Beta-thalassemia Patients Research Articles

The correlation of cardiac biomarkers and myocardial iron overload based on T2* MRI in major beta-thalassemia.

Cardiac hemosiderosis is the primary factor to derive the pathogenesis of cardiac dysfunction in patients with transfusion dependent thalassemia. Biomarkers assessment along with T2 * MRI study could be employed to evaluate the severity of iron deposition-related damage and determination of the diagnostic and prognostic value of these inflammatory factors. The study was conducted on 62 patients (12-44years old) with major thalassemia. The patients were under regular blood transfusion and they had no signs of cardiac defects, and chronic diseases. The serum levels of inflammatory factors (NT-proBNP, CRP, Copeptin HS) were determined before routine transfusion. Cardiac iron overload was assessed by T2* MRI (within the last three months), and T2* lower than 20ms was considered as cardiac siderosis. The obtained results were analyzed using statistical methods. 92% of patients showed an increased level of hs-CRP (> 2µg/dL). All cases showed increased levels of NT-proBNP (> 150pg/mL). Only 29% of subjects showed high level of Copeptin, 25.8% of patients demonstrated cardiac siderosis based on the T2* MRI (< 20ms) results. The serum levels of inflammatory factors were not significantly correlated with cardiac siderosis. Given the obtained results, it could be deduced that the serum levels of inflammatory factors could not be exploited for early detection of cardiac siderosis in major beta-thalassemia patients.

THE FREQUENCY OF HLA-A, B AND DRB1 ALLELES IN PATIENTS WITH BETA THALASSEMIA

HLA class I and II alleles are shown to be associated with certain diseases. A restricted numbers of alleles were found to be related to alloimmunisation in thalassemia population. The role of human leucocyte antigens in thalassemia is trend topic. In this study, the aim was to evaluate the differences in HLA frequencies of beta thalassemia patients comparing with healthy controls.

Achievement of Pre- and Post-Transfusion Hemoglobin Levels in Adult Transfusion-Dependent Beta Thalassemia: Associated Factors and Relationship to Reduction of Spleen Enlargement.

IntroductionThe achievement of blood transfusion hemoglobin targets in transfusion-dependent beta-thalassemia patients is influenced by several factors such as genotype, hypersplenism, blood compatibility, donor blood adequacy, and transfusion interval. Failure to achieve these targets leads to an increase in the size of the spleen. Meanwhile, the post-transfusion hemoglobin of thalassemia patients that is not regularly evaluated has made it difficult to determine donor adequacy. Therefore, this study aims to determine the proportion of patients who achieve optimal pre- and post-transfusion hemoglobin levels, determine the factors involved, and the relationship between achieving hemoglobin levels with spleen enlargement in adult transfusion-dependent beta-thalassemia patients.MethodsThis retrospective cohort study was conducted using total sampling of adult thalassemia transfusion-dependent patients at Cipto Mangunkusumo Hospital. Data were obtained through medical records.ResultsA hundred and ten study subjects fulfilled inclusion criteria. The results showed that the blood transfusion deficit <30 mL/kg/year was associated with achieving pre- and post-transfusion hemoglobin targets (p = 0.008). Furthermore, there were significant differences between the groups that achieved the pre- and post-transfusion target hemoglobin levels on the reduction of spleen enlargement in centimeters (p < 0.001). However, thalassemia genotype, blood compatibility, and transfusion interval did not correlate with the achievement of pre- and post-transfusion hemoglobin.ConclusionThe achievement of pre- and post-transfusion hemoglobin levels in adult transfusion-dependent beta-thalassemia patients significantly reduced spleen enlargement and contributed to better patient outcomes.

Uncertain crisis time affects psychosocial dimensions in beta-thalassemia patients during Covid-19 pandemic: A cross-sectional study.

Psychosocial variables are key factors influencing the delicate equilibrium of chronic patients during crisis time. In this study, we explored distress, anxiety, depression, loneliness, coping strategies, and changes in life habits in 43 beta-thalassemia patients and 86 controls during Covid-19 pandemic. Patients showed higher anxiety levels and a predominant transcendent coping profile compared to controls. Patients significantly differed from controls in outdoor habits. Social isolation and habits changes in uncertain life-threaten situations as Covid-19 pandemic are particularly detrimental in fragile beta-thalassemia patients. Structured support interventions are needed to promote well-being in the Covid-19 era.

Pregnancy outcome in women with transfused beta-thalassemia in France.

Because of chronic anemia, hypogonadotropic hypogonadism, and iron chelation, pregnancy in homozygous and heterozygous compound beta-thalassemia patients stays a challenge. Pregnancies of transfused beta-thalassemia women registered in the French National Registry, conducted between 1995 and 2015, are described. These pregnancies were compared with pregnancies in healthy women and to data previously published in the literature. Fifty-six pregnancies of 37 women were studied. There were 5 twin pregnancies. Assisted reproductive technologies (ART) were used in 9 pregnancies. Median term at delivery was 39 amenorrhea weeks, and median weight at birth was 2780g. Cesarean section was performed in 53.6% of the pregnancies. There were 6 thromboembolic events, 6 serious infections, 6 pregnancy-induced hypertensions (PIH), 6 intrauterine growth retardations (IUGR), 5 severe hemorrhages, 4 gestational diabetes, 3 alloimmunizations, 2 heart diseases, and 1 pre-eclampsia. There were 5 infections and 4 osteoporosis in the first year of post-partum. ART and cesarean sections were more often used in the beta-thalassemia group, compared to control subjects. Thromboembolic events, PIH, hemorrhage at delivery, and IUGR were more frequent in the beta-thalassemia group. Time to delivery was not different, but infant weight at birth was significantly smaller in the beta-thalassemia group. In the post-partum period, global maternal complications were more frequent in the beta-thalassemia group. Pregnancy in transfused beta-thalassemia women is safe with rare obstetrical and fetal complications. Cesarean section remains often chosen, and infant weight at birth remains smaller than that in the general population, despite delivery at full term.

Prevalence of iron deficiency anemia and beta thalassemia carriers among relatives of beta thalassemia patients in Nile Delta region, Egypt: a multicenter study

BackgroundScreening of β thalassemia among close relatives is more feasible in highly prevalent countries with limited resources. The purpose of this study is to determine the prevalence of β thalassemia carriers and iron deficiency anemia among relatives of β thalassemia patients in Mid Delta, Egypt.MethodsThis is a cross-sectional multi-center study conducted on 2118 relatives of patients with β thalassemia from different Egyptian governorates in the Mid Delta region. They were subjected to history taking with precise determination of geographic location, general examination, and the following investigations: complete blood counts, serum ferritin for those who showed microcytic hypochromic anemia, and high-performance liquid chromatography for those who were not diagnosed as iron deficiency anemia.ResultsThe total prevalence of iron deficiency anemia among close relatives of confirmed β thalassemia patients in the Nile Delta region was 17.19%. The highest prevalence of iron deficiency anemia (45.05%) was reported in Al-Gharbia Governorate, followed by Al-Menoufia Governorate (21.67%), and the lowest prevalence was that of Al-Sharkia Governorate (4.91%). The differences were highly statistically significant (p < 0.001). β thalassemia carrier prevalence rate in the studied relatives was 35.84%, with the highest prevalence detected in Al-Sharkia Governorate (51.32%), followed by Kafr-Alsheikh and Al-Dakahilia Governorates (41.78%, 37.13%) respectively, while Al-Menoufia Governorate had the lowest prevalence rate (25.00%). These differences were also highly statistically significant (p < 0.001).ConclusionMore than one-third of relatives of patients with β thalassemia are carriers of the disease, while 17.19% suffer from iron deficiency anemia. This study demonstrates the importance of tracing the high number of beta thalassemia carriers among relatives of patients with β thalassemia in Egypt.

Correlation of Transferrin Saturation and Serum Ferritin with Bone Mass Density in Adult Transfusion Dependent Beta-Thalassemia Patients.

BackgroundThe use of regular blood transfusions and iron chelation therapy to treat thalassemia has improved survival and increased the incidence of osteoporosis. Moreover, iron toxicity is one of the contributing factors that reduce bone mass density in adult transfusion-dependent beta-thalassemia patients. Therefore, this study aims to determine the proportion of low bone mass density in adult thalassemia patients and transferrin saturation, as well as serum ferritin, which correlates to the skeletal condition.MethodsThis is a cross-sectional study conducted in Thalassemia and Hematology Medical Oncology Clinics of Cipto Mangunkusumo Hospital in March 2016. The anthropometric data and hemoglobin levels were obtained before transfusion. Subsequently, the average ferritin levels, bone mineral density, and radiographic results were obtained.ResultsThe percentage of adult thalassemia major and intermedia patients with low bone mass density was 68%. Also, there was a weak inverse correlation between bone mass density and transferrin saturation (r = −0.329, p = 0.01), while no correlation was shown between bone mass density and ferritin (r = −0.088, p = 0.504). The transferrin saturation cutoff point value used to distinguish the incidence of low and normal bone density in patients with transfusion-dependent beta-thalassemia was 89.5%. In addition, there was weak correlation between Singh index and bone mass density (r = 0.273, p = 0.038).ConclusionAmong the transfusion-dependent beta-thalassemia patients, 68% had low bone mass density, which inversely correlated to transferrin saturation. Furthermore, the cutoff value of transferrin saturation to differentiate the incidence of low and normal bone density in thalassemia major compared to thalassemia intermedia was 89.5%. Singh Index correlates weakly with bone mass density and might be used to detect low bone mass density in remote healthcare facilities.

MDS-279: Efficacy and Safety of Luspatercept in Patients with Anemia: A Systematic Review

Context: Luspatercept is an erythroid maturation agent that has been shown to improve anemia by influencing late-onset erythropoiesis. Objective: To determine safety and efficacy of luspatercept in patients aged >18 years of age and diagnosed with either myelodysplastic syndrome or beta-thalassemia. Design: Systematic review. Methods: A literature search was performed on PubMed, Embase, clinicaltrials.gov, Web of Science, and Cochrane using the MeSH terms “anemia” and “Immunoglobulin fc fragments” from database inception until 4/20/2021. After screening 420 articles, 2 randomized clinical trials (RCT, N=565) and 2 phase II trials (N=122) were included. Results: In 4 clinical trials (N=687), subcutaneous luspatercept (0.125 mg/dl to 1.75 mg/dl) was administered every 21 days for at least 48 weeks or 5 cycles to treat anemia in beta-thalassemia (N=288) and MDS (N=211) patients. The median pre-transfusion hemoglobin level was 7.6 g/dl in MDS patients and 10 g/dl in beta-thalassemia patients. Median red cell transfusion burden varied between 14 RBC units/24 weeks to 8 RBC units/8 weeks. Cappellini et al. and Piga et al. (N=400) showed >33% reduction in RBC transfusion burden in 71% (n=159/224) of patients (vs 29.5% with placebo) and >20% reduction in 80% (n=51/64) of patients with beta-thalassemia. Platzbecker et al. and Fenaux et al. (N=287) showed more than 4 RBC unit reduction/8 weeks in 47% (n=100/211) of patients with MDS treated with luspatercept (vs 21% with placebo). High-dose-treated patients had a mean increase in Hb ranging from 0.36 g/dl to 1.52 g/dl. The most common side effects included headache, back pain, bone pain, fatigue, and diarrhea in 19.6% (n=98), 19.4% (n=97), 13% (n=65), 9% (n=45), and 7.4% (n=37), respectively. More than grade 3 adverse effects were bone pains, hyperuricemia, and back pain in 6.4% (n=32), 1.2% (n=6), and 0.6% (n=3), respectively. Conclusion: Luspatercept showed better efficacy than placebo in beta-thalassemia and MDS patients to treat anemia and was well-tolerated by these patients. High-dose luspatercept has shown promising results in terms of erythroid response, measured as either a reduction in transfusion burden or a mean increase in hemoglobin levels. A number of clinical trials are ongoing to assess its efficacy in myelofibrotic disorders to further extend its usage.

Auditory cortex hypoperfusion: a metabolic hallmark in Beta Thalassemia

BackgroundSensorineural hearing loss in beta-thalassemia is common and it is generally associated with iron chelation therapy. However, data are scarce, especially on adult populations, and a possible involvement of the central auditory areas has not been investigated yet. We performed a multicenter cross-sectional audiological and single-center 3Tesla brain perfusion MRI study enrolling 77 transfusion-dependent/non transfusion-dependent adult patients and 56 healthy controls. Pure tone audiometry, demographics, clinical/laboratory and cognitive functioning data were recorded.ResultsHalf of patients (52%) presented with high-frequency hearing deficit, with overt hypoacusia (Pure Tone Average (PTA) > 25 dB) in 35%, irrespective of iron chelation or clinical phenotype. Bilateral voxel clusters of significant relative hypoperfusion were found in the auditory cortex of beta-thalassemia patients, regardless of clinical phenotype. In controls and transfusion-dependent (but not in non-transfusion-dependent) patients, the relative auditory cortex perfusion values increased linearly with age (p < 0.04). Relative auditory cortex perfusion values showed a significant U-shaped correlation with PTA values among hearing loss patients, and a linear correlation with the full scale intelligence quotient (right side p = 0.01, left side p = 0.02) with its domain related to communication skills (right side p = 0.04, left side p = 0.07) in controls but not in beta-thalassemia patients. Audiometric test results did not correlate to cognitive test scores in any subgroup.ConclusionsIn conclusion, primary auditory cortex perfusion changes are a metabolic hallmark of adult beta-thalassemia, thus suggesting complex remodeling of the hearing function, that occurs regardless of chelation therapy and before clinically manifest hearing loss. The cognitive impact of perfusion changes is intriguing but requires further investigations.

The Correlation Between Iron Overload and Endocrine Function in Adult Transfusion-Dependent Beta-Thalassemia Patients with Growth Retardation.

BackgroundIron overload is a major problem in patients with transfusion-dependent beta-thalassemia (TDT). Reports on the correlation between iron overload and endocrine function with growth retardation in such a population in Indonesia have not been established. Therefore, this study aims to obtain a profile of iron load and endocrine function of adult transfusion dependent beta-thalassemia patients and their correlation with growth retardation.MethodsA cross-sectional study was performed, involving adult homozygous and HbE beta-thalassemia patients receiving blood transfusions at the Cipto Mangunkusumo Hospital, Jakarta. Iron overload was represented by serum ferritin (FS) and transferrin saturation (TS), while the endocrine function was examined by the Thyroid Stimulating Hormone-sensitive (TSHs), free T4 (fT4), and insulin-like growth factor-1 (IGF-1). The results were analyzed using bivariate analysis plus Pearson and Spearman correlation tests.ResultsIn general, 58 subjects were selected from 224 adult transfusion dependent beta- thalassemia patients, consisting of 31 males (53.4%) and 27 females (46.6%). Furthermore, their median age was 21 (18–24) years, while the subclinical hypothyroid proportion was 32.7% and low IGF-1 levels were detected in 79.3% of the total population. There was a weak negative correlation between FS and fT4 (Spearman rho=−0.361; p=0.003), as well as IGF-1 (Spearman rho=−0.313; p=0.008), but FS and TSHs had no correlation (Spearman rho=0.074; p=0.29). Also, there was no correlation between ST with TSHs (Spearman rho=0.003; p=0.492), fT4 (Spearman rho=0.018; p=0.448), and IGF-1 (Spearman rho=−0.142; p=0.143).ConclusionBased on serum ferritin, iron overload is discovered to have a negative correlation with free T4 and insulin-like growth factor-1.

Hepatitis C Viral Infection Among Beta-Thalassemia Patients: A Study From the Centre for Excellence in Thalassemia and Other Blood Disorders.

BackgroundHepatitis C virus (HCV) is a single-stranded RNA virus, which is frequently transmitted through blood transfusions, contact with infected blood or blood products, and vertical transmission. Injectable drug abusers and transplant recipients are predisposed to HCV infection. It causes acute hepatitis, which may progress to chronic hepatitis, and in severe untreated cases, patients may develop cirrhosis and hepatocellular carcinoma (HCC). Since there is no vaccine available against HCV infection, prevention remains the mainstay, at least among the susceptible populations that include thalassemia patients.MethodsA prospective case-control study was conducted at the center for excellence in thalassemia and other blood disorders attached to the Prathima Institute of Medical Sciences (PIMS), a tertiary care teaching hospital at Karimnagar, Telangana, India. Blood samples of 100 beta-thalassemia patients and age-matched non-thalassemic persons were screened for antibodies against HCV by an enzyme-linked immunosorbent assay (ELISA) based rapid immunochromatographic method, and the chemiluminescence assay using the Abbott AxSYM (Abbott Laboratories, Abbot Park, IL, USA). During the same period, the prevalence of HCV was assessed among non-thalassemic patients attending in-patient and out-patient wards of PIMS hospital.ResultsOf the 100 cases of beta-thalassemia, 28 (28%) were HCV positive. All the age-matched non-thalassemic controls were negative for HCV antibodies. Among the positives, 20 (71%) were males, and eight (29%) were females. The prevalence of HCV among non-thalassemic patients attending the hospital during the same period was found to be 0.19%.ConclusionsHCV infection among the beta-thalassemia patients was abnormally high as compared to the others. Thalassemia patients are potentially predisposed to HCV infection and other blood-borne viral infections. Thorough screening of blood before transfusion is warranted. HCV infection may further increase the morbidity and mortality of beta-thalassemia patients and other patients with blood disorders who acquire the infection due to frequent blood transfusions.

SARS-CoV-2 infection in patients with β-thalassemia: The French experience.

IntroductionBecause of iron overload complications, thrombosis and infectious predisposition, patients with severe forms of thalassemia are likely to be at increased risk of COVID-19 complications.ResultsA national survey conducted during the year 2020 across the French reference centers for hemoglobinopathies identified 16 cases of COVID-19 confirmed by RT-PCR in beta-thalassemia patients. Their age ranged from 11 months to 60 years. 15 patients were transfusion-dependent and 6 were splenectomized. Concerning iron overload related complications, none had diabetes or cirrhosis and only one had experienced heart failure. All 4 pediatric patients were pauci-symptomatic during the viral episode. Three patients (41, 49 and 57 years old) developed COVID-19 pneumonia requiring oxygen therapy without the need for mechanical ventilation. Neutropenia (absolute neutrophils count < 0.5 10 9/L) was observed in 2 patients receiving long-term treatment with hydroxycarbamide and deferiprone. No thrombosis event, organ failure or death occurred. All patients recovered.ConclusionSeverity of COVID-19 in this population of young and middle-aged patients appeared increased compared to the general population but remained mild to moderate as already described in the few series reported in the literature. Occurrence of adverse events related to chronic treatment administered in thalassemia disease may be favored by the infectious episode.

Evaluation of Relationship between Serum Ferritin Level and Cardiac Complications in Thalassemia Patients in Pasteur Hospital of Bam City in 2018

Introduction and objective: Cardiac complications are the most common cause of mortality in beta thalassemia patients. Hence, this study was conducted with the aim of evaluating the relationship between serum ferritin level and cardiac complications in Thalassemia patients at Specific Diseases Center in Bam city in 2018. Methodology: This is a descriptive-analytical study. Fifty-five patients with thalassemia major in Bam city were selected using a convenient sampling method. They were examined in terms of the prevalence of cardiac complications and their relationship with serum ferritin level was evaluated using SPSS 23 software and descriptive and inferential statistical tests. The significance level was considered p-value&lt; 0.05 in this study. Results: The mean age of the patients was 17.84 ± 6.72. The mean serum ferritin level was 3674.07 ± 2192.21 mg / dl. Only 3 out of 29 patients (5.8%) had an ejection fraction (EF) reduction in echocardiography. In other echocardiographic studies, 13.7% of patients had MILD MR Heart valve dysfunction and 3.9% had MILD TR heart valve dysfunction and 1 person (1.9%) had both dysfunctions simultaneously. Moreover, 13 patients (25.5%) had diastolic cardiac dysfunction. There was no statistically significant relationship between the serum ferritin level of the studied people and echocardiographic findings (p-value &lt;0.05). Discussion and Conclusion: Based on the results of this study and other studies, serum ferritin may not be relied as a definitive indicator for the evaluation of cardiac function. However, it is recommended that the importance of iron removal to be considered in patients’ training programs and different indicators to be used to evaluate the cardiac complications as the most important complication in thalassemia patients. Keywords: Thalassemia, Ferritin, Cardiac complications

Serum Metabolite Profiles Are Strongly Correlated with Membrane Lipid Alterations in Beta Thalassemia Patients

Background-Aim. Despite significant improvements in the diagnosis and treatment of beta thalassemia, it is still challenging to understand how genetic variation affects disease progression. In addition, the search for new personalized therapies targeting ineffective erythropoiesis and the increasing demand for tools to monitor the long-term effects of existing therapies provide the setting for metabolomics integration in thalassemia studies. Metabolomics enables the profiling of large numbers of small molecules in cells, tissues and biological fluids. These molecules include amino acids, carbohydrates, lipids, nucleotides and their metabolites. Currently, several different analytical platforms exist for metabolomics, and both untargeted and targeted methodologies are being employed. According to our knowledge, studies for metabolite identification in the blood or urine of beta thalassemia patients are still scarce. We hypothesized that untargeted metabolomics approach that assess changes in global metabolite profiles may provide valuable information regarding the biochemistry of disease processes and identify new biomarkers.Patients and methods. Thirty one patients with beta thalassemia (21 transfusion dependent, TD, 10 non-transfusion dependent, NTD) were enrolled in the study, while 9 apparently healthy individuals matched for age and sex respectively, to patients, served as controls. Other clinical parameters such as type of iron chelators, serum lactate dehydrogenase, serum ferritin as well as cardiac and liver MRI T2* were enrolled in the study. Untargeted serum metabolites from fasting serum samples were analyzed using Ultra-High Performance Liquid Chromatography followed by tandem Mass Spectrometry (UHPLC-OrbitrapMS). The injection volume was 10μl and the analysis lasted 30 min. Finally, significant metabolites were identified with multivariate statistical analysis using Simca P (Umetrics).Results. The main results of the study showed that: a) 183 metabolites were detected in patient and control samples, b) mapping the results of analyses, patients compared to controls had 124 metabolites with significantly lower concentration, 5 metabolites with comparable concentration and 54 metabolites with significantly higher concentration, and c) metabolic pathway analysis revealed alterations mainly in the glycerophospholipids, porphyrin, linoleic acid, alpha-linoleic acid and arachidonic acid metabolism as well as in primary bile acid biosynthesis. Lysophosphatidylcholines (LysoPC), which result from partial hydrolysis of membrane phosphatidylcholines were significantly upregulated (p<0.05). No significant differences were noted between TD and NTD patients even when other clinical parameters were checked.Conclusions. Our findings showed significant alterations in serum metabolome of patients with TD and NTD beta thalassemia. Also we demonstrated important metabolic abnormalities indicative of membrane lipid alterations due to oxidative damage. Further analytical targeted approach of the unidentified metabolites will provide useful information on this field. DisclosuresNo relevant conflicts of interest to declare.

Quantifying the Pathophysiology of Beta-Thalassemia Using a Novel in-Silico Model of Red Blood Cell Production and Lifespan

Background: From a qualitative perspective the pathophysiology of beta-thalassemia (BT) is generally well understood. Reduction in hemoglobin (Hb) beta-chain synthesis relative to the normal rate of alpha-chain synthesis causes a free alpha-chain excess (ACE) that is toxic to the RBC and its precursors. Circulating RBCs are hemolyzed in the spleen, shortening their lifespan from the normal value of 120 days. RBC precursors in the bone marrow undergo early apoptosis leading to reduced RBC production relative to other anemic states (so called “ineffective erythropoiesis”). Together with low MCH levels these mechanisms lead to Hb levels ranging from 10 - 12 g/dL in BT trait, 7 - 10 g/dL in non-transfusion dependent (NTD) BT, below 7 g/dL in transfusion-dependent (TD) BT at baseline and above 9 - 10.5 g/dL in TD patients receiving regular transfusions administered every 2 to 5 weeks. To quantify the mechanisms responsible for the different BT phenotypes and the response to transfusion in TD patients, we have developed an in-silico model of RBC production and lifespan.Methods: The theoretical amount of ACE per cell was estimated by assuming that the alpha-chain level corresponds to an MCH of 30 pg and the non-alpha chain level (beta, gamma and delta chains) corresponds to the MCH of the BT phenotype, which varies from ~12 to 20 pg in TD BT to ~16 to 23 pg in NTD BT and ~18 to 24 pg in BT trait. The in-silico model consists of a bone marrow module - representing the production and aging of reticulocytes, Hb synthesis and entry to the bloodstream (equivalent to the RBC production rate, PRBC); a circulation module - representing the total blood volume (TBV), conversion of reticulocytes to mature RBCs, attainment of the final MCH, normal aging of RBCs, and a hemolytic process in BT (with rate constant kH that depends on the ACE level); and a transfusion module - representing the volume of transfused blood (VTF) with hematocrit H, a normal RBC age-distribution, and a separate hemolytic process (with rate constant kH_Tf). Reticulocyte lifespans in the bone marrow and circulation were set to ~3 days and ~1 day, respectively, but can vary oppositely at high PRBC (stress erythropoiesis). A key assumption of the model is that PRBC is down-regulated by the Hb level according to a sigmoidal Hill function, which was calibrated using PRBC data from normal subjects and patients with sickle cell disease, and was assumed to have a maximum value 10-fold the normal PRBC rate. In BT the PRBC function is also modulated by a factor FBT, dependent on the ACE level. Additional data from BT patients were used to derive the kH and FBT values. The model was expressed in ordinary differential equations using the Berkeley Madonna platform (Version 8.3.18).Results: To simulate the spectrum of BT phenotypes, MCH levels were varied from 15 pg to the normal value of 30 pg and the ACE levels, kH and FBT values were computed from the model. The simulated steady-state dependences of Hb vs. MCH (Figure 1A) and Reticulocyte count vs. Hb level (Figure 1B) are in good agreement with published literature data. For virtual patients (VPs) with MCH levels of 23, 21 and 18 pg, typical of BT trait, NTD and TD phenotypes, respectively, the estimated ACE levels were 0.22, 0.28 and 0.38 fmole/cell; kH values were 0.01, 0.019 and 0.037 day-1 and values of FBT were 0.65, 0.6 and 0.55. The effective RBC lifespans for these VPs were 68, 47 and 23 days, respectively. Regular transfusions (VTF = 15 mL/kg; H = 0.6) were simulated over 24 weeks for a TD VP (MCH = 18 pg; baseline Hb = 6.61 g/dL) to maintain the Hb level above 9 g/dL. In Figure 2A, where kH_Tf = 0 (no hemolysis of transfused blood), the transfusion interval stabilizes at 3.71 weeks. In Figure 2B, where kH_Tf = 0.0165 day-1(an effective RBC lifespan of 50.7 days), the transfusion interval stabilizes at 2 weeks. Reticulocyte counts decrease markedly in both cases. To achieve a ~3 g/dL increment in the Hb level, TBV must equal 100 mL/kg (~40% greater than normal).Conclusions: Our in-silico model explains the phenotypic variation of Hb levels and reticulocyte counts in BT in terms of the effects of ACE on the hemolysis rate constant (kH) and the fractional reduction in RBC production (FBT). The 2-week transfusion interval required in some patients to maintain Hb above 9 g/dL is explained by a shortened lifespan of the transfused blood. More clinical data would be helpful to confirm and refine these observations to better understand the key drivers of disease pathology in BT. [Display omitted] DisclosuresMazer:Roche: Employment, Equity Ownership. Hermosilla:Roche: Employment. Koerner:Roche: Employment.

Decitabine As Hemoglobin F Inducer in Hemoglobin E/β Thalassemia

IntroductionPhenotypic severity of HbE-beta thalassemia depends on hemoglobin F Level. Gamma globin chain induction has the potential of increasing HbF and decreasing transfusion dependence, and disease severity. Decitabine as a hypomethylating agent can activate repressed gamma globin gene and lead to increase in hemoglobin F.ObjectivesTo study effect of Decitabine on hemoglobin level, hemoglobin F and transfusion requirement as well as its adverse effects.Materials and MethodsThirty patients of HbE Beta thalassemia were enrolled. Both transfusion dependent (TDT) and non-transfusion dependent patients (NTDT) were included after obtaining informed consent. Inclusion criteria included - age greater than 18 years, free of transfusion for at least 90 days before entry (only for NTDT to get better idea of baseline hemoglobin), without any co-morbidity.Participants received 0.2 mg/kg of 5-aza-2′-deoxycytidine (decitabine) subcutaneously on two consecutive days a week for at least 12 weeks. Complete hemogram was done every two weeks and HPLC at every four week interval, till two months after last dose of drug. Patients were transfused packed red blood cells (PRBC) if symptomatic or if Hb < 5gm/dl.ResultsThirty patients (21- NTDT and 9 - TDT), were included in this study. Study comprised of 16 males (53.3 percent) and 14 females (46.7 percent) with a mean age of 29.33 years (summarized in table 1). Hemoglobin increment of > 1gm/dl was seen in 7 (33.3 percent) and >0.5 gm/dl was seen in 8 (38.1 percent) patients of NTDT group. For NTDT group peak mean increment in hemoglobin was 0.938 gm/dl (p value <.001, 95 percent confidence interval 1.33 to 0.539). Detailed results and paired analysis given in table 2. Graph A and Graph B shows trends in hemoglobin and hemoglobin F percentage respectively.Transfusion requirement decreased to 0.24 units compared to 0.96 units per patient per month for TDT patients over a period of last one year. Out of the nine transfusion dependent patients five (55 percent cases) became transfusion independent and continued to remain so during mean follow up period of 6 months (range: 4months to 10 months), three patients continued to remain transfusion independent even after discontinuation of therapy.Decitabine was well tolerated, no hematological toxicity was documented. Regarding non-hematological toxicities, 1 patient complained of chest tightness (grade 1), 1 patient had malena (grade III), endoscopy of this patient showed gastric erosion, 3 patients developed respiratory tract infection (grade I/II- managed on day care basis), 1 patient complained of small joint pain (grade I).DiscussionVarious drugs like hydroxyurea, 5-azacytidine, decitabine, erythropoietin stimulating agents have been evaluated as hemoglobin F inducing agents. Hydroxyurea has shown beneficial effect in HbE Beta Thalassemia patients, with range of response being in between 1% and 90%, and averaging at 20% (Musallam KM et. al Blood 2013). The efficacy of agents such as hydroxyurea is compromised by the suppressive effects on bone marrow function. Hydroxyurea has mutagenic effect also. (Bradai M et al. Transfusion. 2007).Few studies noted a decline in hematological response beyond 12 months (Rigano P et al. BJH 2010). So an alternative is required.Hypomethylating agents can cause activation of gamma globin gene and hence, use of decitabine can be a promising strategy. The only study done previously, showed increased total hemoglobin and absolute fetal hemoglobin. Treatment was well tolerated, with the main adverse event being an elevation in platelet counts (Oliviero NF et al. Blood 2011).In the present study relatively larger number of patients were followed up for a longer period of time and included both TDT and NTDT group.Decitabine was found to increase both hemoglobin and hemoglobin F in NTDT group. In the TDT group it decreased transfusion requirement significantly with increase in hemoglobin F percentage.Even though this study showed good response in HbE/ Beta thalassemia, a randomized control trial with hydroxyurea, with even longer duration of follow up needs to be done to compare both the drugs.ConclusionDecitabine is well tolerated, and is efficacious in increasing hemoglobin F percentage in HbE Beta thalassemia patients. There is decrease in transfusion requirement in TDT group. There is improvement in total hemoglobin as seen in NTDT group. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Efficacy and Safety of Deferasirox in Chelation Naïve HbEβ Thalassemia Patients: Initial Experience from a Tertiary Centre of Eastern India

Introduction: In India, more than 10,000 new cases of thalassemia are born every year. In Eastern India, Hb E Beta thalassemia accounts for more than 50 % of the disease burden (Olivieri NF et al, Indian J Med Res 2011;134:522-31). Initially patients were used to get chelation with deferoxamine or deferiprone mostly, but with wide availability of Deferasirox (DFX) it has become the most commonly used chelating agent in Eastern India, however. Limited data are available on chelation from this part of the country. Objective: To assess the response to DFX in chelation-naïve patients with HbE beta thalassemia in terms of changes of serum ferritin level and to document its adverse effects in these patients. Materials and Methods: The study was undertaken from January 2014 to September 2015 at the thalassemia clinic of Institute of Haematology and Transfusion Medicine, Medical College, Kolkata, India. Sixty five patients of HbE beta thalassemia with serum ferritin level >1000 ng/ml and no history of any sort of chelation therapy were enrolled. Evaluation was done to rule out any pre-existing chronic liver disease, renal disease, gastro-intestinal bleed or anaphylaxis. Deferasirox was given at the dose of 40 mg/kg daily to thalassemia major patients and at the dose of 10 mg/kg daily to non-transfusion dependent thalassemia (NTDT) patients. The adverse effects of Deferasirox on HbE beta thalassemia patients were closely monitored. Serial changes in serum ferritin, bilirubin, ALT and creatinine clearance were noted every 3 months. Results: 23% of total patients were NTDT. Mean baseline hemoglobin was 6.72±0.62 gm/dl and mean baseline serum ferritin was 2122±622 ng/ml. Nausea, vomiting, pain abdomen were the most common adverse effects seen (Figure 1). There was no incidence of drug discontinuation or dose reduction. 34% patients had no adverse effects. In rest of the patients, gastrointestinal symptoms were the most commonly associated complaints with DFX therapy. Proteinuria was also found in 21.4 % patients. There was significant reduction of serum ferritin level on repeated measurements. Alterations of bilirubin or ALT were found, but it was statistically not significant. Decrease in creatinine clearance was seen in significant number of patients on DFX. There was no significant association of absence or presence of adverse effects with concomitant hydroxyurea therapy in NTDT patients (Table 2). Discussions: DFX was well tolerated by the patients. Gastrointestinal symptoms, most commonly nausea followed by vomiting and pain abdomen, were the most common adverse effects as seen in other studies like EPIC trial (Ann Hematol 2013 92:211-219). No serious adverse effects like hypoaccusis, GI bleed, anaphylaxis, anasarca as mentioned in other studies (Ali Taher et al. Br J Haematol. 2009;147:752-759) leading to stoppage or dose reduction of DFX were observed. Mixed regression analysis for repeated measures revealed significant decrease in serum ferritin level in comparison to previous ferritin level with DFX therapy (Table No 1), as shown in similar study by Capellini et al (Blood. 2006;107:3455-3462). There was no statistical correlation with absence of any adverse effects when compared with concomitant hydroxyurea therapy, when applicable. Conclusion: Deferasirox was found to be effective in reducing serum ferritin level in Indian HbE beta thalassemia patients without any major adverse drug effects, although more studies with longer duration are needed to achieve robust evidence. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector

Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector

Osmotic hemolysis is a donor-specific feature of red blood cells under various storage conditions and genetic backgrounds.

Transfusion research has recently focused on the discovery of red blood cell (RBC) storage capacity biomarkers and the elucidation of donor variation effects. This shift of focus can further strengthen personalization of transfusion therapy, by revealing probable links between donor biology, RBC storage lesion profile, and posttransfusion performance. We performed a paired correlation analysis of osmotic fragility in freshly drawn RBCs and during cold storage in different preservative solutions at weekly intervals until unit's expiration date (n= 231), or following 24 h reconstitution in allogeneic plasma (n= 32) from healthy controls or transfusion-dependent beta-thalassemia patients. We observed exceptional correlation profiles (r > 0.700, p < 10-5 in most cases) of RBC osmotic fragility in the ensemble of samples, as well as in subgroups characterized by distinct genetic backgrounds (sex, beta-thalassemia traits, glucose-6-phosphate dehydrogenase deficiency) and storage strategies (additive solutions, whole blood, RBC concentrates). The mean corpuscular fragility (MCF) of fresh and stored RBCs at each storage time significantly correlated with the MCF of stored RBCs measured at all subsequent time points of the storage period (e.g., MCF values of storage day 21 correlated with those of storage days 28, 35 and 42). A similar correlation profile was also observed between the osmotic hemolysis of fresh/stored RBCs before and following in vitro reconstitution in plasma from healthy controls or beta-thalassemia patients. Our findings highlighted the potential of osmotic fragility to serve as a donor-signature on RBCs at every step of any individual transfusion chain (donor, blood product, and probably, recipient).

Investigating the Role of Ferritin in Determining Sexual Underdevelopment in Beta-Thalassemia Major Patients: A Cross-Sectional Analysis From Pakistan.

BackgroundBeta-thalassemia major, a genetic disorder, delineates a vast spectrum of hematological and endocrinological complications. Elevated serum ferritin levels in beta-thalassemia patients represent various transfusion-related complications including infection, hemochromatosis, and severe iron overload that might lead to endocrinopathies such as hypogonadism leading to sexual underdevelopment. Our study, thus, aims to explore the role of ferritin in determining sexual underdevelopment in such patients. MethodsThis multicentric cross-sectional study included a total of 120 beta-thalassemia patients. The sexual development of the patients was assessed using the Tanner staging system. Serum ferritin levels and other demographical parameters of the patients were collected. Independent-samples t-test, chi-square test, and receiver operating characteristic (ROC) curve were used to analyze the data.ResultsOut of 120 patients, 70 patients were males with a mean age of 18.95 ± 4.21 years. According to the Tanner staging system, 48 patients were sexually underdeveloped while 72 patients achieved sexual maturity. ROC curve analysis showed that ferritin levels at a cutoff value of 4900 mg/dL were 73.7% sensitive and 71.1% specific to predict sexual underdevelopment in beta-thalassemia patients.ConclusionsElevated serum ferritin levels were moderately sensitive and specific in predicting sexual underdevelopment in beta-thalassemia patients. This can serve as a low-cost parameter in determining sexual underdevelopment in such patients. More prospective cohort studies are needed to establish the association between elevated serum ferritin levels and sexual underdevelopment.