Effect Of Iron Chelation Therapy Research Articles

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans.

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.

A novel C19ORF12 mutation in two MPAN sisters treated with deferiprone

BackgroundMitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare and devastating disease caused by pathogenic mutations in C19orf12 gene. MPAN is characterized by pathological iron accumulation in the brain and fewer than 100 cases of MPAN have been described. Although the diagnosis of MPAN has achieved a great breakthrough with the application of the whole exome gene sequencing technology, the therapeutic effect of iron chelation therapy in MPAN remains controversial.Case presentationWe reported that two sisters from the same family diagnosed with MPAN had dramatically different responses to deferiprone (DFP) treatment. The diagnosis of MPAN were established based on typical clinical manifestations, physical examination, brain magnetic resonance imaging (MRI), cerebrospinal fluid analysis (CSF) and gene sequencing results. The clinical presentations of the two sisters with MPAN due to novel gene locus mutations were similar to those previously reported. There is no other difference in basic information except that the proband had a later onset age and fertility history. Both the proband and his second sister were treated with deferiprone (DFP), but they had dramatically different responses to the treatment. The proband’s condition deteriorated sharply after treatment with DFP including psychiatric symptoms and movement disorders. However, the second sister of the proband became relatively stable after receiving the DFP treatment. After four years of follow-up, the patient still denies any new symptoms of neurological deficits.ConclusionThe findings of this study enriched the MPAN gene database and indicated that DFP might ameliorate symptom progression in patients without severe autonomic neuropsychiatric impairment at the early stage of the disease.

Iron Chelation Therapy in COVID-19 Infection

The recent outbreak of corona virus and coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus is a global concern. Despite efforts to clarify the physiology and potential therapy, specific guidelines for the treatment of COVID-19 disease have yet to be established, and many therapeutic options are under investigation. Accumulating evidence suggests that dysregulation of iron homeostasis contributes significantly to the pathogenesis of COVID-19 through its toxic effects by the formation of reactive oxygen species (ROS). This review focuses on summarizing the available literature and relevant studies conducted to date on the possible therapeutic effects of iron chelation therapy in the treatment of COVID-19 disease. Scientific databases (PubMed, Scopus, Google Scholar) were searched for relevant articles using the following keywords: COVID-19, SARS-CoV-2, coronavirus, clinical management, iron chelators/chelation. Research articles, reviews, research letters, case reports, and commentaries were considered. Although there is ample evidence of the potential beneficial effects of using iron chelators as adjuvant treatment in COVID-19, further research on this topic is needed.

Diagnosis and treatment of transfusion-related iron overload

Background: Iron overload is frequently found in transfused patients with chronic anemia and congenital hemochromatosis. Iron toxicity adversely affects organs, including the heart, liver, and endocrine glands. Iron chelation helps patients with transfusion-related iron overload improve organ dysfunction and prolong survival.Current Concepts: Iron overload is classified into primary and secondary causes. Acquired causes of secondary iron overload include ineffective erythropoiesis, chronic transfusion, and chronic liver diseases. The effectiveness of iron chelation therapy in reducing or maintaining body iron has been demonstrated in many studies of patients with transfusion-induced anemias. Deferasirox, a once-daily oral iron chelator for adult and pediatric patients with transfusion-induced iron overload, is available in Korea. The initial daily dose of deferasirox recommended by Korean guidelines is 20 mg/kg body weight, taken on an empty stomach at least 30 minutes before meals. Serum ferritin levels should be maintained below 1,000 ng/mL.Discussion and Conclusion: Iron chelation therapy should be considered when a patient has undergone large red blood cell transfusions, and there is evidence of organ iron overload to improve organ dysfunction and survival.

A Systematic Review and Meta-Analysis of the Effect of Iron Chelation Therapy on Survival in Patients with Lower Risk Myelodysplastic Syndrome

Background: Anemia is the most common cytopenia among patients with myelodysplastic syndromes (MDS) often necessitating regular red blood cell (RBC) transfusions. As a result, most patients develop iron overload (IO). RBC transfusion dependency and IO have been associated with worse clinical outcomes, including inferior overall survival (OS), in MDS patients. While iron chelation therapy (ICT) is recommended by most clinical guidelines and experts for select MDS patients, the use of ICT remains controversial in the absence of published, randomized controlled trials. To evaluate the impact of ICT on survival among lower risk MDS patients, we performed a systematic review and meta-analysis (SRMA) of the literature.Methods: We conducted an SRMA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines. PubMed and Embase electronic databases were searched through October 2016 with search terms “MDS” OR “myelodysplastic syndrome” AND “iron chelation” OR “iron chelating” OR “iron overload” AND “survival” OR “death” AND “study” OR “trial.” Additionally, the Cochrane Library, the World Health Organization (WHO) International Clinical Trials Registry, and abstracts from recent American Society of Hematology annual meetings (years 2014-2016) were searched. One study, published in 2014, had an updated analysis in 2017 that was used for the current analysis. Information abstracted included data relating to study and patient characteristics, outcome measures (mortality and progression to acute myeloid leukemia [AML]), and measures of effect (calculated odds, hazard ratios [HRs], and confounding variables for adjustment). A Random Effects model was used to compute an adjusted HR (aHR) among the different studies. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. Study heterogeneity was assessed using the Cochran Q and the I2 statistic. Publication bias was assessed through visual examination of a funnel plot and with the Egger's test for small-study effects.Results: Of the 331 records screened, 23 were assessed for eligibility, and 9 were included (Figure 1). Of these 9 studies, 6 were considered to be of high quality based on the NOS. All 9 were observational studies (4 prospective and 5 retrospective); 8 were identified as including patients with the International Prognostic Scoring System (IPSS)-defined low and intermediate-1 risk MDS. In these 8 studies, ICT was associated with an overall lower risk of mortality (aHR 0.43; 95% confidence interval [CI] 0.30-0.60; p < 0.01) (Figure 2). The pooled estimate of the ratio of median unadjusted survival times was 2.02 (95% CI 1.64-2.49), indicating that the median OS for patients receiving ICT was approximately twice that for patients who did not receive ICT. There was evidence of significant heterogeneity across studies for this outcome measure with I2 = 64% and Cochran's Q statistic = 19.8 (p = 0.006). Although the direction of effects did not change, heterogeneity was significant in prospective studies (I2 = 73%; Cochran's Q statistic = 7.4, p = 0.02), but not in retrospective studies (I2 = 9.8%; Cochran's Q statistic = 4.4, p = 0.35). In the 2 studies that reported on benefits of adequate chelation, any degree of chelation was found to confer a survival benefit, but this was to a lesser degree than the survival benefit accrued by those who received higher adequate doses. ICT seemed to decrease the risk of progression to AML (odds ratio 0.526; 95% CI 0.37-0.74; p < 0.001) in the studies that reported on this outcome (Figure 3); these studies displayed no significant heterogeneity. The impact of ICT on end organ damage could not be assessed due to non-uniform reporting of studies.Conclusions: This SRMA suggests a significant reduction in the adjusted risk of mortality among IPSS low and intermediate-1 risk MDS patients treated with ICT. Furthermore, our analysis suggests that ICT is associated with delayed progression to AML, although the causality of these associations cannot be established based on this study. Randomized controlled studies are needed to confirm these findings. [Display omitted] DisclosuresBallas:Novartis: Honoraria, Speakers Bureau. Zeidan:AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau; Otsuka: Consultancy.

A Systematic Review of the Effect of Iron Chelation Therapy on Survival in Patients with Sickle Cell Disease and β-Thalassemia

Background: Patients with sickle cell disease (SCD) and beta (β)-thalassemia often require regular blood transfusions; however, each unit of blood contains approximately 200 mg of iron, which can rapidly lead to iron overload (IO). This can result in iron deposition in the heart, liver, and endocrine organs, ultimately leading to organ failure, including cardiac disease, liver fibrosis, and metabolic disorders. The introduction of iron chelation therapy (ICT) with deferoxamine (DFO) and more recently deferiprone (DFP) and deferasirox (DFX) has had a significant impact on IO, demonstrating reductions in serum ferritin level and liver iron content. Although ICT has become the standard of care over the past few decades, there are limited data on the effects of these agents on overall survival. The objective of this systematic review is to evaluate the impact of ICT on survival in patients with transfusion-dependent SCD or β-thalassemia.Methods: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols(PRISMA-P) guidelines. Electronic databases, including Embase, PubMed, Cochrane Library, and the World Health Organization (WHO) Clinical Trials Search Portal, along with American Society of Hematology annual meeting abstracts from 2010-2015 were searched to identify English language articles that were relevant to the topic. Search terms included “sickle cell anemia” or “SCA,” “sickle cell disease” or “SCD,” “beta thalassemia” or “thalassemia,” “iron chelation,” “iron overload,” “survival,” “death,” “study,” and “trial.” Abstracts identified by the literature were independently reviewed and only articles with unanimous support were included; when the eligibility of an abstract was disputed, a full copy of the article was retrieved for review. References were excluded for lack of evidence of survival analysis, comparison between regimens, or if trials had fewer than 25 patients. Details of the included studies were collected for categorization. Although a meta-analysis of the data was initially planned, there were too few studies with similar study parameters to complete the analysis.Results: For SCD, the literature search yielded 203 articles of which 6 were deemed relevant (Figure 1). Of these, 3 were excluded and 3 (published between 2001 and 2014) were included. Reasons for exclusion included small patient number, no comparator, and being a theoretical paper. Only 1 of the 3 was a randomized clinical trial (RCT). For β-thalassemia, theliterature analyses yielded 398 articles of which 40 were deemed relevant (Figure 2). After reviewing the articles, 22 were excluded while 18 (published between 1991 and 2015) were included. Reasons for exclusion included small patient number, no comparator, no survival data, no chelation data, or a focus on hematopoietic stem cell or bone marrow transplantation. Only 3 of the 18 were RCTs; the remainder were retrospective and/or longitudinal studies. Most data on effectiveness of ICT were from longitudinal studies that suggest treatment outcomes have improved significantly over time mainly due to the introduction of new and improved iron chelation agents, including oral treatments and combination therapy. Effectiveness was also investigated in studies evaluating treatment compliance that suggest survival is improved in patients compliant to ICT. Compliance has been enhanced with the introduction of oral agents such as DFP and DFX compared with DFO, which requires daily subcutaneous injections.Conclusions: This systematic review identified few RCTs of ICT reporting survival in SCD and β-thalassemia. Despite limited data, the available literature suggests that ICT improves overall survival in SCD and β-thalassemia. Survival may also have been affected by factors such as hydroxyurea usage and the number of blood transfusions. Newer oral treatments have improved compliance, shown to be an important factor in survival, although there have not been any prospective long-term RCTs adequately powered to compare the efficacy among available iron chelation agents in either SCD or β-thalassemia. [Display omitted] DisclosuresBallas:Novartis: Honoraria, Speakers Bureau. Zeidan:Takeda: Speakers Bureau; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Otsuka: Consultancy.

Novel dynamic outcome indicators and clinical endpoints in myelodysplastic syndrome; the European LeukemiaNet MDS Registry and MDS-RIGHT project perspective.

Available evidence suggests that in most patients with LR-MDS the risk of death is not related to disease progression but is mainly attributable to non-leukemic death. 2,17 In addition, a proportion of these patients have prolonged survival that precludes the design of clinical trials adopting OS as a primary endpoint. These challenges have resulted in potentially biased assessment of the effectiveness and appropriate use of the available interventions in this patient population. The EUMDS Registry has identified novel meaningful outcome indicators and clinical endpoints, and reliable measures of response to HCI (Figure 4). The results of our analysis indicate that RBCT density is strongly associated with a decreased OS, even at relatively low dose densities. In addition, we observed that an early decrease in platelet count is an independent adverse prognostic indicator in LR-MDS, and combining relative platelet drop and transfusion dependency allows early identification of patients at risk of rapid progression, and may guide early therapeutic interventions, including allogeneic hematopoietic stem cell transplantation or experimental interventions. Taken together, these results indicate that regular RBCT requirement, early platelet count kinetics, and restriction in HRQoL are early independent and meaningful outcome indicators, and reliable measures of effectiveness of therapeutic interventions, evaluated in this set of studies. These findings support the integration of RBCT requirement and HRQoL in the general core outcome sets and in response criteria in patients with LR-MDS, and have important implications for clinical practice and the design of clinical endpoints. Our results strongly support the adoption of freedom from transfusion as a meaningful clinical endpoint in patients with LR-MDS. Anemia is the main determinant of therapeutic intervention in patients with LR-MDS, and ESA are recommended as first-line treatment for patients with symptomatic anemia. 10 The observational studies within the EUMDS Registry showed that the response rate, as well as the capacity of these agents to delay the onset of a regular RBCT need, is most pronounced in RBCT-naive patients. These results identified early initiation of treatment with ESA as a major treatment response indicator, and indicate that ESA should be recommended in LR-MDS patients with symptomatic anemia before starting regular RBCT. After the onset of RBCT dependency, patients with LR-MDS are prone to long-term accumulation of iron. 1,43 The EUMDS Registry studies provided evidence that elevated LPI levels are associated with reduced survival in RBCT dependent patients, whereas iron chelation therapy normalizes LPI levels. These findings suggest that NTBI and LPI may serve as early indicators of iron toxicity and a means to measure the effectiveness of iron chelation therapy in patients with LR-MDS. However, qualified NTBI and LPI are only currently available in specialized laboratories. 44 Large observational cohorts with detailed clinical and laboratory data, like the EUMDS cohort, are the ideal framework in which to identify well defined MDS subtypes that may benefit from novel targeted treatments. An example of such a subtype is MDS with loss of parts of chromosome 5, namely del5q; these patients have a relatively favorable outcome on lenalidomide treatment. In order to identify homogeneous subsets of patients within MDS, preliminary evidence has suggested that recently identified mutations in splicing factors may recognize distinct disease entities within myeloid neoplasms. 45 Splicing modulators are now in pre-clinical testing, and are very likely to lead to the introduction of effective drugs for specific groups of MDS patients. Luspatercept, a specific inhibitor of growth and differentiation factor-11, a member of the transforming growth factor β superfamily, induced substantial improvement of anemia, especially in patients with ring sideroblasts. 46 Characterization of individual cases by new genetic markers (one of the main objectives of the MDS-RIGHT project) will allow refined classification of patients into biological subgroups that are expected to respond differently to therapeutic interventions to guide discontinuation of those interventions that are less effective or less cost-effective. The main question is whether RCT data and retrospective cohort data in selected tertiary care centers are representative of the 'real world' data of the older patients with LR-MDS in the general population. A careful comparison of the 'real world' data and the RCT data will be needed in order to provide a clear answer to these questions. Meanwhile, the current analyses of data collected over 10 years in the EUMDS Registry provides relevant and important information which could help assess prognosis and response to standard interventions in this older patient group.

Therapeutic applications of chelating drugs in iron metabolic disorders of the brain and retina.

Iron is essential for normal cellular function, however, excessive accumulation of iron in neural tissue has been implicated in both cortical and retinal diseases. The exact role of iron in the pathogenesis of neurodegenerative disorders remains incompletely understood. However, iron-induced damage to the brain and retina is often attributed to the redox ability of iron to generate dangerous free radicals, which exacerbates local oxidative stress and neuronal damage. Iron chelators are compounds designed to scavenge labile iron, aiding to regulate iron bioavailability. Recently there has been growing interest in the application of chelating agents for treatment of diseases including neurodegenerative conditions, characterized by increased oxidative stress. This article reviews both clinical and preclinical evidence relating to the effectiveness of iron chelation therapy in conditions of iron dyshomeostasis linked to neurodegeneration in the brain and retina. The limitations as well as future opportunities iron chelation therapy are discussed.

Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

BackgroundAceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment.MethodsData on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations.ResultsTherapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration.ConclusionsEarly initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.

Annals for Educators - 21 April 2020.

Annals for Educators - 21 April 2020.

Effect of Chelation Therapy and Blood Transfusion on Trace Elements in Thalassemia Patients

Background: β-Thalassemia major is considered to be one of the most common inherited hemolytic anemia. Enhanced years of survival of thalassemia have led to unmasking related complications related to alterations in certain trace elements like magnesium, calcium, phosphorus, copper, zinc etc.&#x0D; Objective: Present study was conducted to evaluate the effect of iron chelation therapy and blood transfusion on certain trace elements (Magnesium, Calcium, Phosphorus, Copper, Zinc) in β-thalassemic patients on chelation therapy more than one year.&#x0D; Materials and Methods: In the present cross sectional study, 100 β-thalassemic patients receiving chelation therapy for atleast 1year were recruited from Civil Hospital Ahmedabad, Gujarat during February, 2017 to December, 2018 and equal number (n=100) of healthy subjects were taken as a control group in the age range of 8 to 15 years of both sexes (male &amp; female). The levels of serum magnesium, calcium, phosphorus, zinc, and copper in serum were analyzed and results were correlated with normal healthy subjects.&#x0D; Results: A significant increase in serum copper (P≤ 0.01) and phosphorus (P≤ 0.001) were observed levels while a significant (P≤ 0.05) fall in magnesium, calcium and zinc levels recorded in β-thalassemic patients in comparison to healthy control subjects.&#x0D; Conclusion: Aforementioned observations suggested that fluctuations in the trace elements levels in β- thalassemic children receiving blood transfusion and iron chelation therapy could leads to different complications like hemolyzed red cells, infections &amp; hemochromatosis renal damage, hypoparathyroidism etc. if remains untreated. Hence routine assessment of these elements is recommended for better management.

Effect of iron chelation therapy on EPO-STAT5 signalling pathway and EPO resistance in iron-overloaded low-risk myelodysplastic syndrome patients

ABSTRACT Objectives: Background/aims: We aim to explore low-risk MDS patients’ ESA response and the difference between iron-overloaded (IO) group and the control group in the expression of SOCS1, STAT5 and BCL2L1 which play a key role to EPO-STAT5 signal pathway. Methods: 56 low-risk MDS patients were divided into experimental group, IO patients; control group, non-IO patients. Among experimental group, 28 IO patients were treated with iron chelation therapy (ICT). SOCS1, phosphorylated STAT5 (p-STAT5) and BCL2L1 protein concentration in bone marrow supernatant have been analyzed by ELISA, STAT5a+b protein concentration in bone marrow mononuclear cells (BMMC) have been analyzed by Western blot, and mRNA expression of them have been detected in BMMC by RQ-PCR. The percentage of CD71+ cells in BMMC, apoptotic rate of CD71+ cells and ROS expression in CD71+ cells were detected by Flow cytometry. Results: Compared with the control group, the sEPO concentration, the efficacy of ESA and the expression of SOCS1, apoptotic rates of CD71+ cells and ROS expression in CD71+ cells in IO group were increased, the expression of STAT5 and BCL2L1 was reduced. Interestingly, after receiving ICT, some patients with EPO resistance have responded again to ESA treatment, with the decrease of the expression of SOCS1, apoptotic rates of CD71+ cells, ROS expression in CD71+ cells and the increase of the expression of STAT5 and BCL2L1. Conclusion: Iron overload can increase EPO resistance and the expression of SOCS1, inhibit the expression of STAT5 and BCL2L1. ICT could allivation of EPO resistance.

Nigella sativa improves anemia, enhances immunity and relieves iron overload-induced oxidative stress as a novel promising treatment in children having beta-thalassemia major

IntroductionThalassemias are treated by regular blood transfusions and iron chelation therapy. Iron overload-induced oxidative stress helps the pathogenesis of thalassemia-induced anemia, atherogenesis, immune suppression and tissue damage. Nigella sativa (NS) is a safe medicinal plant that has exhibited immune stimulant, antioxidant and tissue-protective effects that may benefit thalassemic patients. It is widely used in Arabic prophetic medicine Patients and methods25 blood transfusion-dependent children having homozygous β-thalassmia major (11 Males and 14 females ranging from 6 to 18 years) received oral NS powder (2 g/day added to foods or drinks) for 3 consecutive months. Investigations carried out for all children included evaluating: complete blood count, serum ferrtin, T cell subsets determination (CD4 and CD8), malondialdehyde (MDA) level and total antioxidant capacity (TAC). ResultsNS significantly increased blood hemoglobin (from 7.50 ± 0.22–9.48 ± 0.6 g/dl) (p < 0.001), WBCs count (from 9683.33 ± 284.65–12070 ± 89 cells/cc) (p < 0.001) and neutrophils (from 3243.92 ± 168.81–4868.23 ± 387.92 cells/cc) (p < 0.001). NS enhanced cell-mediated immunity significantly via increasing CD4 counts (from 1319.88 ± 74.56–2007.64 ± 90.34 cells/ μl) (p < 0.001) and CD8 counts (from 727.09 ± 42.81–1145.31 ± 77.58 cells/μl) (p < 0.001) after NS treatment. Blood platelets and serum ferritin did not change significantly. However, iron overload-induced oxidative stress significantly decreased e.g. MDA significantly decreased (from 21.624 ± 0.31–14.864 ± 0.50 nmol/L) (p < 0.001) while TAC significantly increased (from 3.93 ± 0.11–7.69 ± 0.14 mmol/L) (p < 0.001) after NS treatment. ConclusionNS decreased iron overload-induced oxidative stress and hemolytic anemia. NS is a promising treatment for thalassemia to potentiate therapeutic effects and alleviate side effects of iron chelation therapy. Limitations to this study included the small number of patients and the relatively short post treatment follow-up time. Future research regarding the use of NS for the treatment of thalassemia is highly recommendedThis clinical trial was registered in: ClinicalTrials.gov. Trial ID: NCT02816957

Systematic review and meta-analysis of the effect of iron chelation therapy on overall survival and disease progression in patients with lower-risk myelodysplastic syndromes.

The impact of iron chelation therapy (ICT) on overall survival (OS) and progression to acute myeloid leukemia (AML) in patients with iron overload and International Prognostic Scoring System low- or intermediate-risk myelodysplastic syndromes (MDS) is not well understood. We conducted a systematic review and meta-analysis of published studies of ICT in patients with MDS to better elucidate these relationships. We searched PubMed, EMBASE, Cochrane databases, and the World Health Organization Clinical Trial Registry for studies reporting the impact of ICT on OS in patients with low- or intermediate-risk MDS. Studies were examined for demographics, effect measures, and potential bias risk. Fixed and random-effects models were used to calculate adjusted OS and adjusted hazards ratio (aHR) estimates, respectively, among the different studies. Nine observational studies (four prospective and five retrospective) were identified. For patients with MDS, ICT was associated with an overall lower risk of mortality compared with no ICT (aHR 0.42; 95% confidence interval (CI) 0.28-0.62; P < 0.01); however, there was significant heterogeneity across the studies. In studies reporting progression to AML, ICT was not associated with decreased risk of progression (odds ratio 0.68; 95% CI 0.31-1.43; P < 0.030). This systematic review and meta-analysis of nine nonrandomized trials demonstrated significant reduction in risk of mortality in patients with iron overload and low- or intermediate-risk MDS treated with ICT; however, a causal relationship cannot be established. Randomized, controlled trials are needed to more definitively evaluate the relationship between ICT and survival in patients with iron overload and low- or intermediate-risk MDS.

The effect of iron chelation therapy on overall survival in sickle cell disease and β-thalassemia: A systematic review.

Red blood cell transfusions have become standard of care for the prevention of life-threatening anemia in patients with β-thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event-free survival in patients with β-thalassemia and SCD. Eighteen articles discussing survival in β-thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second-generation oral agents, appears to be associated with improved overall and event-free survival in transfusion-dependent patients with β-thalassemia and patients with SCD.

Effect of iron chelation therapy on EPO-Stat5 signaling pathway and Treg expression in IPSS low risk/medium risk-1 group myelodysplastic syndrome patients

Effect of iron chelation therapy on EPO-Stat5 signaling pathway and Treg expression in IPSS low risk/medium risk-1 group myelodysplastic syndrome patients

Role of liver magnetic resonance imaging in hyperferritinaemia and the diagnosis of iron overload.

Hyperferritinaemia is a frequent clinical problem. Elevated serum ferritin levels can be detected in different genetic and acquired diseases and can occur with or without anaemia. It is therefore important to determine whether hyperferritinaemia is due to iron overload or due to a secondary cause. The main causes of iron overload are intestinal iron hyperabsorption disorders and transfusion-dependent disorders. Iron homeostasis and iron overload are quantified by different diagnostic approaches. The evaluation of serum ferritin and transferrin saturation is the first diagnostic step to identify the cause of hyperferritinaemia. The assessment of liver iron concentration by liver biopsy or magnetic resonance imaging (MRI) may guide the further diagnostic and therapeutic workup. Liver biopsy is invasive and poorly accepted by patients and should only be carried out in selected patients with hereditary haemochromatosis. As a non-invasive approach, MRI is considered the standard method to diagnose and to monitor both hepatic iron overload and the effectiveness of iron chelation therapy in many clinical conditions such as thalassaemia and myelodysplastic syndromes. Accurate evaluation and monitoring of iron overload has major implications regarding adherence, quality of life and prognosis. There are different technical MRI approaches to measuring the liver iron content. Of these, T2 and T2* relaxometry are considered the standard of care. MRI with cardiac T2* mapping is also suitable for the assessment of cardiac iron. Currently there is no consensus which technique should be preferred. The choice depends on local availability and patient population. However, it is important to use the same MRI technique in subsequent visits in the same patient to get comparable results. Signal intensity ratio may be a good adjunct to R2 and R2* methods as it allows easy visual estimation of the liver iron concentration. In this review a group of Swiss haematologists and radiologists give an overview of different conditions leading to primary or secondary iron overload and on diagnostic methods to assess hyperferritinaemia with a focus on the role of liver MRI. They summarise the standard practice in Switzerland on the use of liver iron concentration MRI as well as disease-specific guideline recommendations.

Iron chelation therapy in low risk myelodysplastic syndrome.

Anaemia is the commonest cytopenia seen in patients with myelodysplastic syndrome (MDS), and the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron, which leads to the accumulation of body iron over time. It is accepted that this ultimately causes end organ damage and may impact on both morbidity and mortality. In addition, recent data has increased our interest in the subject with regard to the potential impact on stem cell transplant outcome and an anti-leukaemic effect of iron chelation therapy. There is still debate over which patients should receive iron chelation therapy, but the emergence of new diagnostic and prognostic markers in MDS may help decision making in the clinic setting.

Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassaemia

Aims: To compare insulin sensitivity, β-cell function and iron status biomarkers in non-transfusion-dependent thalassaemia (NTDT) with iron excess during pre- and post-iron chelation. Methods: Subjects with NTDT, aged older than 10 years, with serum ferritin >300 ng/ml, were included. Iron chelation with deferasirox (10 mg/kg/day) was prescribed daily for 6 months. Results: Ten patients with a median age of 17.4 years were enrolled. The comparison between pre- and post-chelation demonstrated significantly lower iron load: median serum ferritin (551.4 vs. 486.2 ng/ml, p = 0.047), median TIBC (211.5 vs. 233.5 µg/dl, p = 0.009) and median non-transferrin binding iron (5.5 vs. 1.4 µ<smlcap>M</smlcap>, p = 0.005). All patients had a normal oral glucose tolerance test (OGTT) both pre- and post-chelation. However, fasting plasma glucose was significantly reduced after iron chelation (85.0 vs.79.5 mg/dl, p = 0.047). MRI revealed no significant changes of iron accumulation in the heart and liver after chelation, but there was a significantly lower iron load in the pancreas, assessed by higher T2* at post-chelation compared with pre-chelation (41.9 vs. 36.7 ms, p = 0.047). No adverse events were detected. Conclusions: A trend towards improving insulin sensitivity and β-cell function as well as a reduced pancreatic iron load was observed following 6 months of iron chelation (TCTR20160523003).

Effects of iron chelation therapy on allogeneic hematopoietic stem cell transplantation in myelodysplastic syndrome patients with iron overload

目的探讨祛铁治疗对骨髓增生异常综合征（MDS）患者异基因造血干细胞移植（allo-HSCT）后造血重建和相关并发症的影响。方法回顾性分析57例伴铁过载的allo-HSCT治疗的MDS患者的临床资料，根据血清铁蛋白（SF）水平分为有效祛铁组（移植前SF <1 000 µg/L）和铁过载组（移植前SF≥1 000 µg/L）。探讨有效祛铁治疗对移植后造血重建及相关并发症的影响。结果①57例患者中30例在移植前行祛铁治疗，27例未行祛铁治疗。30例行祛铁治疗的患者中19例（63%）归入有效祛铁组[移植前SF中位数为561(223~846）µg/L]，11例归入铁过载组[移植前SF中位数为1 262 (1 100~2 352）µg/L]。27例未行祛铁治疗患者移植前SF中位数为1 540(1 320~3 112）µg/L，均归入铁过载组。②有效祛铁组、铁过载组分别有19例（100.0%）、34例（89.5%）获得干细胞完全植入，粒系重建时间分别为12(10~18) d、12(11~30) d（P=0.441），血小板重建时间分别为13(12~30) d、15(10~32) d（P= 0.579）。③有效祛铁组感染发生率低于铁过载组[36.8%（7/19）对82.4%（28/34），P=0.002]。④有效祛铁组急性移植物抗宿主病（aGVHD）发生率低于铁过载组[26.3%（5/19）对64.7%（22/34），P=0.010]。有效祛铁组aGVHD均为Ⅰ/Ⅱ度，铁过载组Ⅰ/Ⅱ、Ⅲ/Ⅳ度患者分别为16、6例。⑤铁过载组6例患者移植后早期继续祛铁治疗，SF由2 870（2 205~3 580）µg/L降至1 270 (1 020~1 650）µg/L，且耐受性良好。⑥有效祛铁组中位无病生存时间与铁过载组比较，差异无统计学意义[28.9（0.3~89.5）个月对21.2(0.1~81.0）个月，χ2=3.751，P=0.053]。结论铁过载显著增加MDS患者移植相关并发症；移植前有效的祛铁治疗可明显降低移植后感染及aGVHD发生率和严重程度。