Iron Chelation Therapy Research Articles

PCR132 Symptoms and Impacts of Transfusion-Dependent Beta-Thalassemia: A Qualitative Interview Study and the Development of a Conceptual Model

Transfusion-dependent β-thalassemia (TDT) is a severe form of β-thalassemia that requires lifelong red blood cell transfusions (RBCTs) and iron chelation therapy beginning in infancy. To date, the impacts of TDT and current treatments on health-related quality of life (HRQoL) have not been qualitatively explored from a patient perspective.

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

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

Transition of Care for Patients with Thalassemia.

Thalassemia is one of the most common hemoglobinopathies affecting a large number of people in India and other countries of South-East Asia. For patients with most severe form of the disease- Transfusion Dependent Thalassemia (TDT), stem cell transplantation or gene therapy are only curative treatment which are not available to most of the patients because of lack of experts, financial constraints and lack of suitable donors. In such situations, most cases are managed with regular blood transfusion and iron chelation therapy. With this treatment, over the years, survival of the patients has improved and 20-40% cases are entering into adulthood. In the absence of structured transition of care programs, currently most adult TDT patients are being managed by pediatricians. This article highlights the need for transition of care for TDT patients, barriers to transition and how to overcome the barriers and process of transition of care to adult care team. The importance of empowering the patients in self-management of the disease and educating the adult care team to achieve the desired outcome of transition program is highlighted.

Abstract #1404780: Implementing a Screening Protocol for Endocrinopathies in Patients with Secondary Hemochromatosis due to Sickle Cell Anemia

Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy characterized by hemolytic anemia, intermittent small vessel occlusion, and organ dysfunction. Red blood cell transfusions are a therapeutic mainstay in SCD, which can lead to iron overload and endocrine disease. However, due to diagnostic difficulties and lack of data, there is not a wide consensus in approach. This has led to many practitioners screening for endocrinopathies only once patients are symptomatic. In this study, we implemented a standardized protocol for screening of iron overload and certain endocrinopathies in a single-study cohort of patients with SCD to assess viability in real-world practice and to detect disease prior to significant burden. We studied 19 patients diagnosed with SCD or sickle-cell trait (SCT) at a single institution. Patients had serum testing for ferritin and a metabolic panel at usual clinical visits. Iron overload was diagnosed with serum ferritin levels of at least 1000 ng/mL. If iron overload was detected, additional testing for 25-Hydroxyvitamin D (OHD), Thyroid Stimulating Hormone (TSH), Parathyroid Hormone (PTH), and Insulin-Like Growth Factor-1 (IGF-1) was obtained. Nineteen patients (12 men and 7 women) were included with a mean age of 32 years old. Twelve patients and seven patients were diagnosed with SCD and SCT, respectively. The average ferritin levels of SCD and SCT patients were 4874 and 270 ng/mL, respectively. Nine patients had ferritin levels greater than 1000 ng/mL, eight of which were diagnosed with SCD, one was diagnosed with SCT, and seven of which were prescribed iron chelation therapy. Of these nine patients, the average random glucose was 103 ng/mL. The average serum calcium corrected for albumin levels was 9.3 ng/mL. Seven of eight patients were found to have low 25-OHD levels with two of four patients showing elevated serum PTH. One of six patients had abnormal thyroid testing, with an elevated TSH and normal free thyroxine. Three of five patients showed abnormal IGF-1 testing, with low IGF-1 levels and low IGF-1 binding protein levels. This study successfully implemented a protocol for screening for endocrinopathies in a cohort of SCD and SCT patients at a single institution. We showed evidence that many patients with iron overload demonstrated abnormalities in 25-OHD, PTH, TSH, and IGF-1. The few studies that have been done to analyze this topic have shown findings of growth failure, osteopenia, hypogonadism, hypothyroidism, and glucose intolerance in SCD and SCT patients. This study did not explore bone disease or sex hormone function due to difficulty in performing these tests and obtaining insurance payor coverage. An additional limitation includes low sample size. However, this study replicates real-world care for these patients due to these barriers, making these methods easily translatable to other clinical settings. Our findings suggest implementation of a standardized protocol for iron overload and endocrinopathy screening in SCD and SCT patients is not only viable but could also detect disease before symptom onset when intervention is more effective.

Iron-loaded deferiprone can support full hemoglobinization of cultured red blood cells

Iron, supplemented as iron-loaded transferrin (holotransferrin), is an essential nutrient in mammalian cell cultures, particularly for erythroid cultures. The high cost of human transferrin represents a challenge for large scale production of red blood cells (RBCs) and for cell therapies in general. We evaluated the use of deferiprone, a cell membrane-permeable drug for iron chelation therapy, as an iron carrier for erythroid cultures. Iron-loaded deferiprone (Def3·Fe3+, at 52 µmol/L) could eliminate the need for holotransferrin supplementation during in vitro expansion and differentiation of erythroblast cultures to produce large numbers of enucleated RBC. Only the first stage, when hematopoietic stem cells committed to erythroblasts, required holotransferrin supplementation. RBCs cultured in presence of Def3·Fe3+ or holotransferrin (1000 µg/mL) were similar with respect to differentiation kinetics, expression of cell-surface markers CD235a and CD49d, hemoglobin content, and oxygen association/dissociation. Replacement of holotransferrin supplementation by Def3·Fe3+ was also successful in cultures of myeloid cell lines (MOLM13, NB4, EOL1, K562, HL60, ML2). Thus, iron-loaded deferiprone can partially replace holotransferrin as a supplement in chemically defined cell culture medium. This holds promise for a significant decrease in medium cost and improved economic perspectives of the large scale production of red blood cells for transfusion purposes.

Impact of Iron Overload and Iron Chelation with Deferasirox on Outcomes of Patients with Severe Aplastic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation

Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of transplantation. This study aimed to examine the impact of pretransplantation iron overload (IO) on the outcomes of allo-HSCT in patients with SAA. It also investigated whether iron chelation (IC) therapy is necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. The study consisted of 2 parts. In cohort 1, which was retrospective and conducted from April 2012 to December 2018, SAA patients receiving their first allo-HSCT were divided into 2 groups based on their pretransplantation serum ferritin (SF) level: the IO group (SF >1000 ng/mL; n=17) and the non-IO group (SF ≤1000 ng/mL; n=48). Cohort 2, a prospective clinical trial conducted from January 2019 to July 2020, included SAA patients diagnosed with IO who were treated with IC therapy using deferasirox at a dose of 10 to 30 mg/kg. Patients were separated into 2 groups based on their pretransplantation SF level: the IC success (ICsuccess) group (SF ≤1000 ng/mL; n=18) and the IC failure (ICfailure) group (SF >1000 ng/mL; n=28). All participants were evaluated for the correlation between pretransplantation SF level and transplantation outcomes. A P value <.05 was considered statistically significant. There was no significant difference in the speed of engraftment among the 3 cell lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the 2 groups in both cohorts. Of note, however, in cohort 1, both 1-year overall survival (OS) (41.2% versus 83.3%; P < .001) and 3-year OS (35.3% versus 83.3%; P < .001) were significantly worse in the IO group. Furthermore, 180-day transplantation related mortality (TRM) (47.1% versus 14.6%; P=.005) and 1-year TRM (52.9% versus 16.7%; P=.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, 1-year OS (88.9% versus 42.9%; P=.003) and 3-year OS (83.3% versus 42.9%; P=.007) were significantly better in the ICsuccess group, whereas 180-day TRM (11.1% versus 39.3%; P=.040) and 1-year TRM (11.1% versus 57.1%; P=.003) were significantly lower in the ICsuccess group. These differences were confirmed in both univariate and multivariate analyses. This study involving 2 cohorts shows that pre-HSCT IO has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with an SF level <1000 ng/mL was found to be necessary and could potentially improve the outcomes.

Evaluation of diastolic dysfunction in multi-transfused thalassemia patients

Background: An important complication of thalassemia is iron deposition in the cardiac tissue resulting in degeneration, fibrosis and dysfunction. Cardiac disease is the primary cause of death. Aims and objectives were to detect early cardiac involvement in patients with transfusion dependent thalassemia by conventional doppler echocardiography and tissue doppler imaging while they are still asymptomatic. Methods: 150 patients in the age group of 2-18 years who were receiving regular and frequent blood transfusions were enrolled in this study. Institutional ethical clearance was taken. After informed consent, 2D echocardiography was performed on all the patients. Previous blood reports reviewed. Various parameters like mitral flow pattern, LVEF and Tricuspid regurgitant jets were taken into account to diagnose cardiac dysfunction. Results analysed by standard statistical tests. Results: Out of 150 patients, 58% were males and 42% were female patients. The 13 (8.6%) patients were diagnosed as having diastolic dysfunction. Out of 150, majority (86.6%) were below the age of 15 years, 81.33% children were diagnosed as having thalassemia before the age of 2 years, 97% patients were on regular iron chelation therapy, 32% patients had pre-transfusion Hb &lt;7 gm/dl, 78.66% patients had S. ferritin levels &gt;2500 ng/ml and more number of males (7.33%) have undergone splenectomy than females. Conclusions: Diastolic dysfunction on Doppler echocardiography is an early sign of myocardial dysfunction in patients with beta thalassemia.

Efficacy of Hydroxyurea in Transfusion-Dependent Major β-Thalassemia Patients: A Meta-Analysis.

The present meta-analysis was conducted to determine the efficacy of hydroxyurea in patients with transfusion dependent major β-thalassemia.The present meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines.A systematic search was carried out to evaluate the efficacy of hydroxyurea in patients with transfusion-dependent B-thalassaemia using electronic databases, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. The keywords used to search for relevant studies included "hydroxyurea", "thalassemia", "transfusion-dependent", and "efficacy".Outcomes assessed in the present meta-analysis included transfusion in one year and intervals between transfusions (in days). Other outcomes assessed in the present meta-analysis were fetal hemoglobin (%), hemoglobin (%), and ferritin levels (ng/dl). Total of five studies were included in the analysis enrolling 294 patients with major B-thalassemia.The pooled analysis reported that the mean interval between transfusions was significantly higher in patients receiving hydroxyurea compared to those not receiving hydroxyurea (mean deviation {MD}: 10.07, 95% CI: 2.16, 17.99).Hemoglobin was significantly higher in patients receiving hydroxyurea compared to its counterparts (MD: 1.71, 95% CI: 0.84, 2.57).Patients receiving hydroxyurea had significantly lower ferritin levels compared to those not receiving hydroxyurea (MD: -299.65, 95% CI: -518.35, -80.96).These findings suggest that hydroxyurea may be a promising and cost-effective alternative to blood transfusions and iron chelation therapies for beta-thalassemia patients. However, the authors noted that further randomized controlled trials are needed to validate these findings and to determine the optimal dosages and treatment regimens for hydroxyurea in this patient population.

Evaluation of conventional renal function tests in β-thalassemia major patients in Nineveh province

β-thalassemia is an inherited anemia, caused by impaired β-globin chain synthesis. The disease leads to serious health problems unless treated by regular blood transfusion and iron chelating therapy. However, complications from continuous therapy may arise due to iron overload and toxicity of iron chelating therapy, it may affects many organs in the body including the renal system. The present study was directed to study the changes in conventional renal function tests that may occur in β-thalassemia patients. The present study consisted of two groups of β-thalassemia patients; group A, 40 transfusion dependent β-thalassemia patients receiving only regular blood transfusion, age ranged 1-4 years; Group B, 40 transfusion dependent β- thalassemia patients receiving regular blood transfusion and deferroxamine chelation therapy, age ranged 4-20 years old. In addition to a control group C, 40 subjects, age ranged 1-20 years. Blood samples were collected and serum was separated for measurement of creatinine, urea, and ferritin. Urine samples were also collected for measurement of microalbuminuria. There was a significant decrease in serum creatinine, and a significant increase in serum urea in group B when compared with their control (P≤0.01). In addition, there was a significant increase in serum ferritin in groups A and B when compared with their controls (P≤0.01). On the other hand, there were no significant changes in microalbuminuria between groups A and B when compared with their controls. The results of the present study showed no deterioration in renal functions in β-thalassemia patients in both groups A and B regarding serum creatinine and urea in addition to microalbuminuria, although, subclinical alteration in renal functions could be expected in those patients, so that measurement of other early markers of renal dysfunction is occasionally recommended.

Evaluated the Correlation Between Serum Ferritin and Iron Overload of Liver, Spleen and Heart in β-Thalassemia Major Patients by MRI T2&amp;lt;sup&amp;gt;*&amp;lt;/sup&amp;gt; Method

β-Thalassemia major often results in an excess of iron in the body due to frequent blood transfusions and enhanced absorption of iron in the gastrointestinal tract. Early detection of this condition and administering sufficient iron chelator therapy can significantly decrease the risk of complications and fatalities resulting from iron overload. MRI (Magnetic Resonance Imaging) T2^* is an accurate non-invasive method for assessing organ iron overload in β-Thalassaemia major patients. This study evaluated the correlation between serum ferritin and iron overload of liver, spleen, and heart in β -Thalassaemia major patients by MRI T2^* method. The design was a cross-section, descriptive study. We used MRI-T2^* to evaluate the correlation between serum ferritin and iron overload of liver, spleen, and heart in 24 Thalassaemia major patients admitted in Cho Ray hospital from 10/2013 to 1/2014, using a 1.5T MRI system (Siemens) with a body coil. T2^* measurements were taken in the liver, spleen, and myocardium using different gradient echo pulse sequences. T2^* values were calculated within homogeneous regions of interest (ROI) in the liver avoiding major blood vessels, spleen, and the entire thickness of the interventricular septum in the myocardium. Pearson correlation coefficient was used to evaluate correlations in the study with a significance threshold of p < 0.05 using SPSS 16.0 software. As results, moderate negative correlation between serum ferritin and liver, spleen MRI T2^* relaxation time (r = 0.57 and 0.755) and a weak negative correlation between serum ferritin and heart MRI T2^* relaxation time (r = 0.303). Liver and heart MRI T2^* readings were poorly correlated (r = 0.28). In conclusion, MRI T2^* is useful to evaluate the iron overload status in β thalassemia patients.

Abstract 3898: Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma

Abstract Lung cancer is the second most common and leading cause of cancer-related deaths worldwide with 85% of these cases being non-small cell lung carcinoma (NSCLC). Unfortunately, despite improvements in NSCLC outcomes, many of these tumors develop resistance against principal chemotherapies (e.g., cisplatin (CisPt) and doxorubicin (Doxo)), inducing abysmally low survival prognosis. Deferasirox (Def), an FDA-approved iron chelation therapy, is a drug under study for cancer therapy due to iron plays a key role in cell growth and energy production. Herein, we determined the effect of Def alone and in combination with CisPt and Doxo on NSCLC A549 cells. Viability assays results showed that Def has synergistic cytotoxic effects in combination with CisPt and Doxo at low uM concentrations after 24 h of incubation using the Chou Talalay method. In addition, qPCR gene expression studies showed that Def induced a significant downregulation of EGFR, VEGF, MMP9, MMP2, CHD4 genes related to resistance and metastatic process. In addition, we determined the overexpression of NDRG1 gene mediated by Def confirming the chelation of iron and disruption of iron metabolism. Overall, this work will set the basis for adjuvant therapies against chemoresistance and metastasis processes using an iron chelator. Citation Format: Natalia I. Ortiz Alvelo, Grace Torres, Sthephanie Estrada, Daraishka Pérez, Yancy Ferrer, Yamixa Delgado. Synergistic combination of the iron chelator deferasirox with cisplatin and doxorubicin chemotherapies against nonsmall cell lung carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3898.

5627905 TECHNOLOGY ACCESS AND PREFERENCES FOR SMARTPHONE APP INTERVENTION TO OPTIMIZE IRON CHELATION ADHERENCE AMONG ADOLESCENTS, YOUNG ADULTS, AND PARENTS OF INDIVIDUALS RECEIVING CHRONIC TRANSFUSIONS

Background: Iron chelation therapy (ICT) is an essential medication for people with thalassemia and other hematological disorders requiring long-term red blood cell transfusion to minimize the risk of iron overload. Suboptimal adherence to iron chelation medication is prevalent and has been associated with increased risk of iron overload, resulting in increased morbidity, mortality, and healthcare utilization. Widespread use of personal technology makes mobile health (mHealth) an attractive platform to promote adherence. Aims: The objective of this study was to examine access to mobile technology and preferences for an mHealth intervention to improve adherence to ICT. Methods: This is an analysis of a cross-sectional survey that was administered through REDCap using tablets during pRBCs transfusion visits at Ann & Robert H. Lurie Children’s Hospital of Chicago. Parents of children receiving chronic transfusions, as well as adolescents and young adults (AYAs) receiving chronic transfusions were enrolled between August 2018 and June 2019. Patients had to have a hematologic diagnosis requiring chronic transfusions, be on an iron chelation therapy, and be 12 years or older to complete the survey. Parents were required to have a child older than 24 months who met these criteria. Results: A total of 60 participants were included (median age [IQR] 31.5 [20-39]; female, 36.7% [40/60]), with a total of 29 parents and 31 patients. The most endorsed mHealth app features among participants, both parents and patients, included laboratory monitoring (91.7%, 55/60), reminders to take ICT (83.3%, 50/60), and education about ICT (81.7%, 49/50). In particular, parents’ most endorsed features included laboratory monitoring (93.1%, 27/29), and education about ICT (86.2%, 25/29) (Figure 1). On the other side, AYA’s most endorsed features included laboratory monitoring (90.3%, 28/31) and reminders to take iron chelation medication (90.3%, 28/31) (Figure 1). There were no significant differences between parents and patients in their preferences, although there was a trend towards a greater proportion of patients compared to parents who preferred positive feedback in the form of encouraging messages when taking medications as an app feature (87.1% vs. 68.96%, p =0.09). Conclusions: Parents and AYAs reported a strong interest in multiple mHealth app features. Participants provided valuable insight into optimal strategies and preferred app features for developing a multifunctional technology-based behavioral intervention (mHealth app), to promote ICT adherence for AYA with thalassemia or other chronic-transfusion dependent conditions.

5613341 REAL-WORLD CHANGES IN KIDNEY FUNCTION FOR PATIENTS WITH SICKLE CELL DISEASE OR OTHER ANAEMIAS RECEIVING IRON CHELATION THERAPY IN THE US

Background: Treating sickle cell disease (SCD) and other anaemias with frequent blood transfusions increases the bodily iron burden, which can be mitigated through iron chelation therapy (ICT).1 As these populations age, impaired kidney function becomes more prevalent, which is also impacted by disease progression and use of ICT.1 An understanding of how kidney function changes over time for real-world patients on ICT is critical for optimal long-term management. Aims: To evaluate real-world changes in kidney function, specifically in estimated glomerular filtration rate (eGFR) and serum creatinine levels in patients with SCD or other anaemias and who received ICT in the United States (US). Methods: Electronic medical records were gathered from the TriNetX electronic database, representing 46 US healthcare organisations. Records were dated between 1999 and 2021 (data cutoff date: September 7, 2021). The baseline period for each patient was defined as the 365 days prior to the date ICT was first dispensed; the follow-up period was the following 730 days (24 months). eGFR and serum creatinine assessments during the follow-up period were analysed using a mixed model repeated measures approach, adjusted for first iron chelation event, age, sex, race, time of assessment, and baseline eGFR, creatinine, and haemoglobin. Eligible patients had to have at least 2 eGFR measurements during follow-up. Study endpoints were changes in eGFR, serum creatinine level, proteinuria, and albuminuria over time, as well as the proportion of patients with SCD or other anaemias who developed kidney impairment (eGFR <60 mL/min/1.73m2) during follow-up. Results: Analyses of eGFR and creatinine levels were conducted on a total of 1527 patients diagnosed with SCD (n = 1510) or other anaemias (n = 17). More patients were first dispensed deferasirox (n =1237) than deferoxamine (n = 223) and deferiprone (n = 67). Compared to baseline, eGFR values remained stable over 24 months after patients were dispensed deferiprone, while there were statistically significant decreases in eGFR over the same period for those given deferasirox or deferoxamine (Table 1). The proportions of patients with SCD or other anaemias who developed kidney impairment during follow-up were 13.9% (deferasirox), 9.2% (deferoxamine), and 11.9% (deferiprone). There were statistically significant reductions in eGFR and statistically significant increases in serum creatinine over 24 months from baseline among patients who first received deferasirox and deferoxamine (Table 1). Proteinuria and albuminuria analyses were not completed due to insufficient data; similarly, a small number of patients in the database were diagnosed with other anaemias to support distinct, formal analysis for this patient group. Summary/Conclusion: The data from this real-world US analysis indicate patients who were prescribed deferiprone had worse baseline kidney function prior to initiation of ICT. The data also indicate that deferiprone has a lesser detrimental impact on kidney function as measured by eGFR and serum creatinine level. This study could not assess treatment adherence. Although there are limitations owing to the retrospective nature of the data, the results may assist clinicians should in their choice of ICT for patients who have or are at risk for developing kidney impairment.Reference 1. Bhandari, Galanello, Eur J Haematol 2012; 89:187

5597199 AGEING WITH SICKLE CELL ANEMIA AND HOW TO FACE IT

Background: Sickle Cell Anemia, a hereditary monogenic disorder is caused by homozygous sickle mutation (Hb SS). Sickle erythrocytes promote vaso-occlusion and haemolysis, which are two major hallmarks of the disease. Vaso-occlusive crisis results from the sickle red cells obstructing and reducing blood flow to the vital organs leading to ischemia, necrosis and pain(2). Data show that other blood cells i.e. leukocytes and thrombocytes are involved in this process as well, and the process starts from up regulation of P-selectin which contributes in cellular interaction and vaso-occlusion later on(3,4). All these cells stick together and can’t easily move through the blood vessels. This situation can block small blood vessels and the movement of healthy, normal oxygen-carrying blood(5,6). Repeated episodes lead to bone and organ infarction and necrosis; organs damage occur over time. Hemochromatosis occurs as well, as a result of blood transfusions or/and persistent hemolysis. Patients suffering from this kind of anemia feel exhausted and need strictly monitoring for every health issues they represent, especially when they get older(8). Because of this pathologic condition’s complexity, the best method of treatment is a combined approach(1). Sickle Cell Disease is a very polymorphous disease and its severity varies largely in each patient, thats why the management has to be in a personalized model(7). Aims: To give an overview and our considerations related to Sickle Cell Disease in Albania Methods: To achieve the goal of treating and managing medically people living with Sickle Cell Disorder, we monitor every single sign and laboratory fluctuation happening to these patients in every clinical visit. F.A. is a female with Sickle Cell Disorder, 41 years old, diagnosed in early infancy and since then she has been treated with blood transfusions initially(in her hometown until 19 years old) and later on with pure red blood cells and iron chelation therapy in our clinic. This treatment was performed once per month. She was receiving Hydroxycarbamide as well. She started to be non compliant to ICT (iron chelation therapy) and as a consequence she has been presented with very high value of ferritin level (above 5000 ng/ml). On 2013 she gave birth to a baby. A severe haemolysis was seen over time, she was put in transfusions twice per month. No changes in ultrasound or images. Two years ago she demonstrated a severe anaemia, arterial hypertension and proteinuria. She was diagnosed with Chronic Kidney Disease grade 3. Since then she had a personalised supportive therapy and this year was put in dialysis. Results: According to our experience and our point of view Sickle Cell Disease seems to have a moderate burden in our country. A new era of novel drugs seem to encourage and realize better achievement in SCD management. Sharing best experiences and our clinical cases between us, may affect positively the quality and management of these diseases. Summary: A better understanding and a strictly monitoring of patients suffering from Sickle Cell Disease could help health professionals and patients themselves to cooperate and develop new modalities towards managing these polymorphous conditions.

5567917 COST COMPARISON OF TRANSFUSION CHOICES IN OMAN FOR PATIENTS SUFFERING FROM SICKLE CELL DISEASE

Background: Sickle cell disease(SCD) management can be challenging, requiring different therapeutic approaches because SCD could induce multiple complications. Red blood cell(RBC) transfusion is well known as one of the disease-modifying therapies available for long-term management. It’s supported by multiple randomized clinical trials for the prevention of disease complications such as stroke in adults and children with SCD.RBCs can be delivered via three methods: Simple transfusion(ST), manual exchange(ME) and automated red blood cell exchange(aRBCX). In ST, patients receive additional units of blood. The purpose is to raise the haemoglobin (Hb) to a steady state and maintain the oxygen-carrying capacity of blood. ME transfusion consists of removing the patient’s sickle-shaped RBCs and replacing them with healthy ones— lowering the concentration of sickled cells without increasing blood viscosity. This is performed using repeated alternating isovolumetric phlebotomy and blood transfusion. aRBCX involves removing sickled RBCs from the patient and rapid replacement with healthy RBCs while maintaining isovolemia. An advantage of aRBCX is the avoidance or minimization of costly iron chelation therapy to treat iron overload. Aim: SCD management is an important cost driver for health systems. The intent of this research was to compare the cost-effectiveness of different transfusion modalities. We wanted to compare the all-inclusive costs. and wanted to perform this evaluation in Oman, as the incidence of SCD ranges between 0.2% and 0.07%. This disease is considered one of Oman’s most common genetic blood disorders. Method: In-depth data about variables that drive costs have been collected to populate a de novo cost model. We collected data from the Royal Hospital and Sultan Qaboos University Hospital. Cost drivers that we took into consideration were disease incidence, cost of blood transfusion, medical equipment, disposables, cost of staff, complications, iron chelation therapy, hospitalization, and lives lost. The assessment took place in June 2020. The cost of the treatment intervention, cost of disease-related complications and the yearly cost of treatment imputable to each transfusion modality represented the most significant differences across the three transfusion choices. By populating the model with resources provided by the two above-mentioned hospitals, we could demonstrate the cost differences between transfusion choices and the potential benefits that healthcare providers can experience. The results demonstrate significant differences across cost parameters, such as Cost of treatment, Cost of treatment-related potential effect, Cost of complications, Cost of life years lost, and Estimated total yearly cost per patient. Results and conclusion: aRBCX promotes a reduction in overall resource utilization and improved patient outcomes. aRBCX is approximately 47% less costly than ST, and is approximately 23% less costly when compared to ME. By highlighting the consequence of treatment choice and its financial impact, we aim to support the adoption of aRBCX in comparison to alternative transfusion choices and validate future reimbursement considerations. aRBCX cost savings may lead to better adoption. We recommend researchers rerun these calculations with the model on an individual hospital basis.

Long-term Effect of Hematopoietic Stem Cell Transplantation on the Quality of Life of Patients with β-thalassemia Major in Guangxi, China - A Cross-sectional Study.

The purpose of our study was to compare the quality of life (QOL) of patients with hematopoietic stem cell transplantation (HSCT) for more than 2 years for β -thalassemia major (β-TM) with that of β-TM patients with conventional therapy (blood infusion and iron chelation) and that of the general population. This was a cross-sectional comparative study on the QOL of 225 β-TM patients treated with blood transfusion and iron chelation therapy, 133 β-TM patients who had undergone HSCT or 270 ageand sex-matched healthy individuals from Guangxi, China. Child-self and parent-proxy reports of the PedsQL 4.0 Generic Core Scales were used to prospectively evaluate QOL. The incidence of acute GVHD was 14.3% (grade III-IV in 4.5% of patients), and that of chronic GVHD was 3.8%. This was lower than that of previous studies since the inclusion of anti-thymocyte globulin (ATG). Patients who underwent transplantation from a voluntary donor had higher QOL scores and lower rates of acute GVHD, chronic GVHD and comorbidities than those receiving stem cell sources from an HLA mismatched related donor (haploidentical donor). Transplants with PBSCs or UCBT, PBSCT+BMT, BMT, or BMT+UCBT as stem cell sources did not have any impact on QOL. The QOL of β-TM patients was very similar to that of the general population. More complications (P<0.001), shorter post-transplantation time (P<0.001), and older age at HSCT (P=0.01) were associated with poorer child QOL (P=0.020). Additional analyses investigating QOL of β-TM patients receiving conventional treatment with β-TM revealed poorer outcomes than the cohort of transplanted patients. β-TM patients can be cured by HSCT and regain QOL as good as that of the general population. β-TM patients are suggested to undergo HSCT as soon as possible to avoid complications related to iron overload and blood infusion.

5610357 REDUCTION IN BLOOD TRANSFUSION BURDEN FOLLOWING INITIATION OF VOXELOTOR OR CRIZANLIZUMAB: A CASE SERIES

Background: Patients with sickle cell disease (SCD) often require blood transfusions. While transfusions may improve disease complications, resultant iron overload can lead to end-organ damage. Other transfusion complications include forming of alloantibodies and transmission of infection. Crizanlizumab and voxelotor have been shown respectively to reduce the frequency of vasoocclusive crises (VOCs) and improve anemia. This case series describes 5 patients with SCD who had a clinically significant decrease in transfusion burden following initiation of these therapies. Cases: Patient A is a 63-year-old woman with HbSBeta+thal and avascular necrosis (AVN) who was on intermittent erythrocytapheresis (apheresis) for symptomatic anemia and developed iron overload. Her serum ferritin was elevated despite chelation therapy. Upon initiation of voxelotor, the frequency of apheresis was reduced. She had a sustained improvement in her baseline hemoglobin (hgb) level as well as symptoms of anemia. Her ferritin decreased from 1253 to 714 ng/mL within 5 months and iron chelation therapy was discontinued. She had no change in acute care visits for VOCs (Table 1). Patient B is a 52-year-old woman with Hb SS, AVN and chronic pain who received intermittent simple transfusions for symptomatic anemia requiring 5 units of blood in the 12-months preceding initiation of voxelotor. She did not require any transfusions in the 12-month period following start of voxelotor. Hydroxyurea was discontinued once voxelotor was initiated due to antecedent myelosuppression at doses greater than 200mg. She had a sustained improvement in hgb as well as symptoms of anemia. She had a slight increase in acute care visits for VOCs (Table 1). Patient C is a 48-year-old man with Hb SS and retinopathy who was on monthly apheresis for many years to prevent VOCs. He had iron overload but declined iron chelation. To offset the transfusion associated iron overload, he opted to discontinue apheresis in favor of initiation of voxelotor and reinitiate hydroxyurea which had previously been discontinued. Following cessation of transfusions, he had a sustained improvement in hgb and no change in acute care visits for VOCs (Table 1). His port, placed solely for apheresis, was removed. His serum ferritin decreased from 2913 to 161 ng/mL in 18 months. Patient D is a 30-year-old man with Hb SS, AVN, chronic pain, and priapism who was on monthly apheresis for many years to prevent VOCs. He developed iron overload, however had poor compliance with chelation. After initiation of crizanlizumab for VOC prevention, the number of units utilized for apheresis was gradually tapered. Despite this, his hgb remained stable, he had no change in acute care visits for VOCs (Table 1) and reported an improvement in priapism frequency. Patient E is a 42-year-old woman with Hb SC, retinopathy, AVN, and chronic pain who received monthly apheresis for prevention of VOCs. Crizanlizumab was added for VOC prevention. She had sporadic childcare available, thus she missed some of her apheresis sessions. Despite this inadvertent decrease in transfusions, her hgb remained stable, and she had a decrease in acute care visits for VOCs (Table 1). Conclusion: In SCD patients who receive frequent simple or exchange blood transfusions for indications other than stroke prevention, tapering the amount of blood administered is possible, and should be considered when these patients are treated with crizanlizumab or voxelotor.

Evaluation of the Serum Level of Vascular Endothelial Growth Factor in Patients with Beta-Thalassemia Major and Sickle/Beta-Thalassemia, and its Correlation with Clinical and Laboratory Parameters

BACKGROUND: The most prevalent inherited disorders of red blood cells are hemoglobinopathies, with thalassemia and sickle cell diseases (SCDs) being the most common. In SCD and thalassemia major, angiogenesis has been identified as a substantial contributor to vascular-mediated tissue damage. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis. This study aims to assess the circulating level of serum VEGF in beta-thalassemia (β-thal) and sickle β-thal patients and also to explore the correlation with clinical and laboratory data. PATIENTS, MATERIALS AND METHODS: This is a cross-sectional study conducted on 80 individuals, clinical data were gathered, complete blood count, serum ferritin, and serum VEGF tests were done. RESULTS: Patients' age ranged from 1.5 to 17.5 years, males formed (70%). Platelet count was significantly higher in β-thal compared to sickle/β-thal (S/β-thal) patients, with a P = 0.015. Mean serum ferritin in patients was significantly higher in β-thal compared to S/β-thal patients, P &lt; 0.001. Patients' serum VEGF levels were noticeably higher than controls with P = 0.01. Strong positive correlation of serum VEGF with platelet count among the patients (r = 0.603, P &lt; 0.001). A significant positive correlation was observed between serum VEGF and the age of starting chelation therapy in thalassemic patients (r = 0.475, P = 0.006). CONCLUSIONS: Serum VEGF levels were significantly higher in patients compared to healthy controls, and there is a significant positive correlation between serum VEGF levels and the age at which iron chelation therapy was initiated as well as between serum VEGF levels and platelet counts in patients.

Thalassemia and Nanotheragnostics: Advanced Approaches for Diagnosis and Treatment

Thalassemia is a monogenic autosomal recessive disorder caused by mutations, which lead to abnormal or reduced production of hemoglobin. Ineffective erythropoiesis, hemolysis, hepcidin suppression, and iron overload are common manifestations that vary according to genotypes and dictate, which diagnosis and therapeutic modalities, including transfusion therapy, iron chelation therapy, HbF induction, gene therapy, and editing, are performed. These conventional therapeutic methods have proven to be effective, yet have several disadvantages, specifically iron toxicity, associated with them; therefore, there are demands for advanced therapeutic methods. Nanotechnology-based applications, such as the use of nanoparticles and nanomedicines for theragnostic purposes have emerged that are simple, convenient, and cost-effective methods. The therapeutic potential of various nanoparticles has been explored by developing artificial hemoglobin, nano-based iron chelating agents, and nanocarriers for globin gene editing by CRISPR/Cas9. Au, Ag, carbon, graphene, silicon, porous nanoparticles, dendrimers, hydrogels, quantum dots, etc., have been used in electrochemical biosensors development for diagnosis of thalassemia, quantification of hemoglobin in these patients, and analysis of conventional iron chelating agents. This review summarizes the potential of nanotechnology in the development of various theragnostic approaches to determine thalassemia-causing gene mutations using various nano-based biosensors along with the employment of efficacious nano-based therapeutic procedures, in contrast to conventional therapies.

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.