Deferasirox Research Articles

Comparative analysis of deferasirox and deferiprone iron chelator on the growth pattern of Bengali β-thalassemia major children of West Bengal, India

Background: Ineffective erythropoiesis and excessive red blood cell transfusions are the major source of iron overload in case of thalassemia major patients. It is mainly accountable for the growth retardation, morbidity, and mortality in patients with beta thalassemia major. The availability of effective iron chelators and proper knowledge regarding the iron toxicity can significantly improve the rate of survival in thalassemia patients. Aims and Objectives: The study was done to compare the efficacy and safety of the deferiprone (DFP) with deferasirox (DFX) in regulating the growth pattern among the thalassemia major patients. Materials and Methods: The height and weight were plotted on the World Health Organization recommended growth charts for 0–5 years and 5–19 years old boys and girls during the follow-up visits. Comparison between the role of DFP versus DFX was evaluated by t-test. Results: There is no statistically significant (P=0.11 in males and P=0.06 in females) difference between DFP versus DFX while considering height velocity. A similar observation was obtained in case of weight velocity (P=0.78 in males and P=0.56 in females) and basal metabolic index (BMI) index (P=0.44 in males and P=0.53 in females). Conclusion: Both DFX and DFP have no significant correlation in regulating the height, weight, and BMI of thalassemia children.

Alteration of osteoclast activity in childhood cancer survivors: Role of iron and of CB2/TRPV1 receptors.

Childhood cancer survivors (CCS) are predisposed to the onset of osteoporosis (OP). It is known that iron overload induces osteoclasts (OCs) overactivity and that the iron chelator Deferasirox (DFX) can counteract it. The Cannabinoid Receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for OP. In this study we isolated OCs from peripheral blood of 20 CCS and investigated osteoclast biomarkers expression and iron metabolism evaluating iron release by OCs and the expression of several molecules involved in its regulation. Moreover, we analyzed the effects of CB2 and TRPV1 stimulation in combination with DFX on osteoclast activity and iron metabolism. We observed, for the first time, an osteoclast hyperactivation in CCS suggesting a role for iron in its development. Moreover, we confirmed the well-known role of CB2 and TRPV1 receptors in bone metabolism, suggesting the receptors as possible key biomarkers of bone damage. Moreover, we demonstrated a promising synergism between pharmacological compounds, stimulating CB2 or inhibiting/desensitizing TRPV1 and DFX, in counteracting osteoclast overactivity in CCS to improve their quality of life.

Iron chelator deferasirox inhibits NF-κB activity in hepatoma cells and changes sorafenib-induced programmed cell deaths

ObjectiveThe improvements of antitumor effects and tolerability on chemotherapy for advanced hepatocellular carcinoma (HCC) are warranted. Here, we aimed to elucidate the mechanism of the combining effect of tyrosine kinase inhibitor sorafenib (SOR) and iron chelator deferasirox (DFX) in human hepatoma cell lines, HepG2 and Huh-7. MethodsThe types of programmed cell deaths (PCDs); necrosis/necroptosis and apoptosis, were evaluated by flow cytometry and fluorescent microscopy. Human cleaved caspase-3 was analyzed by ELISA for apoptosis. GSH assay was used for ferroptosis. PCDs inhibition was analyzed by adding apoptosis inhibitor Z-VAD-FMK, ferroptosis inhibitor ferrostatin-1, necroptosis inhibitor necrosulfonamide, respectively. The expression of NF-κB was quantified by Western blotting. ResultsIn SOR monotherapy, cleaved caspase-3 expression was increased in all concentrations, confirming the result that SOR induces apoptosis. In SOR monotherapy, GSH/GSSG ratio was decreased on concentration-dependent, showing that SOR also induced ferroptosis. Lipid Peroxidation caused by SOR, corresponding to ferroptosis, was suppressed by DFX. In fluorescence microscopy of SOR monotherapy, apoptosis was observed at a constant rate on all concentrations, while necroptosis and ferroptosis were increased on high concentration. In sorafenib and deferasirox combinations, sub G1 phase increased additively. In SOR and DFX combinations, the cytotoxic effects were not suppressed by ferrostatin-1, but suppressed by Z-VAD-FMK and necrosulfonamide. In each monotherapy, and SOR + DFX combinations, the expression of NF-κB in nucleus was suppressed. Regarding PCD by SOR and DFX combination, ferroptosis was suppressed and both apoptosis and necroptosis became dominant. ConclusionSuppression of NF-κB is possibly involved in the effect of DFX. As a result, SOR and DFX combination showed additive antitumor effects for HCC through the mechanism of programed cell deaths and NF-kB signal modification.

Upregulation of MHC-I and downregulation of PD-L1 expression by doxorubicin and deferasirox codelivered liposomal nanoparticles for chemoimmunotherapy of melanoma

Tumor immunotherapy is a promising strategy to activate the immune system and eliminate tumors. Major histocompatibility complex I (MHC-I) is usually applied to potentiate antigen presentation, but it is associated with upregulation of programmed death ligand 1 (PD-L1) expression, which is unfavorable for activation of immune responses. Moreover, poor permeability of various therapeutic antibodies results in the limited immune response rates of most patients. It is necessary to develop combined small molecule drug delivery systems for simultaneous upregulation of MHC-I expression and downregulation of PD-L1 expression, promoting effective tumor treatment. A moderate dose of doxorubicin hydrochloride (DOX) can induce upregulation of MHC-I expression, while deferasirox (DFX) can inhibit the PI3K-Akt pathway, which potentially downregulates PD-L1 expression. In the present study, we designed a pH-sensitive liposome to incorporate DOX in the hydrophilic cavity and embed DFX in the hydrophobic shell, forming a dual delivery system (DOX-DFXL). In a B16F10 melanoma-bearing mouse model, DOX and DFX were released in acidic tumor microenvironment, which further lead to enhanced antigen presentation and infiltration of T cells into tumor tissues as a result of tumor remission. This codelivery system holds great potential for clinical applications of tumor immunotherapy.

Efektivitas Deferasirox pada Pasien Thalasemia Mayor: Artikel Review

Thalassemia is a heterogeneous grouping of genetic disorders resulting from decreased synthesis of the alpha or beta chains of hemoglobin. Anemia and iron overload are the main causes of morbidity and mortality due to thalassemia disease. Iron chelation has improved the survival and quality of life of patients with thalassemia major. Deferasirox (DFX) was developed as monotherapy for the treatment of transfusion iron overload. Search data in this literature study using an electronic database, namely Science Direct, Pubmed with the keywords thalassemia, deferasirox and efficacy. The search results obtained 1015 articles and 5 articles that matched the inclusion and exclusion criteria. The total patients in this study were 410 people from 5 countries. The results of the review article found that deferasirox was effective in reducing iron in the body as seen from the LIC (Liver Iron Concentration), T2* heart and serum ferritin in patients with thalassemia major.

Beta-thalassaemia major: Prevalence, risk factors and clinical consequences of hypercalciuria.

SummaryRegular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β‐thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24‐h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24‐h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones.

Dose of deferasirox correlates with its effects, which differ between low-risk myelodysplastic syndrome and aplastic anaemia.

Patients with low-risk myelodysplastic syndrome (MDS) and aplastic anaemia (AA) often need transfusions, which may accelerate iron overload. The aim of this study was to evaluate the efficacy, safety and dose-effect relationships of deferasirox (DFX) in patients with low-risk MDS and AA who were refractory to regular treatment in a real-world setting. Patient data were recorded, and dose-effect relationships of DFX were calculated after the first 6months. Total annual exposure to DFX was calculated after 12 months and expressed as the accumulated exposure time at a dosage of 20 mg/kg/day. Sixty-one patients with low-risk MDS and 51 with AA were enrolled. The minimum dosage of DFX needed for a significant serum ferritin (SF) decrease was 20 mg/kg/day at 6months, and the minimum accumulation of DFX had to reach 9months at 20 mg/kg/day by 12 months for patients with low-risk MDS. For patients with AA, the minimum dosage was 10mg/kg/day at 6months, and the minimum accumulation had to reach 3months at 20 mg/kg/day by 12 months. With the same exposure, significant improvements in haematological parameters were also observed in AA. Lower liver enzymes compared with baseline were observed. Gastrointestinal disorders and elevated serum creatinine were the most common side effects. Higher exposure to DFX correlated with longer overall survival (OS). A significant decrease in SF and an improvement in haematologic parameters, organ function and even OS can be achieved if the accumulated DFX dose reaches a certain level. Patients with low-risk MDS need a higher dose than those with AA.

Switching indication of PEGylated lipid nanocapsules-loaded with rolapitant and deferasirox against breast cancer: Enhanced in-vitro and in-vivo cytotoxicity

Breast cancer (BC) is considered the leading cause of mortality and morbidity among adult women worldwide, and it is associated with many genetic or hormonal factors. Despite the advanced therapeutic and theranostic strategies for BC treatment, cancer metastasis and relapse are often observed among patients which lead to therapeutic failure. Accordingly, among the repositioned medication against BC proliferation is neurokinin receptor antagonists and iron chelating agents especially rolapitant HCl (RP) and deferasirox (DFO), respectively. However, RP and DFO are classified as class II with low aqueous solubility. Both drugs were nanoformulated into PEGylated lipid nanocapsules (LNCs) for enhancing their aqueous solubility and augmenting their efficacy. RP-LNCs, DFO-LNCs and their combinations were evaluated according to particle size (PS), zeta potential, polydispersity index (PDI) and surface morphology. Importantly, the antitumor effect of these novel molecules and their nanoforms was evaluated against the suppression of Ehrlich Ascites tumor model using female mice. Results revealed that RP-LNCs, DFO-LNCs and RP/DFO-LNCs exerted PS from 45.23 ± 3.54 to 60.1 ± 3.32 nm with PDI around 0.20 which indicates homogenous particles distribution. Also, RP-LNCs, DFO-LNCs and RP/DFO-LNCs displayed surface charges of +16.6 ± 6.9, −13.3 ± 5.82 and − 20.2 ± 5.40 mV, respectively. The obtained LNCs conferred a high potent cytotoxic effect against MCF7 cancer cells as compared to parent drugs, with IC50 of 10.86 ± 0.89, 3.34 ± 0.99 and 2.24 ± 0.97 μg/mL for RP-LNCs, DFO-LNCs and RP/DFO-LNCs, respectively. The in-vivo pharmacodynamics effect of the developed nano-formulations showed superior antitumor effect for the individual drugs rather than their combinations as compared to the control group. The current study confirmed the potential of RP and DFO nanoforms as promising therapeutic agents for BC treatment.

P1511: EFFICACY AND SAFETY OF COMBINATION IRON CHELATION THERAPY WITH DEFERIPRONE AND DEFERASIROX IN PATIENTS WITH Β-THALASSEMIA MAJOR: A SYSTEMATIC LITERATURE REVIEW

Background: Iron overload can occur in patients with thalassemia syndromes because of hyperabsorption and/or frequent blood transfusions. Currently, 3 iron chelators are approved for clinical use: deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX). Combination iron chelation therapy may be prescribed for patients who do not adequately respond to monotherapy, have increased heart and/or liver iron overload, or have dose-dependent toxicity. It is important to optimize chelation to reduce iron-associated morbidity and early mortality and to improve quality of life. Oral DFP is typically administered as a monotherapy or in combination with DFO or DFX. Combination therapy was approved for clinical use by the European Medicines Agency in 2016; additionally, a recent British Society for Haematology guideline states that DFP+DFX is a highly effective combination therapy, although the safety and efficacy of DFX in combination with other iron chelators is not well established. Aims: A systematic literature review was conducted to evaluate the efficacy and safety profile of combination chelation therapy with DFP+DFX in patients with transfusion dependent β-thalassemia major (TDT). Methods: A systematic search was performed of the Embase and MEDLINE databases to identify trials related to the use of combination iron chelation therapy (DFP+DFX) in patients with TDT. The literature search was conducted in May 2021 and was not restricted to a specific start date. The search strings were established by logical association of appropriate words and MESH terms. The publications were screened based on a priori exclusion and inclusion criteria (eg, case-report exclusion). Results: Eight clinical study publications (7 prospective, 1 retrospective) of 1725 screened articles assessed the DFP+DFX combination for a total of 181 patients (Table). One publication was a pharmacokinetic (PK) study. Of the 7 studies, 6 reported a consistent reduction in at least 1 of the 3 studied endpoints (serum ferritin, liver, and cardiac iron). The PK study reported an additive effect in the total iron excretion in comparison with monotherapy. The adverse events reported with DFP+DFX were consistent with what has previously been reported for DFP or DFX monotherapy; no new adverse events were observed. The most common adverse events across the 7 studies included gastrointestinal symptoms, elevation in alanine aminotransferase and/or aspartate aminotransferase, arthralgia or joint symptoms, an increase in creatinine levels, proteinuria, and red-colored urine. The numbers of patients reported with neutropenia and thrombocytopenia were low (neutropenia, n=7 patients; thrombocytopenia, n=8 patients); agranulocytosis was not observed. Two studies reported serious adverse events, of which 1 (acute cholecystitis) was related to treatment. Image:Summary/Conclusion: This systematic literature review suggests that DFP+DFX combination iron chelation therapy can be a highly effective therapeutic option for improving iron overload, with an acceptable tolerability profile. This review supports the safety and efficacy of the combination, as approved by the EMA. Limitations of this analysis include small sample size and nonrandomization in most studies.

P1555: IRON CHELATION THERAPY IN CONGENITAL HEMOLYTIC ANEMIAS: AN ITALIAN SINGLE CENTER STUDY

Background: Congenital hemolytic anemias (CHAs) can be associated with iron overload due to chronic hemolysis, ineffective erythropoiesis and, in some cases, red blood cell transfusions. Because of the rarity of these conditions, the appropriate management of iron chelation is poorly known and mainly based on thalassemia experience. Aims: To evaluate frequency, duration, efficacy and tolerability of iron chelation in patients with CHAs followed at our reference center. Methods: Clinical and laboratory data were retrospectively collected from patients who had documented history of iron chelation. Data were collected at time of diagnosis, at time of starting chelation and at variable times from treatment beginning. Follow-up data were censored at February 1st 2022. Results: 206 patients were retrospectively reviewed (151 with membrane defects, 31 with enzyme defects and 24 with congenital dyserythropoietic anemias – CDAs, Table 1). Twenty-six patients (13%) received iron chelation, mostly those with enzyme defects (35%) or CDAs (38%); at variance, only 4% of patients with membrane defects required chelation (p < 0.0001). Transfusion status showed that 31% of patients had history of transfusion-dependence (TD) (5 with Pyruvate kynase deficiency and 3 CDAs), 38% had received occasional transfusions and 31% had never received transfusions. Iron chelator was parenteral deferoxamine (DFA) or oral deferasirox (DFX), with a median daily dose of 573 mg for DFA and 584 mg for DFX. Median duration of treatment was 91 months with a wide range (3 – 372), including patients who received intermittent dosing (42%) and those on continuous chelation (58%). Concerning efficacy, median variation of serum ferritin from baseline was -51%, ranging from -94% to +6% (the latter in a patient who received a suboptimal dose). Overall, 64% of evaluable patients reduced ferritin below 500 ng/mL. Notably, a 33 year-old woman affected by CDA type II, with history of transfusion dependence since birth to age 9 y/o (time of splenectomy), developed cardiac iron overload with a cardiogenic shock. After a 4-year course of DFA, laboratory and imaging tests for iron overload markedly improved and her cardiac function recovered. Regarding toxicity, 5 out of 22 (23%) patients reported reversible renal (n = 2) and gastrointestinal adverse events (n = 2); one patient developed a non-fatal anaphylactic shock, leading to switch to a different chelator (from DFA to DFX). Image:Summary/Conclusion: Iron chelation was required in 13% of patients with CHAs, mostly among CDAs and enzyme defects, independently from transfusion requirements. It allowed a reduction of iron parameters in about 2/3 of cases with a good tolerability.

P1558: EARLY-START DEFERIPRONE IN INFANTS/YOUNG CHILDREN WITH TRANSFUSION-DEPENDENT BETA THALASSEMIA: EVIDENCE FOR IRON SHUTTLING TO TRANSFERRIN—RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL (START)

Background: Children with transfusion-dependent beta thalassemia will develop iron overload unless treated with an iron chelator such as deferiprone (DFP), deferasirox (DFX), or deferoxamine (DFO). Current practice delays chelation therapy until patients reach the iron overload criteria of serum ferritin (SF) levels ≥1000 µg/L or >10 transfusions. This “late-start” strategy was thought to minimize toxicity risks of iron depletion from biological stores or iron-bound proteins, such as transferrin, observed during “early-start” studies with DFO. This delay may increase the risk of iron overload toxicities later in life due to labile iron accumulation in organs difficult to reach with chelation. DFP is a membrane-permeable iron chelator with a lower iron affinity (pFe3+=19.3) than DFO (pFe3+=26.6), DFX (pFe3+=23.5), or transferrin (pFe3+=22.3). These pharmacological properties suggest “early-start” DFP could reduce the risks/toxicities associated with early iron overload and iron depletion by shuttling labile iron to transferrin. Previously, we reported that “early-start” DFP can be safely initiated in infants and young children with beta-thalassemia (START study NCT03591575) and maintain subthreshold SF levels in significantly more patients than placebo for up to 12 months. Aims: To evaluate the ability of “early-start” DFP to shuttle iron to transferrin in infants and young children with transfusion-dependent beta thalassemia using transferrin-saturation (TSAT) measurements from the START study. Methods: Infants or children with beta thalassemia who received ≥2 blood transfusions and had SF levels between 200–600 μg/L were randomly assigned 1:1 to DFP or placebo. Double-blinding continued until study end. Treatment continued until SF levels were ≥1000 μg/L at 2 consecutive visits (SF threshold) or 12 months. Patients started at 25 mg/kg/d DFP, escalated to 50 mg/kg/d DFP, with some to 75 mg/kg/d DFP, depending on iron load. The efficacy endpoint included imputation of % patients not reaching the SF threshold each month. DFP’s ability to shuttle iron to transferrin was evaluated at each month by comparing: 1) proportion of patients with ≥60% TSAT and 2) mean TSAT levels for DFP vs placebo groups. All iron measured in serum is total bound iron, which is the basis for calculating TSAT. The patient’s parent or legal guardian provided written informed consent before any study intervention. Results: Mean (SD) age was 3.0 (2.4) and 2.6 (1.7) years in the DFP (n=32; 63% male) and placebo (n=32; 66% male) groups, respectively. At month 12, 66% of patients receiving DFP remained below the SF threshold versus 39% of patients receiving placebo (p=0.045). Significantly more patients had TSAT ≥60% early with DFP than placebo at months 3–6 (each p<0.05); range: DFP 56%–66%, placebo 16%–34%. Similarly, mean TSAT levels with DFP were significantly higher than with placebo at months 3, 4, 6, 9, and 11 (each p<0.05); range: DFP 60%–69%, placebo 41%–55%. At 12 months, no DFP-treated patients were iron-depleted or reported iron depletion-associated adverse events (AEs). There were no significant differences between DFP and placebo in number of AEs (p=1.00), serious AEs (p=0.43), or AEs possibly related to DFP (p=1.00). Summary/Conclusion: Early-start DFP chelation therapy initiated before reaching current iron-load criteria was safe and efficacious in preventing iron overload in most transfusion-dependent children with beta thalassemia. START provides the first clinical evidence supporting preclinical studies that DFP can shuttle iron from labile pools to transferrin.

Deferasirox shows inhibition activity against cervical cancer in vitro and in vivo

ObjectiveIron depletion may be a novel therapeutic strategy for cancer. This study aimed to assess the inhibition effects of deferasirox (DFX), an oral iron chelator, on cervical cancer. MethodsIn this study, we performed immunohistochemical analysis, enzyme-linked immunoassay, cell viability and invasive ability assay, cell cycle and apoptosis analysis, protein expression investigation, molecular mechanism investigation, and in vivo murine xenograft model to evaluate the impact of DFX on cervical cancer. ResultsThe cervical cancer cell lines viability decreased and cell apoptosis was induced after DFX incubation. Additionally, DFX promoted cell cycle arrest by regulating the expression of cell cycle regulators cyclin D1, cyclin E and proliferating cell nuclear antigen (PCNA) in cervical cancer cell lines. DFX also decreased cell invasion by upregulating the expression of NDRG1 and downregulating c-Myc. The activation of Akt and the MEK/ERK signaling pathway was inhibited by DFX. DFX also significantly suppressed xenograft tumor growth, decreased the levels of ferritin in serum and tumor tissue, reduced iron deposits and reactive oxygen species (ROS) levels in xenografts of DFX-treated group compared with the control group, with no serious side effects. ConclusionPresent study demonstrated the inhibitory effect of DFX against cervical cancer, and provided a potential therapeutic agent for cervical cancer.

Iron Chelators, Such as Deferasirox, When Combined With Hydroxyurea, Provide an Additional Benefit of Iron Chelation in Patients Receiving Chronic Transfusion Therapy

Red blood cell (RBC) transfusions have been established as one of the primary therapies in treating sickle cell anemia. However, they are not free of side effects, with overloading the body with iron being one of the most important. Iron chelation therapy greatly reduces the iron load of the body. In addition, hydroxyurea (HU), an oral chemotherapeutic drug also has a significant role in the treatment of the disease with beneficial effects on many of the clinical problems that arise, mainly in reducing painful crises. The aim of this study was to investigate the effect of synergistic transfusion therapy and HU on the response to deferasirox (DFX) chelation therapy. Eighteen patients with sickle cell disease were divided into two groups based on their treatment, either with simple transfusions and DFX or with a combination of transfusion therapy, DFX and HU, and were evaluated with magnetic resonance imaging (MRI) for liver iron concentration (LIC) and biochemistry. All patients completed the study. The results of the study showed improvement in serum ferritin (FER) levels and LIC after 12 months of therapy in both groups, especially in the group receiving the combination therapy with HU. In addition, there was a noteworthy improvement in serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH) levels with serum creatinine (Cr) levels remaining stable during the study in both groups. Hydroxyurea, when combined with iron chelators such as DFX, provides an additional benefit of iron chelation in patients receiving chronic transfusion therapy.

Deferasirox in the management of iron overload in patients with myelofibrosis treated with ruxolitinib: The multicentre retrospective RUX-IOL study.

Deferasirox (DFX) is used for the management of iron overload (IOL) in many haematological malignancies including myelofibrosis (MF). The 'RUX-IOL' study retrospectively collected 69 MF patients treated with ruxolitinib (RUX) and DFX for IOL to assess: safety, efficacy in term of iron chelation response (ICR) and erythroid response (ER), and impact on overall survival of the combination therapy. The RUX-DFX therapy was administered for a median time of 12.4months (interquartile range 3.1-71.2). During treatment, 36 (52.2%) and 34 (49.3%) patients required RUX and DFX dose reductions, while eight (11.6%) and nine (13.1%) patients discontinued due to RUX- or DFX-related adverse events; no unexpected toxicity was reported. ICR and ER were achieved by 33 (47.8%) and 32 patients (46.4%) respectively. Thirteen (18.9%) patients became transfusion-independent. Median time to ICR and ER was 6.2 and 2months respectively. Patients achieving an ER were more likely to obtain an ICR also (p=0.04). In multivariable analysis, the absence of leukocytosis at baseline (p=0.02) and achievement of an ICR at any time (p=0.02) predicted improved survival. In many MF patients, the RUX-DFX combination provided ICR and ER responses that correlated with improved outcome in the absence of unexpected toxicities. This strategy deserves further clinical investigation.

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.

Determination of manganese in rat blood samples based on ionic liquid-liquid extraction and chelation therapy for evaluation of manganese toxicity in rats

In this study, manganese was extracted in the blood of rats based on desferrioxamine (DFO), deferasirox (DFX) and deferiprone (DFP) as chelators (ligands) by ionic liquid-liquid phase extraction method (ILLEM) before being determined by F-AAS. Also, the toxic effects of manganese on blood serum and hematology parameters such as RBC, WBC, HGB, PLT and HCT were investigated. Male Wistar rats were randomly divided into control and toxic groups. Manganese chloride was administrated orally in low and high doses. Orally (deferasirox and deferiprone) or intraperitoneally (desferrioxamine) for 2 weeks. Results showed that exposure to manganese significantly increased both counts of hematology parameters and concentration of this metal ion in serum compared to the control group. First, manganese was chelated with ligands and then the hydrophobic ionic liquid (IL, [HMIM][PF6]) was added to rat blood samples, after shaking and centrifuging, the upper liquid phase was separated by auto-sampler and mixture of IL/ligand in the bottom of conical tube back-extracted and determined with F-AAS. The linear range, LOD and enrichment factor for 10 mL of blood rats were obtained 25- 180 μg L-1, 6.5 μg L-1 and 19.92, respectively. By chelation therapy manganese was removed from serum and hematology parameters were normal level.

Deferasirox combination with eltrombopag shows anti-myelodysplastic syndrome effects by enhancing iron deprivation–related apoptosis

Iron overload (IO) affected the survival of patients with myelodysplastic syndrome (MDS). Deferasirox (DFX) is widely used in patients with MDS for iron chelation therapy, but is not suitable for...

Stable Luminescent Poly(Allylaminehydrochloride)-Templated Copper Nanoclusters for Selectively Turn-Off Sensing of Deferasirox in β-Thalassemia Plasma.

Highly stable and facile one-pot copper nanoclusters (Cu NCs) coated with poly(allylamine hydrochloride) (PAH) have been synthesized for selectively sensing deferasirox (DFX) in β-thalassemia plasma. DFX is an important drug used for treating iron overloading in β-thalassemia, but needs to be monitored due to certain toxicity. In this study, the PAH-Cu NCs showed highly stable fluorescence with emission wavelengths at 450 nm. The DFX specifically interacted with the copper nanocluster to turn off the fluorescence of the PAH-Cu NCs, and could be selectively quantified through the fluorescence quenching effect. The linear range of DFX in plasma analyzed by PAH-Cu NCs was 1.0–100.0 µg/mL (r = 0.985). The relative standard deviation (RSD) and relative error (RE) were lower than 6.51% and 7.57%, respectively, showing excellent reproducibility of PAH-Cu NCs for sensing DFX in plasma. This method was also successfully applied for an analysis of three clinical plasma samples from β-thalassemia patients taking DFX. The data presented high similarity with that obtained through a capillary electrophoresis method. According to the results, the PAH-Cu NCs could be used as a tool for clinically sensing DFX in human plasma for clinical surveys.

Renal function in \u03b2-thalassemia major patients treated with two different iron-chelation regimes

BackgroundRenal injury in transfusion dependent β thalassemia patients (TDT) has been attributed to iron overload, chronic anemia and iron-chelation therapy (ICT) toxicity. We studied renal function in TDT patients treated with two different ICT regimes.Patients and methodsWe studied 36 TDT patients: 26 received deferasirox (DFX) and 10 were treated with deferoxamine (DFO) +/− deferiprone (DFP).ResultsIncreased uNAG was found in 30% of the DFX group vs. 10% of the DFO+/−DFP group, the mean uNAG level in the DFX group was significantly higher than in the DFO+/−DFP group, (P < 0.05). A moderate negative correlation was found between uNAG levels and mean serum ferritin for the prior 10 years (P = 0.03), more pronounced for the DFO+/−DFP group. Twenty nine patients had had their renal function evaluated 10 years earlier; eGFR significantly declined in patients switched to DFX (P = 0.0093) but not in patients who continued DFO+/−DFP.ConclusionsA high prevalence of renal tubular damage was observed in our TDT patients, particularly those treated with DFX; uNAG was negatively associated with mean 10-year serum ferritin, suggesting ICT’s involvement in tubular injury. A significant decline in eGFR compared to a decade earlier was observed only in patients currently treated with DFX. Strict follow-up of renal function in TDT patients is warranted.

A Prospective Observational Multicenter Study on Deferiprone & Deferasirox in Clinical Practice of Pediatric Patients with Transfusion-Dependent B-Thalassemia

Background: Iron overload is inevitable but a manageable complication of frequent blood transfusion, the effectiveness and safety of two iron chelation therapy in young children with transfusion-dependent B thalassemia (TDB-T) using either deferiprone (DFP) or deferasirox (DFX) were well studied in clinical trials. The primary objectives were; reporting efficacy and frequency of all adverse events (AEs) as compared with published data. Secondary objective was reporting deviation from guidelines, The analysis of clinical data is the first step to design new strategies Methodology: An investigator initiated 2-year multicenter prospective study enrolling over 6 months period; 302 children with TDB-T from 11 centers; keeping pre-transfusion Hb >8gm/dl. When serum ferritin (SF) reached around 1000 ng/ml; they had received according to availability; either DFP liquid solution in a dose; 75 mg/kg/day (n=62) or DFX (n=240); (dispersed tablet; 25% or film-coated tablet 75% in a dose; 20-25 mg/kg/d or its equivalent). CBC was done biweekly in DFP and pre-transfusion in DFX group. Liver transaminases, serum creatinine and (SF) were done /3 months. Changes in growth velocity over time were documented. Results: 66% were males, age at enrolment was; (11-19 and 14-26 months) in DFP and DFX respectively; they had received (6-8) and (7-11) transfusions prior to chelation in both groups respectively in addition to (16-21) during the study. 20% of patients did not achieve the target pre-transfusion Hb level. At initiation of DFP; SF median; 960 (IQR; 122 ng/ml) while those on DFX had SF; median 1070 (IQR 138 ng/ml) both groups had comparable transfusion iron input during the study. At 24 months of regular transfusion-chelation; SF < 1000 ng/ml was noticed in 65% and 60% of the patients respectively with good growth velocity in children using either chelator. Unnecessary over-dosing of DFX > 40 mg/kg was observed in 5%, meanwhile 3.2% had received DFP in a dose >75-100 mg/kg while SF was <1500 ng/ml. Under-reporting of adverse events in both groups was observed; 5% GIT upset, neither arthralgia nor agranulocytosis, neutropenia (3.2%) in DFP group and CBC was not checked biweekly; but only prior to transfusion. 4-5 % had elevated transaminases in both chelators, while patients on DFX reported; GIT upset in 4.2% and rash in 1.6%. Elevated serum creatinine > 33% from baseline on 2 successive visits was observed in 5% in DFX without reducing the dose or re-check. No unexpected, serious severe adverse events were reported in both groups. Poorly controlled patients with SF > 1500 ng /ml at 12 or 24 months were 12, 8% in DFP group; in contrast to 15%, 10% in DFX group respectively; with no statistical difference; (compliance was comparable). The total DFP and DFX discontinuation ratio was 5% in each group. Conclusion: infants and young children with TDB-T naïve to chelation were put on mono-therapy at younger age than reported before. Both chelators were effective, well tolerated and with no severe safety concerns; however deviation from guidelines was observed as; unnecessary over-dosing of DFX and under-reporting of AEs in both groups in real life practice. DisclosuresHamdy: ApoPharma: Honoraria; Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria.