Transfusional Iron Overload Research Articles

Genetic iron overload aggravates and pharmacological iron restriction improves MDS pathophysiology in preclinical study

Although iron overload is a common feature in myelodysplastic syndromes (MDS), it remains unclear how iron excess is detrimental for disease pathophysiology. Taking advantage of complementary approaches, we analyzed the impact of iron overload and restriction achieved through genetic activation (FPNC326S) and pharmacologic inhibition (vamifeport) of the iron exporter ferroportin in a MDS mouse model, respectively. While FPNC326S-induced iron overload did not significantly improve the late stages of erythroid maturation, vamifeport-mediated iron restriction ameliorated anemia and red blood cell maturation in MDS mice, through the reduction of oxidative stress and apoptosis in erythroid progenitors. Iron overload aggravated and restriction alleviated ROS formation, DNA damage and cell death in hematopoietic stem and progenitor cells, resulting in altered cell survival and quality. Finally, myeloid bias, indicated by expanded bone marrow myeloid progenitors and circulating immature myeloid blasts, was exacerbated by iron excess and attenuated by iron restriction. Overall, vamifeport treatment resulted in improved anemia and significant survival increment in MDS mice. Interestingly, the combined therapy with vamifeport and the erythroid maturation agent luspatercept has superior effect in improving anemia and myeloid bias as compared to single treatments, and offers additive beneficial effects in MDS. Our results prove for the first time in a preclinical model that iron plays a pathologic role in transfusion-independent MDS. This is likely aggravated by transfusional iron overload, as suggested by observations in the FPNC326SMDS model. Ultimately, the beneficial effects of pharmacologic FPN inhibition uncovers the therapeutic potential of early prevention of iron toxicity in transfusion-independent MDS.

Physical characteristics and factors affecting in pediatric thalassemia

Background: Thalassemia, one of the most common genetic diseases globally, can contribute to physical developmental delays in pediatric patients due to various factors. Chronic anemia, transfusional iron overload and chelation toxicity are key influences on the growth of children with thalassemia. Objective: This study aims to describe the physical development of pediatric thalassemia patients and assess the factors associated with their physical indices. Methods: A cross-sectional study involving 44 pediatric thalassemia patients receiving treatment at the Pediatric Center, Hue Central Hospital, was conducted from February 2023 to December 2023. Results: The study included 44 participants with an average age of 7.5 ± 4.3 years and an equal distribution of males and females. Of these, 64.5% were transfusion-dependent thalassemia patients. Serum ferritin levels exceeded 1000 ng/ml in 43.2% of participants, and the mean hemoglobin concentration was 67.4 ± 16.1 g/L. Of the evaluated children, 31.8% had height-for-age below -2SD, and 43.2% had weight-for-age below -2SD. Statistically significant associations were observed between height-for-age, weight-for-age, and both blood transfusion dependence and serum ferritin concentration (p < 0.05). However, no significant differences were detected between physical indices and disease type or hemoglobin concentration (p > 0.05). Conclusions: This study found that 31.8% of pediatric thalassemia patients experienced stunting, and 43.2% experienced wasting malnutrition. The degree of blood transfusion dependence and serum ferritin concentration were identified as factors associated with a higher prevalence of stunting and wasting malnutrition in children with thalassemia. Key words: Children, thalassemia, physical index, transfusion-dependent thalassemia, non-transfusion-dependent thalassemia.

Iron chelation therapy for children with transfusion-dependent β-thalassemia: How young is too young?

In this review, we provide a summary of evidence on iron overload in young children with transfusion-dependent β-thalassemia (TDT) and explore the ideal timing for intervention. Key data from clinical trials and observational studies of the three available iron chelators deferoxamine, deferiprone, and deferasirox are also evaluated for inclusion of subsets of young children, especially those less than 6years of age. Evidence on the efficacy and safety of iron chelation therapy for children ≥2years of age with transfusional iron overload is widely available. New data exploring the risks and benefits of early-start iron chelation in younger patients with minimal iron overload are also emerging.

The Importance and Essentiality of Natural and Synthetic Chelators in Medicine: Increased Prospects for the Effective Treatment of Iron Overload and Iron Deficiency.

The supply and control of iron is essential for all cells and vital for many physiological processes. All functions and activities of iron are expressed in conjunction with iron-binding molecules. For example, natural chelators such as transferrin and chelator-iron complexes such as haem play major roles in iron metabolism and human physiology. Similarly, the mainstay treatments of the most common diseases of iron metabolism, namely iron deficiency anaemia and iron overload, involve many iron-chelator complexes and the iron-chelating drugs deferiprone (L1), deferoxamine (DF) and deferasirox. Endogenous chelators such as citric acid and glutathione and exogenous chelators such as ascorbic acid also play important roles in iron metabolism and iron homeostasis. Recent advances in the treatment of iron deficiency anaemia with effective iron complexes such as the ferric iron tri-maltol complex (feraccru or accrufer) and the effective treatment of transfusional iron overload using L1 and L1/DF combinations have decreased associated mortality and morbidity and also improved the quality of life of millions of patients. Many other chelating drugs such as ciclopirox, dexrazoxane and EDTA are used daily by millions of patients in other diseases. Similarly, many other drugs or their metabolites with iron-chelation capacity such as hydroxyurea, tetracyclines, anthracyclines and aspirin, as well as dietary molecules such as gallic acid, caffeic acid, quercetin, ellagic acid, maltol and many other phytochelators, are known to interact with iron and affect iron metabolism and related diseases. Different interactions are also observed in the presence of essential, xenobiotic, diagnostic and theranostic metal ions competing with iron. Clinical trials using L1 in Parkinson's, Alzheimer's and other neurodegenerative diseases, as well as HIV and other infections, cancer, diabetic nephropathy and anaemia of inflammation, highlight the importance of chelation therapy in many other clinical conditions. The proposed use of iron chelators for modulating ferroptosis signifies a new era in the design of new therapeutic chelation strategies in many other diseases. The introduction of artificial intelligence guidance for optimal chelation therapeutic outcomes in personalised medicine is expected to increase further the impact of chelation in medicine, as well as the survival and quality of life of millions of patients with iron metabolic disorders and also other diseases.

Rates of severe neutropenia and infection risk in patients treated with deferiprone: 28 years of data

AbstractPatients treated with deferiprone for transfusional iron overload may experience idiosyncratic drug–induced neutropenia (IDIN) that may increase risk of infection. This analysis examined the rates of severe IDIN and risk of serious infections at different absolute neutrophil count (ANC) levels during deferiprone treatment. Events of severe IDIN (ANC <0.5 × 109/L) and associated serious infections from clinical trials and postmarketing setting were analyzed by discrete ANC levels: group 1, 0.2 × 109/L to 0.5 × 109/L; group 2, 0.1 × 109/L to 0.199 × 109/L; group 3, <0.1 × 109/L. In clinical trials, 22 events of severe IDIN occurred (group 1, n = 9; group 2, n = 3; group 3, n = 10), and rates of severe IDIN per 100 patient-years were 0.45 in group 1; 0.15 in group 2; and 0.50 in group 3 (1990.26 patient-years deferiprone exposure). All serious infections were in group 3 (3/10 [30.0%]). In the postmarketing setting, 176 events of severe IDIN were reported (group 1, n = 65; group 2, n = 20; group 3, n = 91) and rates of severe IDIN per 100 patient-years were 0.06 in group 1; 0.02 in group 2; and 0.08 in group 3 (111 570.24 patient-years deferiprone exposure). Rates of serious infection were 7.7% (5/65) in group 1; 10% (2/20) in group 2; and 13.2% (12/91) in group 3. Our findings suggest a high risk of serious infections with ANC <0.2 × 109/L during deferiprone treatment, a level consistent with the recent neutropenia guidelines.

Roxadustat and transfusional iron overload induced hypothyroidism in a hemodialysis patient: a case report with a literature review

BackgroundAlthough roxadustat has been reported to cause central hypothyroidism, the details of the mechanisms and clinical characteristics of patients who are prone to developing hypothyroidism with roxadustat are uncertain.Case presentationA 53-year-old man with a 3-year history of hemodialysis due to diabetic kidney disease who had been treated with roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, for 2 years was admitted to the hospital because of worsening gait disturbance and impaired consciousness. He had also acquired pure red cell aplasia associated with T-cell large granular lymphocytic leukemia and received multiple blood transfusions. Because his serum concentration of thyroid hormones was low, we diagnosed him with hypothyroidism, and his consciousness level recovered to normal with thyroid hormone replacement therapy. Computed tomography revealed a high-intensity atrophic thyroid gland, and magnetic resonance imaging showed diffusely reduced T2 and T1 signals of the pituitary anterior gland. These findings confirmed the accumulation of iron in the pituitary and thyroid glands. Combined pituitary stimulation tests with thyrotropin-releasing hormone, luteinizing hormone-releasing hormone, and corticotropin-releasing hormone revealed that the patient had pan-hypopituitarism. After discontinuation of roxadustat, the patient was treated with another hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat. One month after switching medication, a stimulation test with thyrotropin-releasing hormone showed normal responses to thyroid-stimulating hormone. The patient was treated with levothyroxine 50 μg daily without any significant symptoms and is currently under follow-up observation as an outpatient.ConclusionsWe encountered a dialysis patient with roxadustat-induced hypothyroidism associated with transfusion iron overload. To our knowledge, this is the first case to clearly show that roxadustat can impair thyroid-stimulating hormone secretion in repeated thyrotropin-releasing hormone stimulation tests. Because the present patient had received roxadustat for more than 2 years before hypothyroidism became apparent, regular monitoring of the thyroid function may be needed in patients with renal anemia who have been treated with roxadustat, especially those at high risk of thyroid dysfunction.

Real-world evidence: Long-term safety of deferiprone in a large cohort of patients with sickle cell disease enrolled in a registry for up to 10 years.

Patients with sickle cell disease (SCD) and other anemias who receive blood transfusions are at risk of organ damage due to transfusional iron overload. Deferiprone is an iron chelator with a well-established safety and efficacy profile that is indicated for the treatment of transfusional iron overload. Here, we report safety data from the large-scale, retrospective Ferriprox® Total Care Registry, which involved all patients with SCD taking deferiprone following the 2011 approval of deferiprone in the United States through August 2020. A total of 634 patients who had initiated deferiprone treatment were included. The mean (SD) duration of deferiprone exposure in the registry was 1.6 (1.6) years (range 0 to 9.7 years). In the overall patient population (N = 634), 64.7% (n = 410) of patients reported a total of 1885 adverse events (AEs). In subgroup analyses, 54.6% (n = 71) of pediatric patients and 67.3% (n = 339) of adult patients reported AEs. The most common AEs reported in patients receiving deferiprone were sickle cell crisis (22.7%), nausea (12.1%), vomiting (8.7%), abdominal discomfort (5.4%), and fatigue (5.4%). Neutropenia was reported in four (0.6%) patients and severe neutropenia/agranulocytosis (defined as absolute neutrophil count <0.5 × 109/L) was reported in two (0.3%) patients. Of patients with evaluable data, all cases of neutropenia and severe neutropenia/agranulocytosis resolved with deferiprone discontinuation. Results from the nearly 10 years of real-world data collected in the Ferriprox® Total Care Registry demonstrate that deferiprone is safe and well tolerated in patients with SCD or other anemias who have transfusional iron overload.

Patterns of Blood Transfusion in Sickle Cell Disease Hospitalizations

Background: Transfusional iron overload causes significant morbidity and mortality in sickle cell disease (SCD). Nevertheless, red blood cell transfusions continue to be essential in its management. This study describes the transfusion patterns among SCD hospitalizations. Methods: Hospitalizations for SCD in the 2017–2018 Nationwide Readmissions Database were divided into two groups based on whether they received transfusions. Descriptive analysis was performed to compare their demographics and complications. Multivariable logistic regression was performed to determine the factors associated with transfusions. Results: Out of 109,783 hospitalizations, 28,300 were transfused, and 81,483 were not transfused. Females and older individuals were higher in the transfused category than the non-transfused category (59.49% vs. 53.52% and 28.86% vs. 21.27%, respectively; p &lt; 0.001 for both). The wealthiest population was more likely to be in the transfused category (11.27% vs. 8.34%; p &lt; 0.001). Admissions to teaching hospitals, large metropolitan hospitals, and highest-volume hospitals were higher in the non-transfused category vs. transfused category (79.89% vs. 72.17%; p &lt; 0.001, 69.26% vs. 65.35%; p 0.003 and 74.71% vs. 63.51%; p &lt; 0.001, respectively). Most admissions were transfused once, with three or more transfusions being given more in the non-teaching hospitals than the teaching hospitals (1.27% vs. 0.41%; p 0.01). Furthermore, a higher proportion of early transfusions occurred in the non-teaching hospitals (65.6% vs. 57.82% for admission days 1 and 2; p &lt; 0.001). Admission to a teaching hospital was associated with lower blood transfusion odds than a non-teaching hospital. Conclusion: A quarter of admissions for SCD receive a blood transfusion. In addition to performing more frequent and early transfusions, the odds of being transfused are higher in non-teaching hospitals.

A Water-Soluble Chitosan Derivative for the Release of Bioactive Deferoxamine.

Deferoxamine (DFO) is a water-soluble iron chelator used pharmacologically for the management of patients with transfusional iron overload. However, DFO is not cell-permeable and has a short plasma half-life, which necessitates lengthy parenteral administration with an infusion pump. We previously reported the synthesis of chitosan (CS) nanoparticles for sustained slow release of DFO. In the present study, we developed solid dispersions and nanoparticles of a carboxymethyl water-soluble chitosan derivative (CMCS) for improved DFO encapsulation and release. CS dispersions and nanoparticles with DFO have been prepared by ironical gelation using sodium triphosphate (TPP) and were examined for comparison purposes. The successful presence of DFO in CMCS polymeric dispersions and nanoparticles was confirmed through FTIR measurements. Furthermore, the formation of CMCS nanoparticles led to inclusion of DFO in an amorphous state, while dispersion of DFO in the polymeric matrix led to a decrease in its crystallinity according to X-ray diffraction (XRD) and differential scanning calorimetry (DSC) results. An in vitro release assay indicated sustained release of DFO from CS and CMCS nanoparticles over 48 h and 24 h, respectively. Application of CMCS-DFO dispersions to murine RAW 264.7 macrophages or human HeLa cervical carcinoma cells triggered cellular responses to iron deficiency. These were exemplified in the induction of the mRNA encoding transferrin receptor 1, the major iron uptake protein, and the suppression of ferritin, the iron storage protein. Our data indicate that CMCS-DFO nanoparticles release bioactive DFO that causes effective iron chelation in cultured cells.

Analysis of the Risk of Infection Stratified By Absolute Neutrophil Counts during Deferiprone-Associated Severe Neutropenia or Agranulocytosis

Introduction Patients with transfusional iron overload receiving iron chelation therapy with deferiprone may experience a decrease in absolute neutrophil counts (ANC) that range from mild (ANC &amp;lt;1.5 x 10 9/L) to severe neutropenia/agranulocytosis (typically defined as ANC &amp;lt;0.5 x 10 9/L), and which put them at risk for infections. In patients taking deferiprone, the risk of infection and/or mortality associated with ANC of &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L is unknown. Our objective was to analyze data from patients taking deferiprone in clinical trials and the postmarketing setting to determine the incidence and severity of infection stratified by ANC levels. s Methods The clinical trial setting involved patients with systemic iron overload who had thalassemia, sickle cell disease, or other anemias and received deferiprone across 15 clinical trials. Data associated with episodes of severe neutropenia/agranulocytosis in patients who had been treated with at least 1 dose of deferiprone were reviewed. For the postmarketing setting, all individual case safety reports since the first market approval of deferiprone on August 25, 1999 to August 31, 2021, were reviewed; cases coded to agranulocytosis were extracted; cases without any reported ANC were removed; and cases with at least 1 ANC value were analyzed. Obtaining confirmed ANC value was not always possible in the postmarketing setting. All infections occuring within ±2 weeks of agranulocytosis onset were identified, graded for severity, and classified as serious, including fatal or life-threatening. Serious events were defined as any event that resulted in death, was life-threatening, required hospitalization or prolonged existing hospitalization, caused disability or permanent damage, caused congenital anomaly, or was classified as an important medical event. Infection events associated with ANC values were categorized into 3 groups based on the nadir ANC (all x 10 9/L): Group A, ANC ≥0.2 to &amp;lt;0.5; Group B, ANC ≥0.1 to &amp;lt;0.2; or Group C: ANC &amp;lt;0.1. Results A total of 977 patients with systemic iron overload received deferiprone in sponsored clinical trials. Among those, 9 patients were in Group A, 3 in Group B, and 10 in Group C. Of the 12 patients in Groups A and B, none had serious, severe, or fatal infections ( Table 1). Three of the 10 (30.0%) patients in Group C experienced serious or severe infections that included (1) parvovirus infection accompanied by diarrhea, a maculopaular rash, and pyrexia resulting in hospitalization; (2) a severe but nonserious respiratory tract infection with esophageal candidiasis in a patient with a history of neutropenia prior to initiating deferiprone; and (3) a fatal case of Pseudomonal sepsis in a patient who had a history of multiple cardiac and pulmonary comorbidities. Deferiprone was permanently discontinued in all 3 patients. From postmarketing data, of a total of 238 adverse reactions that were coded as agranulocytosis, 176 had at least 1 ANC value. Among those, 65 reactions were in Group A, 20 in Group B, and 91 in Group C. Among the reactions in Group A, 5/65 (7.7%) had serious infections and 3 of them (4.6%) had fatal outcomes due to sepsis ( Table 2). Among the reactions in Group B, 2/20 (10.0%) had serious infections, with a fatal outcome in one of them (5.0%); the death was from sepsis and the life-threatening infection involved pneumonia with multiple pulmonary complications. Among the reactions in Group C, 12/91 (13.2%) had serious infections and 8 of them (8.8%) had fatal outcomes; the 8 deaths were associated with sepsis. The 4 serious non-fatal infections involved sepsis; pancytopenia with ANC nadir of 0 accompanied by oropharyngeal pain, fever, and diarrhea that required hospitilization; angioinvasive mucormycosis; and disseminated herpes simplex accompanied by sepsis, resulting in hospitalization. Conclusion Patients receiving deferiprone who become neutropenic are generally at a higher risk of infections or mortality with lower neutrophil levels (ie, ANC &amp;lt;0.2 or &amp;lt;0.1 x 10 9/L compared with ANC ≥0.2 to &amp;lt;0.5 x 10 9/L). Our findings are consistent with the recently published guidelines from the European Hematology Association and the European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias that used agranulocytosis to describe events with ANC of ≤0.2 x 10 9/L in association with a high risk of severe and life-threatening infections.

Iron Overload and Treatment Outcome in an Adult Sickle Cell Disease Cohort

Objective. Blood transfusion plays a prominent role in the management of patients with sickle cell disease (SCD) and has a compounded effect on iron overload, especially when simple top-off transfusions are given. Adults with sickle cell anemia (SCA: HbSS or HbSβ 0-thalassemia), often require episodic blood transfusions on a chronic basis and, hence, are at risk of developing transfusional iron overload. We monitored 83 adult SCD patients with a diagnosis of iron overload during routine treatment and follow up at our clinical center. The aim of this study was to observe and describe treatment outcomes for individuals with iron overload seen at the University of Illinois adult sickle cell center between 2010 and 2023. Method. Patients eligible for the study were aged 18 years or above at the time of their initial visit. Patients were identified from our institutional clinical and translational research informatics data warehouse using computable phenotype algorithms as well as SCD outpatient encounter information to improve accuracy of abstracted data. Results of our queries were abstracted in the form of identified patient data and subsequently reviewed in Epic electronic health record (Epic, Verona, WI). We retrospectively studied adult subjects with SCD seen during routine clinical care between 2010 and 2023. Selected subjects had a diagnosis of iron overload, determined by 2 consecutive ferritin levels &amp;gt;1000ng/ml in steady state plus a significant transfusion history. We extracted data on clinical laboratory markers, abdominal imaging, use of iron chelation at baseline and in the final year of follow up, whether patients were receiving chronic erythrapheresis treatment at baseline and at end of follow up, and if alive at the end of the follow up period. Subjects have variable start date and follow up period, beginning at the start of diagnosis of iron overload and ending in June 2023 or last identifiable follow up visit, or mortality. Result. Baseline characteristics of 83 adult patients included in our study are summarized in table 1. Seventy percent of the patients were female and just about everyone had HbSS disease. The females had older median age (39.5year; IQR 32-50 years) than males. The mean ferritin value was significantly higher than the initial measure after a median follows up period of 5.3 years. During the follow up period, 40% of male patients discontinued iron chelation therapy whereas only 5.6% of females did the same. Multivariable analyses were performed for association between change in ferritin measure (between follow up period) with demographic data and other covariates presented in Table 1. Covariates were eliminated by backward selection. Predictors retained in the final model include follow-up period, initial ferritin value, gender, ALT, AST, and albumin. Females had a higher drop in their follow up ferritin, but this was not significant. Neither use of iron chelation therapy at baseline nor erythrapheresis at baseline predicted a change in ferritin value, however we did not collect information on compliance or duration of therapy. Patients followed up for longer duration, or who have higher ALT, had subsequent higher measure for follow up ferritin. Higher albumin predicted a lower ferritin at follow up. The effects of liver markers on ferritin are likely correlative only. After a median follow up period of 5.3years, about 22% of the patients were confirmed to be deceased. Some patients lost to follow up have an indeterminate alive status. Predictors of mortality in multivariate analysis include follow up ferritin value, albumin, and HCV status. Positive HCV status had a strong association with cirrhosis (p=0.001) as 71% of HCV positive individuals had cirrhosis. In turn 53% of the cirrhotic patients died in the follow up period. Conclusion. Here we present an overview of the clinical outcomes of adult patients with SCD and iron overload during a median follow up period of 5.3 years. Despite limitations of a typical retrospective study, our study illustrates the difficulty associated with the management of transfusional iron overload during routine treatment follow up, especially in patients continuing to undergo episodic transfusion treatment. We also continue to underline the low adherence with chelation therapy in adult populations with SCD and iron overload, and the high mortality associated with the condition.

Updates on Management of transfusion induced Iron Overload: A Systematic Review

Multiple blood transfusions lead to an excess iron buildup in the body's organs, which damages the organs. This systematic review investigated the recently published approaches to manage transfusion-induced iron overload. PubMed, SCOPUS, Web of Science, Science Direct, and Cochrane Library were systematically searched to include the relevant literature. Rayyan QRCI was used throughout this systematic approach. Our results included eleven studies with a total of 1635 patients diagnosed with transfusional iron overload. Iron excess is a major challenge in patients with chronic anemia who require frequent transfusions. Evidence from numerous clinical trials has shown that giving chelation therapy to individuals with transfusion-induced iron overload clearly reduced their iron burden and improved organ function. We found that Amlodipine, lupatercept, and chelating agents are safe and effective options for transfusion dependant thalassemia (TDT) patients. Additionally, Amlodipine or lupatercept combined with chelating agents are more efficient in lowering serum ferritin and o regularly drank green tea experienced significant reductions in iron accumulation. Deferiprone (DFP) has provided sickle cell disease (SCD) patients with a new therapeutic choice. The effects of this oral iron chelator were equivalent to those of deferoxamine (DFX) given subcutaneously in terms of reducing transfusional iron excess. In line with what had previously been seen in thalassemia syndrome patients, DFP showed a tolerable safety profile.

Compliance and clinical benefit of deferasirox granule and dispersible tablet formulation in pediatric patients with transfusional iron overload: in a randomized, open-label, multicenter, phase II study.

CALYPSO (clinicaltrials gov. Identifier: NCT02435212), a randomized, open-label, multicenter, phase II study evaluated the compliance, clinical benefits, and safety of deferasirox granules and dispersible tablets (DT) in pediatric patients with iron overload. Iron chelation therapy-naive and iron chelation therapy-pretreated patients aged 2 to <18 years with transfusion- dependent anemias were enrolled. Patients were randomized 1:1 to deferasirox granules or DT for 48 weeks, stratified by age group and prior iron chelation therapy. In this study, the co-primary objectives are to evaluate compliance and change from baseline in serum ferritin after 24 weeks for both formulations in iron chelation therapy-naive patients. In total, 224 patients, mostly with β-thalassemia major (63.4%), were randomized to granules (N=112) or DT (N=112). Primary analysis was conducted when 96 iron chelation therapy-naive patients had completed 24 weeks of treatment/discontinued early; least squares mean (LSM) compliance in the deferasirox granules and DT groups, was 86.8% and 84.3% (difference 2.6%; P=0.360) respectively, while least squares mean change from baseline in serum ferritin was +4.8 and -171.5 ng/mL (difference: 176.4 ng/mL; P=0.255). Slight differences were observed in the observer/patient-reported outcome scores between the granule and dispersible-tablet groups and the overall scores indicate good adherence, satisfaction/preference, fewer concerns and good palatability with both deferasirox formulations. Safety analyses (N=221) found that the most frequently observed adverse events (granules and DT) were increased urine protein/creatinine ratio (>0.5 mg/mg; 24.5% and 34.2%), upper respiratory tract infection (28.2% and 29.7%), and pyrexia (26.4% and 23.4%). In iron chelation therapy-naive patients, mean compliance and change from baseline in serum ferritin with both deferasirox formulations were not significantly different. The safety profile was comparable between granule and DT formulations, and was consistent with the general safety profile of deferasirox.

EE309 The Economic Burden of B-Thalassaemia, Sickle Cell Disease, and Myelodysplastic Syndrome: A Literature Review

Individuals with sickle cell disease (SCD), β-thalassaemia or myelodysplastic syndromes (MDS) commonly require red blood cell transfusions, increasing their risk of transfusional iron overload. In individuals with SCD, β-thalassaemia, or MDS, both the underlying condition and the treatment regimens can have a significant effect on health related quality of life (HRQoL) and costs, with indirect costs arising from presenteeism, absenteeism, and non-work related productivity losses. The aim of the present study was to review and summarize the literature on the economic burden of SCD, β-thalassaemia and MDS.

Deferiprone (Ferriprox)

&#x0D; CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.&#x0D; The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.&#x0D; This review assesses deferiprone (Ferriprox), 1,000 mg oral tablets and 100 mg/mL oral solution.&#x0D; Indication: The treatment of patients with transfusional iron overload due to sickle cell disease or other anemias.&#x0D;

Deferiprone (Ferriprox)

&#x0D; CADTH recommends that Ferriprox should be reimbursed by public drug plans for the treatment of patients with transfusional iron overload due to sickle cell disease (SCD) or other anemias if certain conditions are met.&#x0D; Ferriprox should be covered based on the criteria used by each of the public drug programs for deferasirox (DFX), the other orally administered treatment for transfusional iron overload for patients with SCD and other anemias.&#x0D; Ferriprox should only be prescribed by clinicians who have expertise managing SCD and if the cost of Ferriprox is not more than the lowest cost iron chelation therapy used to treat transfusional iron overload for SCD or other anemias.&#x0D;

An evaluation of deferiprone as twice-a-day tablets or in combination therapy for the treatment of transfusional iron overload in thalassemia syndromes

ABSTRACT Introduction Regular blood transfusions in patients with thalassemia syndromes can cause iron overload resulting in complications including cirrhosis, heart problems, or endocrine abnormalities. To prevent iron overload toxicity in these patients, three iron chelators are currently FDA-approved for use: deferoxamine, deferasirox, and deferiprone. In the United States, deferiprone has been approved for three times daily dosing since 2011 and has recently gained approval for twice-daily administration. Areas Covered A PubMed literature search was performed with the keywords ‘deferiprone’ and ‘thalassemia.’ Relevant original research studying deferiprone’s effects on transfusional iron overload in patients with thalassemia syndromes was included. Exclusion criteria included case reports and review papers. Deferiprone is effective at reducing serum ferritin levels in patients with iron overload. Twice-daily administration provides a similar level of iron chelation as three times daily dosing with a comparable side effect profile and increased patient acceptability. Expert Opinion New studies are highlighting deferiprone’s potential for combination therapy with either deferoxamine or deferasirox to improve iron chelation. Deferiprone’s ability to significantly decrease cardiac and liver iron content can be utilized in other transfusion-dependent hematologic conditions, as evidenced by its recent approval for use in the United States for sickle cell disease or other anemias.

Prevalence and Management of Transfusional Iron Overload in Syrian Beta Thalassemia Major Patients Pre and during the Syrian Conflict.

The primary aim of this study was to evaluate the prevalence of iron overload and the real-world clinical effectiveness of the iron chelation therapies (ICTs) in Syrian patients with transfusion-dependent beta thalassemia major (BTM) prior to and during the ongoing Syrian conflict. This single-center, two-stage observational study was conducted at Homs National Thalassemia Center (HNTC) prior to (2009) and during (2019) the armed conflict. The prevalence and the severity of iron overload, as well as the effectiveness of four iron chelation regimens, were assessed using serum ferritin (SF) concentrations as a means of monitoring in two cohorts of BTM patients receiving deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX), or a combination of DFO and DFP therapy in both years. Statistical analyses encompassed one-way ANOVA, Kruskal-Wallis, Mann-Whitney U, and chi-square (χ2) tests for the comparisons of the variables and the frequencies between the two cohorts and subgroups. We included all eligible BTM patients at HNTC in 2009 (n = 205) and 2019 (n = 172). Only 84 patients from the 2009 cohort were accessible in 2019. Our findings revealed that 98% and 89% of the patients had iron overload (SF ≥ 1500 ng/mL) and comparable elevated median SF concentrations (3868 and 3757 ng/mL) in 2009 and 2019, respectively (P = 0.275). Furthermore, patients on DFO demonstrated the poorest control of iron overload and the highest SF concentrations (4319 and 5586 ng/mL), whereas those on DFX achieved superior outcomes and the lowest SF concentrations (3355 and 2152 ng/mL) in both years. Twenty-six patients from the 2019 cohort received no ICT for six years (from 2012 to 2018) and experienced extremely severe iron overload with SF levels ranging between 4481 and 16,000 ng/mL. Our findings prove a high prevalence of iron overload and suboptimal chelation outcomes in Syrian BTM patients, both prior to and during the ongoing armed conflict, despite the provision of free ICTs at HNTC. Poor adherence and older age of patients may explain the unfavorable outcomes of DFO and (DFO+DFP) regimens, whereas younger age and higher socioeconomic status may have contributed to the lowest SF and superior outcomes in patients on DFX. This study also demonstrates the crucial role of the National Thalassemia Centers, namely HNTC, in providing health services to BTM patients in times of peace and conflict.

Prevalence of Iron Overload and Chelation Therapy in patients of Thalassemia Major and Knowledge and Attitude of Population towards Iron Chelation Therapy in Sargodha, Pakistan

Background: Whether familial or sporadic, whatever the cause may be, among hereditary hematological disorders, thalassemia accounts for 4.5 out of 10,000 live births worldwide1. Among other complications that these patients have, magnitude of transfusion related iron overload ranges from 9.5%-18%2. Prevalence of post transfusion iron overload in Southeast Asia is much higher than Western world3. Aim: To measure the prevalence of iron overload and chelation therapy in patients of thalassemia major and knowledge and attitude of population towards iron chelation therapy in Sargodha, Pakistan. Methods: This was a cross-sectional study conducted at Rai Hospital, a private-sector hospital and Hilal-e-Ahmar Hospital in Sargodha. Total 390 patients of beta thalassemia major aged 1 month-20 years were included in the study. Data Records of 390 patients of beta thalassemia major, confirmed on hemoglobin electrophoresis admitted in the hospital from June 2021 to June 2022 were included. Data were collected on socio-demographics clinical and laboratory profile. Analysis was done in SPSS Results: The mean age of the participants was 8.79 years, and 51.2 % were males and 48.9 % were females. Iron overload was found in 85.64% % of patients. Highest figure was 18,666ng/ml. Mean serum ferritin level was 3815 ng/ml. 30.2% received regular chelation therapy; 35.3%was on irregular chelation therapy and in 34.3% it was not started yet. Significant factors associated with iron overload and lack of chelation therapy were highly constrained socioeconomic status, repeated and frequent transfusions, lack of knowledge of importance of chelation therapy and unawareness of complications of transfusion. Conclusion: Considering the prevalence and perils of disease itself and treatment related complications government should focus on establishing thalassemia centers nationwide to cater problems faced by these patients where trained doctors and paramedical staff can counsel them regarding disease prognosis and importance of iron chelation therapy in course of disease. Keywords: Prevalence, iron overload, thalassemia major, chelation therapy

EE662 Cost-Effectiveness of Iron Chelation Therapies for the Treatment of Transfusional Iron Overload in Β-Thalassaemia, Sickle Cell Disease, and Myelodysplastic Syndrome: A Literature Review

EE662 Cost-Effectiveness of Iron Chelation Therapies for the Treatment of Transfusional Iron Overload in Β-Thalassaemia, Sickle Cell Disease, and Myelodysplastic Syndrome: A Literature Review