemia Major

The Effect of Deferasirox Dose and Treatment Duration on Frequency of Proteinuria and Renal Functions in Patients with Thalassemia Major

Effect of deferasirox on renal function in thalassemic children

Abstract Background: Iron-chelating therapy causes improvement in the life expectancy of thalassemic patients. Deferasirox (DFX) is an oral iron chelator with an established dose-dependent efficacy, though alteration of renal function has been observed in many studies. In the present study, we evaluated the effect of treatment with DFX on renal function. Materials and Methods: This quasi-experimental study was done in the Thalassemia Center of Bangladesh Shishu Hospital and Institute from June 2019 to July 2021, where 50 thalassemia major and E-β thalassemia children aged 2–18 years old were included. Blood urea nitrogen (BUN), serum creatinine, spot urinary protein creatinine ratio, spot urinary calcium creatinine ratio, and estimated glomerular filtration rate (eGFR) were measured. If renal functions were normal, DFX was started at a dose of 25 mg/kg/day. After 6 months of DFX treatment, the abovementioned investigations were repeated and analysis was done. The study variables were analyzed by paired t-test. P value &lt;0.05 was considered significant. Results: The mean age of the thalassemic children was 5.21 ± 1.72 years. Before treatment, mean serum creatinine was 39.78 ± 3.12 μmol/L, and after 6 months, serum creatinine was increased but not statistically significant. The mean value was 40.50 ± 3.39 μmol/L after 6 months (P value 0.071). There was no significant change of BUN. Initially, the mean BUN was 3.39 ± 0.76 mmol/L, and 6 months after treatment, it was 3.45 ± 0.70 mmol/L. Initially, the spot urinary protein creatinine ratio was 0.12 ± 0.04, and after 6 months, the mean value was 0.43 ± 0.24. it was significantly increased (P value &lt;0.001). Initially, the spot urinary calcium creatinine ratio was 0.068 ± 0.043, and after treatment, it was significantly raised. The mean value was 0.191 ± 0.168 (P value &lt;0.001). After 6 months of treatment with DFX, 35 patients developed mild proteinuria, and eight patients developed hypercalciuria. There was no significant change of eGFR before and after treatment. Conclusions: In this study, we got significant proteinuria and hypercalciuria but nonsignificant changes in serum creatinine, BUN, and eGFR.

Deferasirox alleviates DSS-induced ulcerative colitis in mice by inhibiting ferroptosis and improving intestinal microbiota

AimsUlcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) caused by multiple factors. Studies have shown that epithelial cell damage was associated with ferroptosis in UC. Therefore, our research focused on the effects and mechanism of iron chelator deferasirox in UC. Main methodsThe UC model was induced by 2.5 % dextran sulfate sodium salt (DSS) and administered with deferasirox (10 mg/kg) for 7 days. Histological pathologies, inflammatory response, ferrous iron contents, oxidative stress and ferroptosis regulators were determined. Intestinal microbiota alteration and short-chain fatty acids (SCFAs) production were analyzed through 16S rRNA gene sequencing and targeted metabolomics. Key findingsDeferasirox significantly relieved the DSS-induced UC in mice, as evidenced by weight loss, survival rate, colon length shortening disease activity index (DAI) score and histology score. Deferasirox treatment reduced the level of pro inflammatory cytokines (IL-1β, IL-6, TNF-α and INF-γ). Ferroptosis was induced in mice with UC, as evidenced by ferrous iron accumulation, increased ROS production, SOD and GSH depletion, decreased the expression of GPX-4 and FTH, accompanied by increased expression of TF. Deferasirox treatment strongly reversed the alterations caused by ferroptotic characteristics in DSS-induced mice. Moreover, deferasirox treatment reshaped the composition of intestinal microbiota. The results revealed the genera of norank_f__Muribaculaceae, Lachnospiraceae_NK4A136_group, Prevotellaceae_UCG-001, Odoribacter and Blautia were increased distinctly, while Escherichia-Shigella and Streptococcus were significantly decreased by deferasirox treatment. Targeted metabolomics analysis indicated the SCFAs production enhanced in deferasirox-treated mice. SignificanceOur results suggested that deferasirox could treat DSS-induced UC in mice by inhibiting ferroptosis and improving intestinal microbiota.

ATF4-activated parkin induction contributes to deferasirox-mediated cytoprotection in Parkinson's disease.

The E3 ubiquitin ligase parkin plays neuroprotective functions in the brain and the deficits of parkin's ligase function in Parkinson's disease (PD) is associated with reduced survival of dopaminergic neurons. Thus, compounds enhancing parkin expression have been developed as potential neuroprotective agents that prevent ongoing neurodegeneration in PD environments. Besides, iron chelators have been shown to have neuroprotective effects in diverse neurological disorders including PD. Although repression of iron accumulation and oxidative stress in brains has been implicated in their marked neuroprotective potential, molecular mechanisms of iron chelator's neuroprotective function are largely unexplored. Here, we show that the iron chelator deferasirox provides cytoprotection against oxidative stress through enhancing parkin expression under basal conditions. Parkin expression is required for cytoprotection against oxidative stress in SH-SY5Y cells with deferasirox treatment as confirmed by abolished deferasirox's cytoprotective effect after parkin knockdown by shRNA. Similar to the previously reported parkin inducing compound diaminodiphenyl sulfone, deferasirox-mediated parkin expression was induced by activation of the PERK-ATF4 pathway, which is associated with and stimulated by mild endoplasmic reticulum stress. The translational potential of deferasirox for PD treatment was further evaluated in cultured mouse dopaminergic neurons. There was a robust ATF4 activation and parkin expression in response to deferasirox treatment in dopaminergic neurons under basal conditions. Consequently, the enhanced parkin expression by deferasirox provided substantial neuroprotection against 6-hydroxydopamine-induced oxidative stress. Taken together, our study results revealed a novel mechanism through which an iron chelator, deferasirox induces neuroprotection. Since parkin function in the brain is compromised in PD and during aging, maintenance of parkin expression through the iron chelator treatment could be beneficial by increasing dopaminergic neuronal survival.

Effect of Iron Chelator on Liver Function in Beta Thalassemia Major Patients

Background: Due to Regular blood transfusions and Desferrioxamine therapy, beta-thalassemic patients can live for over 30 years. It is becoming increasingly common for liver diseases to cause mortality and morbidity in these patients. Chelation compliance has improved with the recent addition of the oral single-dose therapy Deferasirox (DFX). This study will investigate the impact of iron therapy on liver function tests in BMT patients. Methodology: The patients enrolled in the study were HBV negative and treated with DFO and DFX after BTM. The LFTs include alanine transferase, Albumin, serum bilirubin and aspartate transferase. Sixty patients with Beta-thalassemia were followed every six months for serum ferritin concentrations. Results: Therapy with Desferrioxamine significantly decrease serum ferritin levels inbeta-thalassemia patients and isconcerned with high reduction in serumalanine transaminase and serum aspartate transaminase. Albumin concentrations remain the same in DFX treatment. Association between serum ferritin levels ALT and AST levels were found. There is a negative correlation between serum ferritin concentration and ALT. Conclusion: Patients with Hepatitis negative having thalassemia with iron overload may have some liver function impairment. As a result of DFX treatment, AST, ALP and ALT levels were significantly reduced.

Evaluation of safety and efficacy of Deferoxamine compared with deferasirox in transfusion dependent beta thalassemia patients: a single center retrospective study

Purpose: The primary cause of mortality and morbidity in thalassemia major is iron overload. The objective of this study was to compare the safety and efficacy of deferoxamine and deferasirox in transfusion dependent beta thalassemia patients. Methods: A retrospective observational study was conducted among 178 patients. Patients were divided into two groups, deferoxamine group (90 patients) and deferasirox group (88 patients). Standardized data collection form was used to collect data. Clinical and demographic characteristics of patients were recorded by checking medical records. The collected data was analyzed using SPSS software. Findings: It was revealed that both drugs, deferoxamine and deferasirox were effective and safe in transfusion dependent beta thalassemic patients. Both are efficacious in reducing serum ferritin level. Their laboratory parameters were within clinically accepted range. Conclusion: Deferoxamine and deferasirox treatment have equal efficacy and safety for transfusion dependent beta thalassemia population. Therefore, oral deferasirox is recommended for more compliance and convenience.

Deferasirox Induces Apoptosis in Mantle Cell Lymphoma in a Mechanism Involving Cyclin-D1, p53 and the Ribonucleotide Reductase

Mantle cell lymphoma (MCL) is a difficult to treat B-cell malignancy characterized by a rapid progressive course and poor prognosis. Despite advances in conventional and novel agents such as bortezomib, lenalidomide and ibrutinib, many MCL patients are still subject to rapid relapses of the disease, responsible for the relatively short overall survival. MCL is characterized by the t(11,14) translocation, resulting in cyclin-D1 (CD1) overexpression and dysregulation of the cell cycle. Recently, it has been demonstrated that depletion of CD1 results in cell cycle arrest, apoptosis and cell death of MCL cells thus labeling CD1 as a therapeutic target of this aggressive malignancy. Accumulating findings indicate that not only overexpressed CD1 but also deregulated signaling pathways such as PI3K/AKT/mTOR and Wnt are accountable for the tumorigenesis of MCL and for the maintenance of its proliferative and survival capacity. We thus believe that MCL treatment should target multiple deregulated signaling pathways and key molecules. Iron chelators have emerged as a novel strategy to treat tumors due to their capacity to target a multitude of key molecules, signaling pathways and cellular processes. Yet, the application of common iron chelators is limited due to their low bioavailability and high toxicities. Deferasirox (DFX), a clinically approved iron chelator applied for the treatment of iron overload, in contrast to the majority of iron chelators, is highly bioavailable and exhibits little to no side effects. To date, DFX is reported as being an orally effective antitumor agent against solid tumors by various mechanisms. In our project, we examined the in vitro impact of DFX on three MCL cell lines; Jeko-1, REC-1 and Z138; aiming thereby to resolve its molecular mode of action. DFX inhibited the growth of the MCL cell lines with 50% inhibitory concentrations (IC50) of 8.07±1.08µM, 1.8±1.03µM and 1.52±1.54µM for Jeko-1, REC-1 and Z138 cell lines, respectively. Moreover, we demonstrated that DFX treatment trigged a rapid and intense (~2-fold) production of reactive oxygen species (ROS), induced severe DNA damage and arrested cells at the G1 phase within 6 hrs. Ultimately, a 72h treatment of 10µM DFX led to apoptosis in 60% to 86% of the MCL cells. Most importantly, we found DFX to substantially reduce CD1 protein levels in a dose- and time-dependent manner. The depletion of CD1 levels was accompanied with its phosphorylation at Thr-286 (pCD1), a phosphorylation known to sentence CD1 to proteasomal degradation. In agreement with previous studies that have shown a correlation between ROS induction, CD1-phosphorylation, CD1 depletion and DNA damage, we found CD1 levels to negatively correlate with increasing DNA damage levels following DFX treatment.Interestingly, the efficacy of DFX treatment was dependent on the p53-status of the respective cell line. The wild-type p53 expressing lines, REC-1 and Z138, were found to be ~5-fold more sensitive to DFX than the p53 negative Jeko-1 cell line. In an attempt to understand this intriguing finding, we found DFX treatment to post-translationally elevate and stabilize p53 levels, most likely by depleting the intracellular heme pool which serves as a negative p53-regulator. Furthermore, we showed that DFX plays an important role in the attenuation of the iron dependent ribonucleotide reductase enzyme (RR); the rate limiting enzyme in dNTP biosynthesis and thus the key enzyme in DNA synthesis, cell cycle regulation and proliferation. DFX inhibited the enzymatic activity of RR with an IC50 of ~25 µM; which is ~20-fold more effective than other established inhibitors such as deferoxamine.In conclusion and pending further analysis, we demonstrated a potent impact of DFX on MCL cells. The vigorous anti-tumoral activity of DFX is most likely mediated via its ability to induce oxidative stress, to inhibit the RR enzyme and to eliminate the main oncogene in MCL pathogenesis; CD1. The depleting of intracellular iron/heme pools and the modulation of p53 only intensify the effect of DFX. The ability to inhibit the RR activity qualifies DFX as a sensitizer to existing DNA damaging radio- and chemotherapy options of MCL. DFX possesses the unique capacity to affect a multitude of cellular mechanisms in an auto-potentiating manner that propose this clinically established molecule as a potential therapeutic option for mantle cell lymphoma. DisclosuresNo relevant conflicts of interest to declare.

Deferasirox Boosts Hematopoietic Recovery after ALLO-Sct

The attainment of transfusion independence after transplant is sometimes hampered by a combination of factors, ranging from infections to the need of combined therapy for clinical complications, as well as control of GVHD. Iron overload is frequently observed in hematological patients before and after hematopoietic stem cell transplantation (HSCT). Whereas several reports have focused on iron overload before transplant, up to now, this is the only report that show full recovery of hematopoiesis and correlate this to deferasirox chelation performed on this particular subset of patients. We report on 19 patients, transplanted for hematological diseases (17 acute leukemia, 1 aplastic anemia, 1 multiple myeloma) heavily transfused before transplant that, considering the iron overload, were treated with deferasirox after HSCT. Before starting deferasirox, the patients were fully engrafted and in complete remission, although transfusion dependent, and with incomplete hematological reconstitution after allogeneic HSCT. Patients were selected according to the following inclusion criteria: 1) transfused pre-transplant with more than 20 RBC units; 2) incomplete hematological recovery; 3) transfusion-dependence; 4) serum ferritin > 1000 ng/mL; 5) normal creatinine value. The workup for other aetiologies resulted negative. All patients received an initial dose of deferasirox 10 mg/kg/day, later adjusted according to side effects. All patients experienced an increase in hemoglobin levels, with a reduction in the frequency of RBC transfusions, followed by transfusion independence (median time: 24 days from the first dose of deferasirox). In addition, it was promptly (median time: 27 days) associated with hematological improvement, with sustained values and no further platelet support or growth factors administration. No relevant modifications with immunosuppressive or myelosuppressive drugs were made during deferasirox treatment. Deferasirox was well tolerated. Basing on our results, we think that deferasirox determined stimulatory, and/or depressive effects on hematopoiesis after allo-HSCT. In conclusion, this clinical experience raises the possibility of a potential additive benefit on hematopoiesis after transplant following iron chelation therapy with oral deferasirox. Further long term studies, in larger cohorts of patients are needed to confirm these data and design an efficient strategy to reduce iron loading after transplant. Acknowledgments: supported in part by AIL Pesaro Onlus. DisclosuresIsidori:Lundbeck: Consultancy, Honoraria.

Is Deferasirox Safe and Effective in Very Elderly Patients (> 75 Years) with Myelodysplastic Syndromes and Transfusional Iron Overload?

Background Deferasirox (DFX) is an oral iron chelator widely employed in the clinical practice to reduce iron overload in patients with myelodysplastic syndromes (MDS); at present, however, there is no specific report on the treatment with DFX in very elderly patients, who represent an important fraction of MDS subjectsAim To appreciate safety and efficacy of DFX treatment in very elderly MDS patients, comparing those treated when older than 75 years with younger subjects as to efficacy and toxicityMethods We evaluated a retrospective cohort of 150 consecutive MDS patients of any age followed in 9 hematological Centers in Italy: sixty-eight patients were older than 75 years and 82 younger when DFX was started. The main features at diagnosis according to age at baseline of DFX treatment are reported in the Table 1: younger patients had a higher rate of high-risk MDS, with lower PLTs values and higher ferritin levels at diagnosis, before any transfusion supportResults The main features at baseline of DFX treatment according to age are reported in the Table 2. Median starting DFX dose was 1,000 mg/day in both groups (p=0.545). As to toxicity, 26/82 patients (31.7%) in younger group vs 32/68 (47.0%) in older group (p=0.061) presented grade ≥ 2 WHO adverse events: a temporary discontinuation of DFX treatment due to toxicity was needed in 16/82 (19.5%) younger patients compared to 15/68 (22.0%) older patients (p=0.552), while a permanent discontinuation of DFX due to toxicity was needed in 8/82 (9.7%) younger patients compared to 13/68 (19.1%) older subjects, with a trend of significance (p=0.056). In both groups, the median values of ferritin remained stable between the baseline and the 12th month (from 1843 to 1858 ng/ml in younger patients; from 1421 to 1413 ng/ml in older patients), notwithstanding the stable transfusion burden in the same period: in the figure 1, median values of ferritin are shown at different time-points during the 1st year of treatment. Median overall survival from DFX start was similar in the 2 groups [62.0 months (95%CI 31.4 - 92.6) in younger patients vs 52.8 months (95%CI 29.3 - 76.2) in older patients, p=0.324)Conclusions Treatment with DFX is feasible and effective also in very elderly patients with MDS and iron overload, with results and toxicity quite similar to younger patients. [Display omitted] DisclosuresGalimberti:Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Breccia:Pfizer: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Incyte: Consultancy. Foà:Amgen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

Pharmacological and clinical evaluation of deferasirox formulations for treatment tailoring

Deferasirox (DFX) is the newest among three different chelators available to treat iron overload in iron-loading anaemias, firstly released as Dispersible Tablets (DT) and more recently replaced by Film-Coated Tablets (FCT). In this retrospective observational study, pharmacokinetics, pharmacodynamics, and safety features of DFX treatment were analyzed in 74 patients that took both formulations subsequently under clinical practice conditions. Bioavailability of DFX FCT compared to DT resulted higher than expected [Cmax: 99.5 (FCT) and 69.7 (DT) μMol/L; AUC: 1278 (FCT) and 846 (DT), P < 0.0001]. DFX FCT was also superior in scalability among doses. After one year of treatment for each formulation, no differences were observed between the treatments in the overall iron overload levels; however, DFX FCT but not DT showed a significant dose–response correlation [Spearman r (dose-serum ferritin variation): − 0.54, P < 0.0001]. Despite being administered at different dosages, the long-term safety profile was not different between formulations: a significant increase in renal impairment risk was observed for both treatments and it was reversible under strict monitoring (P < 0.002). Altogether, these data constitute a comprehensive comparison of DFX formulations in thalassaemia and other iron-loading anaemias, confirming the effectiveness and safety characteristics of DFX and its applicability for treatment tailoring.

On-demand treatment with the iron chelator deferasirox is ineffective in preventing blood-induced joint damage in haemophilic mice.

IntroductionEarly intervention in the devastating process of haemophilic arthropathy (HA) is highly desirable, but no disease‐modifying therapy is currently available. Considering the pivotal role of iron in the development of HA, iron chelation is considered a promising therapeutic approach. A previous study in haemophilic mice demonstrated that treatment with the iron chelator deferasirox (DFX) 8 weeks before joint bleed induction, attenuated cartilage damage upon blood exposure. However, in haemophilia patients this approach is not opportune given the unpredictable occurrence of hemarthroses.AimTo evaluate the effectiveness of on‐demand DFX treatment, initiated immediately after joint bleed induction.MethodsA joint bleed was induced in 66 factor VIII‐deficient mice by infra‐patellar needle puncture. Mice were randomly assigned to treatment with either placebo (drinking water) or DFX (dissolved in drinking water) throughout the study. Five weeks after joint bleed induction, inflammation and cartilage damage were assessed histologically. Joints of ten bleed naive haemophilic mice served as controls.ResultsA joint bleed resulted in significant inflammation and cartilage damage in the blood‐exposed joint compared with those of control animals, in both the placebo and DFX group (all p = <.05). No differences in tibiofemoral or patellar inflammation (p = .305 and p = .787, respectively) nor cartilage damage (p = .265 and p = .802, respectively) were found between the blood‐exposed joints of both treatment groups.ConclusionOn‐demand treatment with DFX does not prevent joint damage following blood exposure in haemophilic mice. DFX seems unable to reach the joint in time to exert its effect before the irreversible harmful process is initiated.

Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients.

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

Changes of liver transaminases levels during one year follow up of Deferasirox treatment in children with β-thalassemia major

Objectives: Abnormal liver function tests lead to interruptions of Deferasirox therapy. The aim of this study is to determine the changes in liver transaminases levels in pediatric patients with β -thalassemia major during one year follow up of Deferasirox treatment.&#x0D; Material and methods: This study was conducted at Ibn Al Atheer center of thalassemia, Mosul city, Iraq during the period from 3rd of February 2013 till 2nd of February 2014. Seventy one pediatric patients with β -thalassemia major were included in the study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured every 4 weeks after starting Deferasirox therapy dose of 30 mg /kg/day for one year.&#x0D; Results: In comparison to mean baseline ALT values, there were significant elevations of mean ALT values in each of the subsequent 4-weekly interval readingsafter Deferasirox therapy. There was nearly eleven times relative risk of having ALT ≥ 5 upper normal level (UNL) in patient with abnormal baseline ALT (Odd ratio 10.96,95% Confidence Interval: lower 2.05, upper 58.58). During a year of study, Deferasirox therapy was associated withALT readings of ≥ 5UNL in 22(31%) of pediatric β-thalassemia patients and that elevation lasted for 4 weeks in 95.5% of patients.&#x0D; Conclusions: Elevated ALT of ≥ 5UNL after Deferasirox therapy was short- lived, and lasted for 4 weeks in 95.5% of patients. It is advisable to start Deferasirox therapy at a dose of 30 mg /kg / day when baseline ALT level is normal.&#x0D; Bangladesh Journal of Medical Science Vol.19(3) 2020 p.453-457

The effect of deferasirox on endocrine complications in children with thalassemia

Endocrine system dysfunctions are the significant complications of excessive iron overload in beta thalassemia patients. The aim of this study was to evaluate the long-term effect of chelation with deferasirox on endocrine complications. The study group consisted of children with beta thalassemia who had been evaluated for the growth and pubertal development, bone metabolism, thyroid/parathyroid functions, glucose metabolism dysfunctions in the department of pediatric hematology of Ankara Dışkapı Child Health and Diseases Hematology Oncology Training And Research Hospital between 2009-2011 and reevaluated after deferasirox chelation therapy in 2018. Thirty-one transfusion dependent beta-thalassemia patients were enrolled for the study. Seventeen (54.8%) patients were male and the mean age was 16.9 ± 3.8 (9-23) years. Splenectomy was performed in 11 patients (35.5%). In the initial evaluation, 26 patients (84%) received deferoxamine and/or deferiprone and five (17%) patients received deferasirox as a chelator; in the final evaluation all patients were receiving deferasirox. The mean duration of deferasirox treatment was 5.9 ± 2.02 years (1-10 years). Of the 26 patients who had endocrine complications between 2009-2011, 18 were recovered. In the final evaluation, eight patients (25%) developed new endocrinopathies. The frequency of endocrine complications seen before the deferasirox treatment (83%) was higher than the frequency of complications while receiving deferasirox treatment (25.8%) (p < 0,05). In this study, it was determined that both existing endocrine abnormalities were reduced and recent developed problems were less likely with long-term deferasirox treatment in thalassemia patients.

Genome-wide transcriptomics leads to the identification of deregulated genes after deferasirox therapy in low-risk MDS patients.

The iron chelator deferasirox is widely used in patients with iron overload. Patients with low-grade myelodysplastic syndromes (MDS) get transfusion dependency and need to be treated with deferasirox to avoid iron overload. Moreover, in some patients an increase in both erythroid and platelets have been observed after deferasirox therapy. However, the mechanisms involved in these clinical findings are poorly understood. The aim of this work was to analyze, in patients treated with deferasirox, the changes in the gene-expression profile after receiving the treatment. A total of 15 patients with the diagnosis of low-grade MDS were studied. Microarrays were carried out in RNA from peripheral blood before and after 14 weeks of deferasirox therapy. Changes in 1457 genes and 54 miRNAs were observed: deferasirox induced the downregulation of genes related to the Nf kB pathway leading of an overall inactivation of this pathway. In addition, the iron chelator also downregulated gamma interferon. Altogether these changes could be related to the improvement of erythroid response observed in these patients after therapy. Moreover, the inhibition of NFE2L2/NRF2, which was predicted in silico, could be playing a critical role in the reduction of reactive oxygen species (ROS). Of note, miR-125b, overexpressed after deferasirox treatment, could be involved in the reduced inflammation and increased hematopoiesis observed in the patients after treatment. In summary this study shows, for the first time, the mechanisms that could be governing deferasirox impact in vivo.