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Transfusion-dependent thalassemia (TDT) is a type of beta-thalassemia that needs regular and long-term blood transfusions. Complications can occur due to the deposition of iron in TDT patients, including endocrine complications causing deficiency of testosterone that plays a role in the secondary sexual development in males. The objective of this study was to understand the correlation between ferritin and testosterone level in male adolescences with transfusion-dependent thalassemia. This cross-sectional observational correlative study was conducted from April to August 2019 on 74 males aged 12-18 years old who were presented to the Thalassemia Outpatient clinic, Dr. Hasan Sadikin General Hospital, Bandung. Blood was collected using phlebotomy for ferritin and total testosterone serum examination. Data were then analyzed using SPSS version 17.0. Low testosterone level (

Transfusion-dependent thalassemia (TDT) patients require regular blood transfusions. The unavoidable consequence is iron overload. Iron chelation therapy is the mainstay of treatment, of which the favorable outcome depends mainly on adherence level. The aim of this study was to assess adherence to iron chelation therapy of TDT patients. A cross-sectional cohort of TDT patients were evaluated on their adherence to chelation therapy using the Thai version of Morisky Medication Adherence Scales (MMAS-8). A total of 70 patients (38 males, 32 females), with a median age of 10 years, were enrolled in the study. Sixteen patients (22.9%) and 54 patients (77.1%) were classified as high and medium-low adherence level groups. The raised serum ferritin value for 6 months previous to enrollment in the high adherence level group is lower than the medium-low adherence level group (276.4 vs. 413.0 ng/mL, p = 0.034, respectively). Factors impacted high adherence to iron chelation including younger age (p = 0.015) and deferasirox (DFX) administration (p = 0.025). The body weight and height in both groups were not statistically different. The most common obstacle to adherence was forgetfulness. The Thai version of MMAS-8 is a practical tool for evaluating adherence to chelation therapy in TDT patients. High adherence level of patients correlates with more controlled serum ferritin level. The younger age and once-daily dose chelation therapy are associated with better adherence.

Objective The objective of this study was to examine the cross-sectional convergent and known-group validity of the Malay-language EQ-5D-3L instrument in children and adults with transfusion-dependent thalassemia (TDT). Methods A cross-sectional health-related quality of life survey involving TDT patients from 12 different treatment centers across Malaysia was conducted using the Malay PedsQL 4.0 Generic Core Scales and the Malay EQ-5D-3L questionnaire. Patients with non–TDT and other hemoglobinopathies were excluded. Convergent, discriminant, and known-group validity of the EQ-5D-3L was assessed against the PedsQL 4.0 Generic Core Scales in children. In the adult population, known-group validity of the EQ-5D-3L was assessed using an a priori hypothesis between patients’ demographic characteristics and health outcomes obtained from literature. Results A total of 370 children and 225 adults were sampled. The mean (standard deviation) EQ-5D-3L scores of the children were 0.892 (0.082) and the adults were 0.887 (0.085). Convergent and discriminant validity was identified when correlated with the PedsQL domain in children. In both groups, known-group validity was evident when comparing groups of patients with reported problems to the group of patients with no reported problems on the EQ-5D-3L domains based on the a priori hypothesis derived from literature. Conclusion This study found convergent, discriminant, and known-group validity of the Malay EQ-5D-3L in a population-based sample of patients with TDT. Hence, the instrument is valid for the assessment of health-related quality of life in children and adults with TDT in Malaysia.

Objectives To assess pubertal development and its determinants in adolescents with transfusion-dependent thalassemia (TDT). Methods In this cross-sectional study from a tertiary teaching hospital in Delhi, records of adolescents aged 17-19 years with TDT on regular transfusion at thalassemia day-care centre were reviewed. Pubertal development and its determinants were assessed. Results Records of 58 (33 male) adolescents with TDT were reviewed. Among them, 42 (72.4%) had normal/delayed onset with spontaneous progression of puberty, while 16 (27.6%) had pubertal arrest/failure and received hormonal replacement therapy (HRT). Short stature was observed in all adolescents on HRT. Amongst other endocrinopathies, only hypoparathyroidism was found to be significantly higher in the HRT group. On multivariate analysis, serum ferritin (OR-1.005, 95% CI 1.002, 1.009) was observed to be the only significant determinant of pubertal arrest/failure. Conclusions A significant proportion of adolescents with TDT continue to have pubertal arrest/failure. High systemic iron load is the key determinant for this.

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Objectives: The objective of this study was to determine the frequency of diabetic abnormalities i.e. Diabetes Mellitus and Impaired Fasting Glucose in Transfusion Dependent Thalassemia patients. Study Design: Cross Sectional study. Setting: Center for Thalassemia Care and Patho-Care Laboratory Rahim Yar Khan, Pakistan. Period: 6 Months from July 2018 to December 2018. Material & Methods: Convenient sampling technique was used. Patients of Transfusion Dependent Thalassemia bearing age more than 10 years were studied. Fasting Plasma Glucose was determined by taking Fasting Blood samples of 151 patients of Transfusion Dependent Thalassemia. A questionnaire was designed and all data collected was recorded. SPSS version 20 used to analyze the data. Results: 151 patients were included in the study; 39.1% females and 60.9 % males. Overall 2.0 % patients were found to have Diabetes Mellitus while 4.6% had Impaired Fasting Glucose. Conclusions: The results of this study indicated that frequency of Impaired Fasting Glucose is higher as compared to Diabetes Mellitus in Transfusion Dependent Thalassemia patients.

Objective: The purpose of this study is to see the correlation between iron overload with the hypogonadal state by analyzing the correlation between ferritin serum, transferrin saturation and pituitary MRI T2 relaxation time with FSH, LH and testosterone levels. Methods: This is a cross-sectional study of 32 male subjects with transfusion-dependent thalassemia. The subjects were collected with a consecutive sampling technique in the thalassemia outpatient clinic in National Hospital in Indonesia. Measurements of serum ferritin, transferrin saturation, FSH, LH and testosterone were taken using ELISA technique. Pituitary MRI T2 relaxation time was done using MRI Avanto 1.5 Tesla. Results: In this study, secondary sexual characteristics were not fully achieved in 62.5% of patients. Low testosterone levels were found in 25% of patients. There was a negative correlation between transferrin saturation and pituitary MRI T2 relaxation time in the normal testosterone level group. Conclusion: This study showed a high rate of patients who had not achieve puberty, but a low rate of patients with low testosterone, which means there is a weak negative correlation between transferrin saturation and pituitary MRI T2 relaxation times.

Initiation of regular transfusion in transfusion-dependent thalassemia (TDT) is based on the assessment of clinical phenotype. Pathogenic HBB variants causing β-thalassemia are important determinants of phenotype and could be used to aid decision-making. We investigated the association of HBB genotype with survival in a cohort study in the four thalassemia centers in Cyprus. HBB genotype was classified as severe (β0/β0 or β+/β0), moderate (β+/β+), or mild (β0/β++ or β+/β++). Risk factors for mortality were evaluated using multivariate Cox proportional- hazards regression. Of the 537 subjects who were followed for a total of 20,963 person-years, 80.4% (95% confidence interval [95% CI]: 76.4-84.7) survived to 50 years of age with increasing rates of liver-, infectionand malignancy-related deaths observed during recent follow-up. We evaluated non-modifiable risk factors and found worse outcomes associated with male sex (hazard ratio 1.9, 95% CI: 1.1-3.0, P=0.01) and milder genotype (hazard ratio 1.6, 95% CI: 1.1-2.3, P=0.02). The effect of genotype was confirmed in a second model, which included treatment effects. Patients with a milder genotype initiated transfusion significantly later and had reduced blood requirements compared to those with moderate or severe genotypes, although pre-transfusion hemoglobin levels did not differ between genotypes. Our results suggest that early treatment decisions to delay transfusion and different long-term treatment strategies in individuals with milder genotypes have led to adverse longterm effects of under-treated thalassemia and worse survival. We propose that HBB genotype determination and use of this information to aid in decision-making can improve long-term outcomes of thalassemia patients.

Patients with beta thalassemia major (TM) are transfusion-dependent (TD) since early childhood and for life. Development of alloantibodies and autoantibodies against red blood cell (RBC) antigens is increasingly recognized as a significant transfusion hazard, especially among heavily transfused patients. The aim of this study is to assess RBC alloimmunization and autoimmunization rates in TD TM patients treated in our Comprehensive Center of Adult Thalassemia, Hemoglobinopathies and Rare Anemias. TD TM patients, regularly transfused every 2-3 weeks, were included in the study. Clinical and RBC transfusion records, including RBC antibodies, since diagnosis in early childhood, were retrieved from patients' files and from the blood bank database. Forty TD TM patients, > 18 years of age, were included in the study. Alloimmunization was demonstrated in 17 (42.5%) patients. Thirty-four alloantibodies were detected, with the most frequent being RH related (12 of 34, 35.3%) followed by those of the Kell system (8 of 34, 23.5%). Age at first transfusion was positively related to the probability of developing alloantibodies (p = 0.02). Splenectomy was found to be correlated with developing alloantibodies (p = 0.016). Logistic regression analysis of the lifelong probability of developing alloantibodies on the age at first transfusion and splenectomy demonstrates a strong positive relationship (p = 0.002). A substantially high rate of alloimmunization was found among adult TD TM patients. Early initiation of RBC transfusions, avoidance of splenectomy and extended Rh and K antigen matching, can reduce the incidence of alloimmunization in TD TM patients.

BACKGROUND/OBJECTIVES Cardiac T2* magnetic resonance imaging (MRI) is the gold standard to determine myocardial iron overload. As availability of Cardiac T2* is not uniform across developing nations, our strategy was to identify a more accessible and cost effective tool to assess myocardial iron accumulation. As children with transfusion-dependent thalassemia also experience various electrocardiographic abnormalities, we performed electrocardiography (ECG) as well as Cardiac T2* MRI on all children registered in our thalassemia unit. MATERIALS AND METHODS Forty-eight transfusion-dependent thalassemia children with transfusion burden ≥12 times/y (6 to 19 y) in the Thalassemia Unit of the Division of Hematology Oncology, Department of Pediatrics were enrolled. Patients were divided into 3 groups based on severity of T2* value, that is group I (T2* 20). A T2* value >20 was taken as normal. ECG and serum ferritin was also performed on the day of MRI. RESULTS Among the various ECG parameters, QRS duration, and QTc interval were significantly increased if cardiac iron overload was high with a P-value of 0.036 and 0.000, respectively. Also, high serum ferritin predicted a decline in T2* value with a P-value of 0.001. QT interval and QTc interval significantly correlated inversely with T2* (P=0.042, r=-0.295 and P=0.002, r=-0.446, respectively) but not QRS duration (P=0.05, r=-0.282). Serum ferritin also was found to have a significant inverse correlation with T2* value (P=0.000, r=-0.497). CONCLUSIONS Abnormalities on ECG, that is prolongation of QRS duration, QT interval, and QTc interval were significantly associated with cardiac iron overload, that is decrease in the value of Cardiac T2* in our study.

Background: In transfusion dependent thalassemic (TDT) patients regular blood transfusion leads to iron overload. This increased iron is deposited in the tissue of various system and causes organ damage. Endocrine dysfunction is very common due to iron deposition into the endocrine glands including parathyroid dysfunction. Objective: To measure plasma intact parathyroid hormone(iPTH), serum total calcium and inorganic phosphate levels in adult male patients with TDT. Methods:This cross sectional study was conducted in the Department of Physiology, Bangabandhu Sheikh Mujib Medical University, Dhaka from March 2018 to February 2019. Total 35 TDT male patients aged 18 to 40 year and 35 age matched apparently healthy male subjects were enrolled for this study as control. The TDT patients were selected from the outpatient department of Hematology and Transfusion Medicine. For assessment of parathyroid function serum albumin, plasma iPTH, serum total calcium and inorganic phosphate levels were estimated by colorimetric method using automated analyzer. For statistical analysis, independent sample t test was done. Results: In this study, plasma iPTH and serum corrected calcium levels were significantly (p < 0.001) lower in patients with TDT than those of healthy control. Again, Serum inorganic phosphate and ALP levels were significantly (p < 0.001) higher in patients with TDT than those of healthy control. Moreover, 2.86% of TDT patients had low iPTH. Conclusion: From this study, it can be concluded that reduced parathyroid function was associated with TDT. J Bangladesh Soc Physiol. 2019, December; 14(2): 77-81

Background Hypertriglyceridemia thalassemia syndrome (HTS) is not a well understood entity, and is mainly identified in the Indian subcontinent. We present a unique case of this syndrome along with severe autoimmune haemolysis that presented with life-threatening anaemia. Observations An infant with transfusion dependent thalassemia (TDT) presented with suspected mismatched blood transfusion leading to severe haemolysis. Severe haemolysis, lipemic serum were initial findings. Detailed evaluation revealed IgG, C3d positive mixed autoimmune haemolytic anaemia (AIHA), severe hypertriglyceridemia that improved with steroids and least mismatched packed red cell transfusion. Conclusion Children with thalassemia presenting with excessive hemolysis may have mismatched transfusion reaction, alloimmunization or an autoimmune hemolysis. Baseline extended blood grouping, detailed immune hemolytic work-up aids in prompt diagnosis. HTS on a background of autoimmune hemolysis is rare and needs urgent medical support.

Aims To explore the impact of incorporating a faster cardiac magnetic resonance (CMR) imaging protocol in a low–middle-income country (LMIC) and using the result to guide chelation in transfusion-dependent patients. Methods and results A prospective UK–India collaborative cohort study was conducted in two cities in India. Two visits 13 months apart included clinical assessment and chelation therapy recommendations based on rapid CMR results. Participants were recruited by the local patient advocate charity, who organized the patient medical camps. The average scanning time was 11.3 ± 2.5 min at the baseline and 9.8 ± 2.4 min (P Conclusion For thalassaemia patients in an LMIC, a simplified CMR protocol linked to therapeutic recommendation via the patient camp model led to enhanced chelation therapy and a reduction in cardiac iron in 1 year.

This meta-analysis was conducted to summarize the comparative effect of NAC and Vitamin E on oxidative status, including total antioxidant capacity (TAC), total oxidative stress (TOS), oxidative stress index (OSI), and hemoglobin (Hb) in patients with TDT.All methods were performed in accordance with the PRISMA checklist. We searched databases including Web of Science (ISI), Scopus, PubMed, and Embase. Meta-analysis was done using Stata statistical software version 16.0.Finally,four randomized-controlled trials (RCT)for NAC and four RCTs for Vitamin E were included.Our meta-analyses showed a significant increase in the weighted mean differences (WMD) of Hband a significant decrease in the WMD of OSI in the NAC group.In subgroup analysis based on age: in the NAC group, a significant increase in the WMD of TAC andHband a significant decrease in the WMD of TOS were detectedonly in children. In theVitamin E group, a significant increase in Hb and a significantdecrease in TOS and OSI were determined in the children subgroup as well.NAC can be used as an effective antioxidant supplementparticularlyin children with TDT. Also, Vitamin Eshowed a beneficial antioxidant effect in TDT children. So, more well-designed randomized, controlled trials for the effect of NAC in adult TDT andthe effect of vitamin E both in adults and children are recommended with more focus on theessential influencing factors on the oxidative status in TDT patients.

Background: Frequent blood transfusion can lead to iron overload which is potentially dangerous for the heart and liver. Silymarin has well-documented protective effects on hepatocytes. The purpose of this study was to evaluate the hepatoprotective effects of silymarin addition to iron chelators in children with thalassemia. Materials and Methods: This randomized, double-blinded, and placebo-controlled trial was performed on 40 subjects with thalassemia major and intermedia in Amir Kabir Hospital, Arak, Iran. Subjects were randomized 1:1 oral to 30 mg/kg deferasirox plus placebo, or deferasirox plus oral 70-140 mg silymarin (twice daily) for 6 months. Cardiac and hepatic iron levels and levels of Gamma-glutamyltransferase (GGT), Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphatase (ALP), total bilirubin, albumin, total protein, and total cholesterol were measured at baseline and after 6 months of treatment. Results: The mean age of patients was 16 years and 60% of patients were female. After 6 months, there were significant increases in the levels of ALT, AST, GGT, and TG in the placebo group as compared to the silymarin group (P < 0.05). In contrast, ALT, AST, and GGT had significant reductions compared to the silymarin group (P =0.05). Patients in the placebo group had a rise in total bilirubin (P = 0.07), but total protein and albumin did not have significant changes in the silymarin group (P > 0.05). Finally, a significant improvement was noted in cardiac iron values in patients using silymarin; 22.2 ± 6.6 ms at baseline vs 26.9 ± 7.1 ms at 6 months (P < 0.05). Conclusion: This study suggests that twice-daily addition of silymarin to deferasirox could improve liver function in children with thalassemia major and intermedia. Silymarin seems safe in pediatrics.

Background: Transfusion dependent thalassemia (TDT) patients will progressively experience iron overload due to repeated blood transfusions. It also causes vitamin D hydroxycholecalcoferol (25OH) depletion in the liver parenchyma. Methods: This was a cross-sectional study of children with TDT in Hemato-oncology outpatient clinic, Dr. Soetomo Hospital Surabaya which has enrolled in the study from January-june 2020. Serum ferritin level by Enzym linked Fluorescent Assay (ELFA) and vitamin D hydroxycholecalciferol (25OH) level was examined by the ADVIA centaur VitD assay method. To determine the correlation between serum ferritin level and vitamin D hydroxycholecalciferol (25OH) Spearman correlation was used, significant if p 1000 ng / ml, 12/30 subjects were considered deficient in vitamin D hydroxycholecalciferol (25OH), with vitamin D hydroxycholecalciferol (25OH) level

Background Transfusion is a lifesaving treatment for lots of patients. However, in chronic blood recipients such as thalassemia patients, there are high concerns about alloantibody production that affects the quality of their life. Therefore, research on risk factors of alloimmunization has been started and followed. This study aimed at the determination of correlation probability between some HLADRB1 alleles and alloimmunization in Iranian thalassemia patients. Materials and methods The present study was conducted on 60 alloimmunized and 60 non-alloimmunized transfusion-dependent thalassemia patients. Antibody screening and identification tests were carried out using the tube method, and HLA-DRB1 genotyping was done using a single specific primer-polymerase chain reaction (PCRSSP). Results The results of antibody screening showed that the most prevalent alloantibodies were Anti-K (46.7 %), and followed by Anti-E (32.5 %), Anti-C (15.8 %), Anti-D (13.3 %), Anti-e (8 %), and Anti-c (5.8 %), respectively. DRB1*07:01 was detected more in non-responder patients (28.3 %). However, data analysis showed that there is no significant relationship between DRB1*07:01, *10, *13:01 frequency among responder and non-responder groups (p = 0·195, 0.648, 0.402, respectively). There was not any significant correlation between HLA-DRB1*10 and *13:01 allele and alloimmunization. There was a significant association between HLA-DRB1*12 and alloimmunization (p Conclusion The findings of this study represented that there is a significant relationship between HLADRB1*12 and Kell and E alloantibodies. Although more developed studies on other HLA alleles are demanded, these findings can be valuable in determining important alloimmunization risk factors to better management of transfusion complications.

Thalassemia is the most common hematological transfusion-dependent disease in Thailand. Even though prenatal diagnosis (PND) can detect the condition, many new cases are diagnosed in pediatric practice. This study assessed the clinical outcome of patients with thalassemia who did PND. One hundred and six participants (53 female, 50%), with a median age of 8.5 years (Interquartile range [IQR] 8.00), were enrolled in the study. Twenty-one participants (19.8%) were prenatally diagnosed with thalassemia, with a median age of 8 years (IQR 9.00), 16 were diagnosed with transfusion-dependence thalassemia (TDT), and 5 participants were diagnosed with non-TDT. Another 80.2% did not prenatally diagnose, with a median age of 9 years (IQR 8.00). The PND group found early diagnosis compared with a non-PND group, at a median age of 6 months versus 15 months. There was a significant early diagnosis ( P

Background: Transfusion dependent thalassemia (TDT) patients require regular blood transfusion and iron chelator therapy to maintain their life. Iron chelator may alter serum zinc and copper level in TDT patients. Objective: To observe serum zinc and copper and ferritin levels in transfusion dependent thalassemic patients treated with iron chelator. Method: The present cross sectional study was carried out in the department of Physiology, BSMMU, Dhaka between September 2017 to February 2019. Thirty cases of TDT, aged 5-40 year were included in the study group. Age and sex matched 30 healthy subjects were also studied as control. All the TDT patients were selected from the outpatient Department of Hematology and Transfusion Medicine, BSMMU, Dhaka. Serum zinc was measured by Spectrophotometric method and serum copper and ferritin levels were measured by colorimetric method. For statistical analysis independent sample t test was used. Result: The mean serum zinc level was significantly (p0.05) different in study groups compared to that of control. In addition, 3.3 % TDT patients had hypozincemia and 13.3% TDT patients had hypercupremia. Conclusion: This study may conclude that low serum zinc level and high copper level may be associated with TDT patients treated by combined deferoxamine (DFO) & deferiprone (DFP) iron chelator. J Bangladesh Soc Physiol. 2019, June; 14(1): 38-42

Background. Thalassemia is one of the most common genetic hematologic disorders in the world. Despite outstanding achievements in prenatal diagnosis and a decrease in the number of patients, thalassemia is still a significant issue in most parts of the world, especially in the Mediterranean countries. Understanding the factors associated with this condition is crucial to help clinicians and policymakers provides social and medical support for patients to facilitate their lives. This study aims to appraise the quality of life (QoL) and its related paraclinical factors in Iranian transfusion-dependent thalassemia patients. Methods and Materials. This study is a cross-sectional study performed in the thalassemia clinic of Imam-Ali Hospital, Karaj, Iran. The demographic, clinical, and laboratory data of 100 patients with transfusion-dependent thalassemia were recorded. The patients’ QoL was measured by the World Health Organization Quality of Life Instruments Brief (WHOQOL-BREF) version questionnaire. The results were analyzed using SPSS software. Results. This study demonstrated that all four features of life are influenced in transfusion-dependent thalassemia patients. Also, higher educational status and lower serum ferritin levels were associated with better scores in assessing the QoL. On the other hand, an elevated level of AST (aspartate transaminase), ALT (alanine transaminase), and FBS (fasting blood sugar) are associated with lower scores. Conclusion. All features of QoL are correlated to the patients’ laboratory findings. Our data suggest that managing patients’ laboratory indices is attributed to their higher QoL. We also suggest regular screening of patients’ QoL to manage disease complications more efficiently.

Background: In thalassemia patients erythrocyte turnover rate increases due to chronic hemolysis and ineffective erythropoiesis leading to increase in uric acid production. Hyperuricosuria is one of the marker of proximal tubular dysfunction. Splenectomy can increase the risk of hyperuricemia by increasing erythrocyte turnover rate in Transfusion Dependent Thalassemia (TDT). Deferasirox enhances uric acid excretion from renal tubules leading to low serum uric acid levels. Methods: An institution based cross-sectional study was conducted from November 2018-March 2020 which included 60 adult TDT patients (≥18 years) attending Adult Thalassemia Day Care Centre at tertiary care hospital. Serum uric acid (mg/dl), 24 hour urinary uric acid (mg/dl), serum ferritin (ng/ml) were done. Results: Hyperuricemia was present in 20%, hypouricemia in 3.33%. Hyperuricosuria was present in 80%. Mean SUA levels were higher in males than females which was statistically significant (5.77±1.66 vs 4.64±1.44, p=0.007). There was statistically significant positive correlation between serum uric acid and serum creatinine(p = 0.0036) and age (p=0.0129). Hyperuricemia was more in subjects with intact spleen but was not statistically significant(p=0.104). Hyperuricemia had negative association with deferasirox therapy [1 (3.03%) vs 11 (40.74%), p=0.0004] compared with normouricemia subjects. Conclusion: Uric acid abnormalities were seen in 23.3% of patients. Hyperuricemia was present in one fourth of the patients and significant risk factors were increasing age, male gender, rising serum creatinine. Deferasirox therapy was negatively associated with hyperuricemia. Tubular dysfunction is relatively common in TDT as more than three fourth patients had hyperuricosuria. Regular monitoring of serum uric acid and urinary uric acid is recommended.

This study was organized to determine the efficacy and safety of deferasirox (DFX) in reducing the SF of patients with transfusion-dependent thalassemia (TDT). This is a retrospective, descriptive study of 101 transfusion- dependent patients with thalassemia major who were followed for 48 months. Twenty-nine patients who used an alternative chelator either alone or combined, who were not compliant to the treatment, changed the drug due to adverse reactions, and had multiple transfusions and did not complete 4 years of DFX use were excluded. A total 72 out of 101 patients completed the study. SF decreases were noted for the 6-12 and18-year age groups, from a median of 1532 ng/mL to 1190 ng/mL, and from 1386 ng/mL to 1165 ng/mL, respectively (p 0.05). The proportion of patients with SF concentrations2000 ng/mL is decreased (29% at baseline decreased to 15% at the end of the study) during the 48 months. The median SF of those who used30 mg/kg/day (n = 38) increased from 767 ng/mL to 1006 ng/mL, whereas the30 mg/kg/day (n = 34) group's SF concentrations decreased from a median of 1575 ng/mL to 1209 ng/mL (p = 0.029). The decrease of median SF values for Syrian patients was statistically significant (p = 0.043). Most common adverse events were gastric irritation symptoms (19.4%). The total DFX discontinuation ratio was calculated as 9.7%. Although dosages between 25-30 mg/kg/day are adequate to stabilize SF concentrations higher dosages are needed to achieve a statistically significant decrease.

Background: Survival in transfusion dependent thalassemia is closely linked to iron overload with severe cardiac iron causing heart failure. MRI guided chelation improves survival in high income countries. We explored the use of rapid MRI to guide therapy in a Lower Middle Income Country (LMIC), India, via locally organized thalassemia patient medical camps. Methods: Rapid cardiac MRI (rCMR) was implemented at two sites with clinical assessment and therapy recommendations based on rCMR findings. Investigations and clinical reassessment were repeated at 13 months. Findings: The baseline visit was attended by 103 patients, the second by 86. Average time of scanning was 10 minutes. At baseline 29% had a cardiac T2* = 17ms). At 13 months more patients were taking 2 oral chelators (21% to 37%, p

Background β-thalassemia is a significant problem in the northeastern part of Iraq, and has imposed a huge burden on the health authorities. Objective To identify the molecular characterization and morbidity prevalence in transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) phenotypes in northeastern Iraq. Patients and Methods This is a cross-sectional study conducted on 242 β-thalassemia patients from 162 families. Reverse hybridization technique and direct gene sequencing were used to characterize β-thalassemia mutations, and medical records of the patients were reviewed with a well-designed questionnaire. Results A total of 22 β-globin mutations arranged in 53 different genotypes were identified: IVS-II-1 (G> A) (35.7%), followed by IVS-I-6 (T> C) (18.0%), and codon 8/9 (+G) (8.5%) were the most frequent. Among disease-related morbidities, bone disease amounted to (66.9%), followed by endocrinopathies (32.2%), hepatobiliary complications (28.9%), and pulmonary hypertension (9.9%), whereas thrombosis, extramedullary hemopoiesis, and leg ulcers were less frequent. Conclusion The overall complications rate was 78.9%, with a growing probability of complications with advanced age, with evidently higher rates in patients with β0β0 and β0β+ genotypes that explain the role of underlying genetic defects in the pathophysiology of disease complications.

Numerous problematic disorders such as vitamin D (Vit-D) deficiency subsequent to large iron loading can be developed in patients with β-thalassemia. The study aimed to estimate Vit-D insufficiency and its risk factors in patients with β-thalassemia. In this multicenter and observational study, all β-thalassemia patients, who referred to 14 hospital-based thalassemia divisions or clinics in Mazandaran province, Iran were included in the study. The data belong to December 2015 until December 2019. The study population was made of transfusion dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) patients. Serum levels of 25-OHD3 have been measured by high performance liquid chromatography (HPLC) method as ng/mL. Demographic and clinical information along with some biological tests, as well as the results of T2*-weighted magnetic resonance imaging were analyzed. Of 1959 registered patients, 487 (24.9%) patients had Vit-D-related data. The prevalence of Vit-D insufficiency (P = 0.03, sensitivity 67%, specificity 49%, positive predictive value [PPV] 47% and negative predictive value [NPV] 68%). In spite of the national programs for treating Vit-D deficiency and our previous efforts for giving supplements to all patients, Vit-D insufficiency/deficiency is still common in our patients. Also, moderate to severe liver siderosis and raised AST were the independent risk factors for the Vit-D insufficiency.

Background Thalassemia is a hereditary hemolytic anemia with a severity ranging from mild, non-transfusion dependent to severe chronic anemia requiring lifelong transfusion. Transfusional iron overload is a major complication in patients with transfusion-dependent thalassemia (TDT). Telomeres are sequences of nucleotides forming the end caps of chromosomes that act as a DNA repair system. Iron overload in thalassemia can cause increased oxidative stress which leads to cellular damage and senescence. This may result in telomere length shortening. The degree of telomere length shortening may reflect the severity of thalassemia. Methods This research aimed to study the leukocyte telomere length in patients with TDT in comparison to non-thalassemic individuals and to identify the clinical and laboratory parameters that are associated with telomere length. We conducted a cross-sectional study in patients with TDT aged ≥18 years. Leukocyte telomere length was measured by real-time quantitative PCR. Results Sixty-five patients with TDT were enrolled onto the study. There were 37 female patients (54.4%). The median age was 27 (18–57) years, and mean pre-transfusion hemoglobin level was 7.1 (± 1.07) g/dL. The mean telomere to single copy gene (T/S) ratios of patients with TDT and the controls were 0.72 ± 0.18 and 0.99 ± 0.25, respectively (p p = 0.0002), and hemoglobin level (p = 0.044). There was no correlation between telomere length and other factors. Conclusions Our study showed that TDT patients had shorter leukocyte telomere length compared with controls. Leukocyte telomere shortening in TDT was an aging-dependent process and associated with lower hemoglobin level.

Early mixed chimerism (MC) can lead to secondary graft rejection post allogeneic hematopoietic stem cell transplantation in transfusion dependent thalassemia (TDT) patients. Reduction of immunosuppression and donor lymphocyte infusions is the mainstay for treating MC. We report our experience of administering unmanipulated stem cell boost (SCB) in reversing progressive early MC. There were 70 transplants done for 69 TDT patients at our center between September 2005 and January 2020. Mixed chimerism was defined by > 5% recipient cells and the severity was assigned according to the proportion of recipient cells as level 1 = 25%. For patients developing MC level 2 and 3, we administered unmanipulated SCB and analyzed its safety and efficacy. Out of 70 transplants 7 (10%) had MC level 2 (3/7) and 3 (4/7). These patients received unmanipulated SCB at a median CD34 cell dose of 4.5 × 10(6)/kg (range—3.5 × 10(6)/kg–5.5 × 10(6)/kg). Overall Response (stable MC and/or transfusion independency) to unmanipulated SCB was seen in 5 patients (71.4%). Five patients (71.4%) developed acute graft versus host disease (GVHD) of which 1 patient expired due to severe GVHD. SCB infusion was well tolerated by majority of our patients. The 3 year overall survival and thalassemia free survival was 85.7% (6/7) and 57.1% (4/7) respectively. Timely monitoring of chimerism is important for detecting early MC. Development of acute GVHD is common after administration of unmanipulated SCB and requires vigilance and prompt management. Unmanipulated SCB is a feasible modality for treating progressive MC and salvaging the graft especially in resource-constrained settings.

Anthropometry and vertebral abnormality in Children with Transfusion-dependent Thalassemia in Phramongkutklao HospitalBackgrounds: Thalassemia is an untreatable inherited hematologic disorder, unless stem cell transplantation, characterized by anemia from decreased hemoglobin production. Growth failure is one of the most common endocrine dysfunction in children with transfusion-dependent thalassemia (TDT) Objective: To evaluate the prevalence and associated factors of anthropometry and vertebral abnormality in transfusion-dependent thalassemia (TDT) children in a single tertiary center. Method: A cross-sectional study was conducted in transfusion dependent thalassemia patients who had visited in pediatric hematology clinic during 1st January 2018 to 31st December 2019. Collaborators had examined by history taking, physical examinations, laboratory and radiology reviewed. Results: Eighty-one collaborators were enrolled. Mean age was 13.7 ± 6.4 years and 46 of them (56.8%) were male. Pre-transfusion Hb and serum ferritin were 8.0 ± 1.0 g/dL and 1,562 + 1,394 ng/mL, respectively. Twenty-one (25.9%) had short stature determined by predicted adult height (PAH) below target adult height (TAH), 27(33.3%) had decreased upper-lower segment ratio for and 21 (26%) had BMI z-score below -2SD for age. Delay puberty was found in 13.2% of patients. Radiological examinations revealed delayed bone age of 4.9% and osteopenia of 25.9% whereas no vertebral fracture was documented. In multivariate logistic regression analysis (backward Wald), Serum ALP (p=0.009), mean pre-transfusion hemoglobin

Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.

Thalassemia is one of the most prevalent monogenic diseases most frequently caused by quantitative defects in the production of β-globin leading to severe anemia. Technological advances in genome sequencing, stem cell selection, viral vector development, transduction and gene-editing strategies now allow for efficient ex-vivo genetic manipulation of human stem cells that can lead to correction leading to a meaningful clinical benefit in thalassemia patients. In this review, the status of the gene-therapy approaches available for transfusion dependent thalassemia are discussed, along with the critical criteria that affect efficacy and lessons that have been learned from the early phase trials. Salient steps necessary for the clinical development, manufacturing, and regulatory approvals of gene therapies for thalassemia are also highlighted, so that the potential of these therapies can be realized. It is highly anticipated that gene therapies will soon become a treatment option for patients lacking compatible donors for hematopoietic stem cell transplant and will offer an alternative for definitive treatment of β- thalassemia. This article is protected by copyright. All rights reserved.

Background: Successful hematopoietic stem cell transplantation (HSCT) could cure the hematological manifestations of transfusion-dependent thalassemia (TDT), but introduces risks of morbidity and mortality. Umbilical cord blood transplantation (UCBT) is considered as an acceptable strategy, by providing a condensed graft versus host disease (GvHD). This paper compares the outcomes of UCBT with HSCT from peripheral blood and bone marrow in TDT patients.Methods: Between 1998 and 2014, 10 patients with TDT underwent UCBT, which were matched with 20 patients undergone BMSCT and 20 patients undergone PBSCT, by using propensity score matching (PSM) for age, gender and thalassemia class. All patients received the same myeloablative conditioning regimen and were transplanted from a fully HLA matched sibling donor. Results: The median follow-up time after HSCT was 5.7 years. Rejection incidence was 70.0% (95% CI = 28.1%-90.4%) after UCBT, 25.6% (95% CI = 8.9%-46.4%) after BMSCT, and no rejection occurred in the PBSCT group. Acute GVHD incidence was 20.0% (95% CI = 2.6%-49.0%), 35.0% (95% CI = 15.1%-55.8%), and 40.0% (95% CI = 18.6%-60.6%) in patients undergone UCBT, BMSCT and PBSCT, respectively (P=0.62). The incidence of chronic GVHD was 7.2% (95% CI = 0.3%-28.7%), and 35.2% (95% CI = 13.7%-57.8%) in patients undergone BMSCT and PBSCT, respectively (P=0.026) and none of the patients in the UCBT group experienced chronic GvHD. Conclusions: Although the overall survival is not significantly influenced by the graft source, due to the high incidence of rejection after UCBT, the probability of thalassemia free survival is very low in these patients.

Objectives To evaluate any association between pre-transfusion hemoglobin (Hb) levels and thalassemia complications and to identify the Hb cutoff values to predict thalassemia complications. Methods We performed a cross-sectional study in thalassemia patients who attended the Adult Hematology Clinic of the tertiary care University Hospital from October 2017 to October 2018. A point-biserial correlation was used to identify any association between Hb levels and thalassemia complications. A receiver operating characteristic (ROC) curve was used to identify the diagnostic ability of Hb levels to predict thalassemia complications and identify Hb cutoff values. Results Out of the 102 patients, there were 53 transfusion dependent thalassemia (TDT) patients and 49 non-transfusion dependent thalassemia (NTDT) patients. In theTDT group, Hb levels showed a negative correlation with severe hepatic iron overload and hypogonadism. The cutoff Hb levels to predict severe hepatic iron overload and hypogonadism were ≤7.01 and 6.81 g/dL, respectively, at which points the area under the ROC curve (AUC) were 0.721 and 0.708, respectively. In the NTDTgroup, Hb levels were negatively correlated with hepatic iron overload, osteoporosis, and pulmonary hypertension. The cutoff values of Hb levels to predict hepatic iron overload, osteoporosis, and pulmonary hypertension were ≤8.24, 7.16, and 7.16 g/dL, respectively, at which points the AUC were 0.923, 0.715, and 0.725, respectively. Conclusions Lower Hb level was associated with more frequent complications in both TDT and NTDT patients. The Hb cutoff levels to predict these complications were identified.

Heart disease remains a leading cause of morbidity and mortality in transfusion-dependent thalassemia (TDT), which can be attributed to several factors but primarily develops in the setting of iron overload. This was a retrospective cohort study utilizing Webthal® patient data from five major centers across Italy. Patients without heart disease were followed-up for 10 years (2000-2010) and data were collected for demographics, splenectomy status, serum ferritin and hemoglobin levels, and comorbidities associated with heart disease. Among 379 patients analyzed (mean age 22.9 ± 5.1years, 47.8% men), 44 (cumulative incidence: 11.6%) developed heart disease during the period of observation. Splenectomy (p = 0.002) and serum ferritin level (p

Thalassemia is among the most common genetic diseases. Patients with severe forms of the disease are transfusion-dependent, leading to iron overload. A condition which can eventually develop in the iron-loaded heart is iron overload cardiomyopathy, a debilitating disease that accounts for the majority of deaths in thalassemia patients. Areas covered: This review article provides a comprehensive summary of the diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients, with discussion covering current weak points and potential improvements of the relevant diagnostic and therapeutic strategies. Expert commentary: Current limitations of various diagnostic techniques for iron overload cardiomyopathy include suboptimal accuracy, untimely detection, or inadequate accessibility, and novel modalities are required to overcome these shortcomings. Treatment should address key pathophysiologic mechanisms of iron overload cardiomyopathy, which include cardiac iron mishandling and iron-induced oxidative injury. Apart from the promotion of iron removal by chelators, prevention of cardiac iron deposition and attenuation of oxidative damage should also be rigorously investigated on a cell-to-bedside basis.

Introduction of MRI techniques for identifying and monitoring tissue iron overload and the current understanding of iron homeostasis in transfusion-dependent (TDT) and non-transfusion-dependent thalassemia have allowed for a more robust administration of iron chelation therapies. The development of safe and efficient oral iron chelators and the insights gained from large-scale prospective studies using these agents have improved iron overload management. A significant reduction in iron toxicity-induced morbidity and mortality and improvements in quality of life were observed in TDT. The appropriate management of tissue-specific iron loading in TDT has been portrayed using evidence-based data obtained from investigational studies.

Introduction: Patients with transfusion-dependent-thalassemia (TDT) are considered as increased risk population for severe and/or morbid COVID-19 infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions following vaccination have been reported, with severe ones being extremely rare. TDT patients may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. The safety profile of vaccination in chronically transfused patients with thalassemia has not been reported. AIM: To evaluate the safety profile of COVID-19 vaccines in TDT patients. Patients and Methods: This is a single institution's, retrospective analysis evaluating all TDT patients, older than 18 years old, who had completed the vaccination protocol at least 30 days before data cut-off time (July 20 th 2021). Adverse events were reported by patients up to 30 days post each dose. Demographic data and hematological data, including mean hemoglobin levels before and up to 30 days after each dose, were recorded. T-test was performed to investigate changes in hematological profile and transfusion burden post vaccination. Results:186 patients (median age:45; range:18-61 years old; male/female:87/99) were included for data analysis corresponding to 53% of all TDT patients followed in our Thalassemia Unit. Distribution of vaccine types were: Comirnaty -BNT162b2 (Pfizer Inc. and BioNTech)90.86% (n =168), Vaxzevria (previously COVID-19 vaccine, AstraZeneca)1.61% (n=3), Moderna (Moderna TX Inc.)6.99% (n =13) and JNJ-78436735 (Janssen Pharmaceuticals Companies of Johnson & Johnson)0.54% (n =2). No patients had confirmed or suspected previous COVID-19 infection. Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The incidence of adverse events after 1 st and 2 nd dose were 43.5% (81/186) and 54.8% (102/186), respectively. Adverse events after 1 st dose included pain at injection site 26.3%( n=49), fatigue 9.7%(n=18), fever 5.4% (n=10),headaches 4.3% (n=8), arthralgia and myalgia 2.2% (n=4), and lymphadenopathy 0.5% (n=1). Adverse events after 2 nd dose included fever 28.5% (n=53), fatigue 17.7% (n=33), pain at injection site 15.6%(n=29), arthralgia and myalgia 11.3% (n=21), headaches 9.1% (n=17), lymphadenopathy 3.2% (n=6), dizziness 0,5% (n=1), tachycardia 0.5% (n=1), diarrhea/ vomiting 0.05% (n=1) and amaurosis fugax 0.5%: (n=1). No grade 4-5 events or anaphylaxis were observed. Two patients (both males, 51 years and 45 years old, respectively) presented with acute hemolytic crisis with hemoglobinuria in 3 rd and 20 th day after the second dose with Pfizer/BioNTech, respectively. They are receiving treatment with corticosteroids without partial response. Both patients had a history of acute hemolysis crisis within the last 3 years. A decrease in Hb levels after either the first or second dose compared to pre-vaccination mean Hb levels was observed (mean=9.9 /sd=0.63 vs mean=9.44 /sd=0.76), (p < 0.001). Conclusions: Compared to the vaccine trials, we observed some lower incidence of vaccine-related adverse events in our cohort of TDT patients, which may be related to the less stringent reporting methods outside official trials. A temporary drop in hemoglobin levels may be noted in chronically transfusion patients, which parallels what is observed when patients are developing infection or inflammation. Of interest, two patients with previous history of alloimmunization, developed hemolysis. Close hematological follow up may be required in TDT patients post vaccination. The risk/benefit of the vaccination is strongly positive for this vulnerable population. Disclosures Kattamis: Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy.

Introduction: Luspatercept inhibits select ligands of the TGF-β superfamily implicated in thalassemic erythropoiesis and promotes late-stage erythroid maturation (Suragani RN, et al. Nat Med 2014;20:408-414). This leads to greater red blood cell (RBC) output from thalassemic marrow and reduces transfusion dependence in TDT (Cappellini MD, et al. N Engl J Med 2020;382:1219-1231). The underlying mechanisms for this clinical outcome are not well understood in a syndrome involving significant iron overload and cyclical stimulation of erythropoiesis between transfusions. Here we report novel physiological and clinical insights from a BELIEVE trial (NCT02604433) biomarker analysis, which demonstrate that hepcidin and erythropoietic changes in TDT lead to iron redistribution from macrophages to hepatocytes on luspatercept. Methods: 336 TDT patients ≥ 18 years of age who took part in the BELIEVE study, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (Cappellini et al. 2020), were randomized 2:1 to receive luspatercept or placebo subcutaneously every 21 days for 48 weeks. This ethically approved study was conducted in accordance with the Declaration of Helsinki. Patients provided written informed consent. Transfusion iron loading rate (ILR) was calculated assuming 1 unit = 200 mg Fe. Liver iron content (LIC) was measured by R2 MRI and R2* MRI, and total body iron stores by Angelucci formula. Serum was assayed for ferritin (SF) nephelometrically (Covance lab), and hepcidin, erythroferrone (ERFE), growth differentiation factor (GDF)15, and transferrin receptor (sTfR1) by ELISA at Intertek (San Diego, CA). Median and interquartile ranges are shown; P value < 0.05 was deemed significant. Results: Within 48 weeks on luspatercept, transfusion iron loading fell by 1.6 g (8 RBC units, ILR difference −0.08 mg Fe/kg/d ± 0.07, range −0.4 to 0.2). Regardless of thalassemic genotype, SF fell by 269.3 ± 963.7 and earliest at 12 weeks by 103.6 ± 690.3 µg/L (both P < 0.0001), with no change on placebo, indicating reduced macrophage iron. However, despite unchanged chelation exposure, no reduction in LIC (5.7 to 6.7 mg/g dw) or calculated body iron stores (3.6 to 4.2 g, not significant) occurred on luspatercept, even though saved iron loading from transfusion was 44% (1.6 g/3.6 g) of baseline body iron stores. On luspatercept, but not placebo, hepcidin fell by 53%, while erythropoietin (EPO), ERFE, GDF15, sTfR1, and reticulocytes rose by 93%, 51%, 59%, 66%, and 112%, respectively (all P < 0.0001). 71% (120/169) patients with and 47% without (17/36) ILR reduction had negative SF trends (P < 0.0001). In patients with SF reduction on luspatercept, bilirubin and LDH rose 50% and 67% (P < 0.0001) indicating increased RBC hemolysis from residual (effective and ineffective) erythropoiesis. ILR change correlated with changes in EPO, hepcidin, sTfR1, and bilirubin, but not with changes in ERFE, GDF15, reticulocytes, or LDH (Figure A). Hepcidin reduction was related to LIC increase post splenectomy (Figure B), suggesting a role for the spleen in preventing hemolytic iron redistribution to the liver. Decrease in SF thus associates with erythroid iron incorporation (sTfR1), hence RBC production that reduces transfusion needs (falling ILR) but enhances hemolytic rerouting of iron to the liver. In a mixed-effect linear regression analysis, transfusion, LIC, baseline SF, time, and treatment predicted SF changes in a benchmark model. We found high baseline LIC lessens the SF outcome, and hepcidin, EPO, and bilirubin jointly explained 66% of the treatment effect of luspatercept on SF. Conclusions: Luspatercept-increased ERFE, likely as a result of increased production or higher frequency of late-stage erythroblasts, partially reduces hepcidin production. Lower hepcidin mobilizes iron stores to facilitate bulk hemoglobinization, erythropoietic response, and transfusion burden reduction. Luspatercept leads to SF reduction that marks hepcidin-dependent iron egress from macrophage compartment to plasma. This relocated iron, variably utilized by thalassemic erythron, refluxes back to plasma for hepatocyte and extrahepatic iron uptake, or as heme iron shunts into the liver through hemolytic pathways from intramarrow ineffective erythropoiesis or peripheral breakdown of newly made thalassemic RBC. Macrophage to hepatocyte iron redistribution in TDT appears to be a mechanism of luspatercept. Figure 1 Figure 1. Disclosures Garbowski: Imara: Consultancy; Vifor: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy. Ugidos: Bristol Myers Squibb: Current Employment. Risueño: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Suragani: Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company. Shetty: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Vodala: BMS: Current Employment, Other: stock options. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Schwickart: BMS (Celgene): Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other, Patents & Royalties; Exelixis: Current Employment, Current equity holder in publicly-traded company. Porter: Celgene (BMS): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla Pharmaceuticals: Honoraria; bluebird bio, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Thalassemia is one of the most common hemoglobinopathies, with around 5% of world's population expected to have some degree and type of thalassemia. Beta thalassemia (BT) occurs due to a deficient production of the beta-globin chain of hemoglobin. BT is classified into minor, intermedia, and major, defined by their clinical and laboratory findings. Extramedullary hematopoiesis is one of the complications of BT, primarily seen in minor/intermedia subtypes. EMH is the production of blood cells outside the marrow as a compensatory response to longstanding hypoxia. Due to chronic transfusions, it is not expected in patients with beta thalassemia major (BTM). However, there are multiple case reports of EMH in BTM. The incidence of EMH in BTM is thought to be Methods: This is a systematic review of case reports, series, and retrospective studies that presented data on the occurrence of EMH in BTM patients. Data were recorded and analyzed in Microsoft Excel 2016 and SPSS 26. The protocol has been registered in PROSPERO: CRD42021242943. Results: Data from 253 cases of EMH in BTM patients were extracted from 2 retrospective studies and 71 case reports (some of the descriptive data from case reports and most of the descriptive data from retrospective studies was missing). The mean age at presentation was 35.3 +/- 0.5 years. Males constituted 57.7% of the total population. Mean hemoglobin at presentation with EMH was 8.2 +/- 2.1 mg/dL. Lower limb weakness was the most common presenting feature (N=23). Other features included localized pain, urinary incontinence, and an incidental finding of EMH. Magnetic resonance imaging (MRI) was the most widely used diagnostic modality (N=226). However, computed tomography scans, positron emission tomography scans, tissue biopsy, myelograms, and X-rays were also used to diagnose EMH. Various treatments were reported either alone or in combination. Overall, blood transfusion was the commonest reported treatment (N=30), followed by radiotherapy (N=20), surgery (N=15), hydroxyurea (N=12), steroids (N=6), and exchange transfusion (N=2). An outcome was reported in 20% of patients, all recovered, with no reported mortality. Conclusion: EMH is considered a rare phenomenon in BTM patients. However, there are many cases reported in which EMH occurred in BTM despite chronic blood transfusions. EMH can occur in any organ system and can present with a varied clinical feature. MRI can effectively diagnose EMH, and conservative management is reported to have similar results compared to invasive treatments. More extensive studies, focusing especially on outcomes, are required to enhance the guidelines on managing EMH in patients with BTM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Cardiac failure is one of the leading causes of death in sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT). For this reason, early detection of silent cardiac dysfunction is crucial for treatment and prevention of heart failure. Speckle-tracking echocardiography (STE) is an easily accessible tool for analyzing myocardial function and this modality has increased sensitivity in detecting asymptomatic disease. Attenuation in cardiac strain has been correlated to early systolic dysfunction among patients with cardiomyopathies. This technique has not been consistently evaluated in children with SCD and TDT. Due to the role of anemia and siderosis in the pathology of cardiac dysfunction, we hypothesized that early myocardial dysfunction correlates with the degree of anemia and hyperferritinemia in SCD. We analyzed the clinical, echocardiographic, STE and laboratory parameters in SCD and compared them to children with TDT and normal controls. We retrospectively analyzed date from consecutive patients with SCD and TDT who received treatment at our institution from 2008 to 2018. Echocardiographic data from children with benign murmurs served as normal controls (NC). Data was independently verified by a pediatric cardiologist. Descriptive and correlation analysis were used; a p-value < 0.05 was considered significant. Echocardiographic data were available for 77 SCD (HbSS and HbS/ ß 0 Thal), 25 TDT (ß 0/ ß 0 and ß +/ ß + Thal)and 138 NC. Mean hemoglobin (Hg) and ferritin values were 9.8 g/dl (6.8-14.6 g/dl); 392 ng/ml (19.3-8,3437.67 ng/ml), respectively for SCD patients and 9.3 g/dl (7-17.03 ng/dl); 2,960 ng/ml (13-13,831 ng/ml), respectively for TDT. Standard echocardiographic parameters left ventricular ejection fraction (LVEF), right VEF and LV shortening fraction (LVSF) were within the normal limits in SCD, TDT, and NC children. Significant differences were observed in the steady-state global circumferential strain (GCS) between the three groups SCD, TDT and NC [-26.5 (mean), 3.6 (SD); -27.6 (mean), 4.8(SD); -25.0 (mean), 3.6 (SD), respectively; p = 0.002] (Table 1). Subset analysis based on ferritin levels (> or < 1000 ng/ml), revealed no significant difference in GCS between the SCD or TDT groups (Table 2). However, global longitudinal strain (GLS) was significantly lower among SCD compared to TDT with ferritin levels greater than 1,000 ng/ml (Table 2). A positive correlation (r = 0.25, p = 0.046) was found between GLS and Hg in SCD patients (n=63) (Figure 1). No significant correlation was found between Hg and GLS in the TDT group (Figure 2). No significant correlation was found between GCS and Hg (r = 0.1, p = 0.42); GLS and GCS and ferritin in the SCD group. LVEF was found to be normal in patients with abnormal strain indices. Cardiac strain indices are abnormal in children with SCD and TDT compared to normal children. Significantly abnormal GLS was noted in hyperferritinemic SCD patients compared to TDT patients. A positive correlation between severity of anemia and GLS was observed in this study in SCD children. Based on these results, we speculate that therapies aimed at ameliorating anemia can potentially improve GLS and thus, early cardiac dysfunction in SCD patients. However, further studies are warranted to understand the contributory role of anemia and hyperferritinemia and its therapeutic implications on early myocardial dysfunction in SCD. Figure 1 Figure 1. Disclosures Sathi: Vertex Pharmaceuticals: Consultancy.

Introduction: Allogeneic stem cell transplantation (HSCT) is a potential curative treatment for TDT. BuCy based regimen has been used widely as a standard myeloablative chemotherapy. However, the use of treosulfan based conditioning regimen has increased over the last decade (Choudhary D et al BBMT 2013). We analysed the safety and efficacy of BuCy based vs Treosulfan/Thiotepa/Fludrabine (Treo/Thio/Flu) regimens in TDT between September 2013 and March 2021. Method: This is an observational retrospective hospital record-based study approved by Institutional Review Board. Regimen used: Treo/Thio/ Flu : Thiotepa 8 mg/kg , treosulfan 14 g/m2/day for 3 days, and fludarabine 40 mg/m2/day for 4 days . Flu/Bu/Cy/ATG : Fludrabine 30mg/ m2/ day for 6 days ,Antithymocytoglobulin 4.5mg/kg in 3 days , Busulfan (per oral) 14mg/kg ( boys) and 12mg/kg (girls) in 4 days, Cyclophosphamide 40mg/kg/day ( boys)and 50mg/kg/day ( girls) for 4 days. Statistical Analysis: Fisher's exact test was used for discrete variables and t-test was used for continuous variables. Log-rank test was used for the difference in survival between the groups. P value < .05 was considered statistically significant. Cox regression for survival analysis was also used for time to event data of the predicted variables. Results: As shown in Table 1, 74 patients were enrolled, out of which 35 (47.2%) patients received BuCy based regimen whereas 39(52.7%) patients received Treo/Thio/Flu. All were fully HLA matched. Median age was 5.5 (1-12) years and 9 (1-15) years respectively. According to Lucarelli classification, number of patients with Class I, II, III were 17, 12, 6 in BuCy group vs 2, 14,18 in Treo/Thio/Flu group respectively. When stratified according to Matthew classification, 06 (17.1%) and 11 (28.2%) patients were in class IIIB respectively (Mathews V et al, BBMT 2007). Source of graft was bone marrow in BuCy group vs peripheral blood stem cell (PBSC) in Treo/Thio/Flu group. Mean CD34 cell dose was 3.82(2.2-9.1) vs 5(1.65-8.01) 106/kg in BuCy vs Treo/ Thio/Flu group respectively. Neutrophils and platelets engrafted at median of 16 days (14-21) and 16 days (9-47 ) in BuCy and 15 days (10-20) and 13 days (9-41) in Treo/ Thio/ Flu. Median duration of follow-up was 28 (23-32.9) months. Two (5.7%) patients had rejection (primary=1, secondary=1) in BuCy group whereas none in Treo/Thio/Flu. Five (14.3%) vs 10 (25.6%) patients developed grade ¾ oral mucositis respectively where 1 patient in each group belonged to Class III. Sinusoidal obstruction Syndrome (SOS) was observed in 02 (5.7%) vs 04 (10.3%) patients (p=0.047) respectively, with no patients affected in Class III. BuCy group had 04(11.4%) patients with acute GVHD, including one patient with grade 3. Treo/Thio/Flu group had 15(38.5%) patients with acute GVHD including 4 patients with grade 3 which had significant impact on survival (p=0.038). We also observed chronic GVHD in 04(11.4%) and 11(28.2%) patients respectively which was mainly limited stage in former and extensive in later which impacted the survival (p=0.031). CMV viremia was observed in 14 (40%) vs 8 (20.5%) patients respectively. We also encountered significant infections in both groups {21 (60%) vs 17 (43.6%)}, however, difference was not statistically significant. Four (5.1%) patients had transplant related mortality (TRM) in Treo/Thio/Flu group, in contrast to none in BuCy group. Commonest cause of death was sepsis. Mixed chimerism was commonly seen in BuCy group {20 (57.1%)} vs Treo/Thio/Flu group {12(30.1%)}.(Table 2) At last follow up, all alive patients except two patients with rejection are transfusion independent. Five-year Thalassemia-free survival (TFS) and overall survival (OS) of entire cohort was 94%+3% and 93%+4% respectively. Estimated OS and Event free survival (EFS) of BuCy vs Treo/Thio/ Flu was 100% vs 89.7% (p=0.060) and 93.9% vs 89.7% (p=0.472) respectively.(Figure 1) Discussion: We observed significant difference in TRM, acute and chronic GvHD and SOS favoring the BuCy group even in class III. On the contrary, we encountered rejections(n=2) and increased number of mixed chimerism in BuCy group which corroborates with previous literature (Fouzia N et al, BMT 2018). Conclusion: In our experience BuCy based conditioning regimen is a safe and effective regimen even in high risk class III TDT, with less TRM in comparison to Thio/Treo/Flu regimen. However, one needs to be vigilant for rejections and mixed chimerism. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The aim of our study was to evaluate the Greek version of the transfusion-dependent quality of life (TranQol) questionnaire and report our experience of using this novel disease-specific quality of life (QoL) measure in patients with transfusion-dependent thalassemia (TDT). The TranQol and SF-36v2 questionnaires were administered to 94 adult TDT patients with a mean age of 32.1 years (SD = 7, range = 19–58), recruited from the Adult Thalassemia Unit of Hippokration General Hospital of Thessaloniki, Greece. The TranQol was evaluated in terms of construct validity, reliability, and responsiveness. There was a moderately strong correlation between the TranQol summary and both the SF-36v2 physical and mental component summaries (r = 0.4, p

With regular blood transfusions and modern medical management strategies, transfusion-dependent thalassemia (TDT) patients are currently living into adulthood, but they still suffer from the chronicity of the disease and its complications. This study was aimed to assess the health-related quality of life (HRQoL) scores in pediatric TDT patients compared with healthy controls.The PedsQL 4.0 Generic Core Scales were administered to 80 pediatric TDT patients (aged 5 to 18 y, child self-report) and their parents (parent-proxy report), as well as age-matched and sex-matched healthy controls (80 participants and their parents).Patients with TDT and their parents rated lower HRQoL scores in all domains (physical, emotional, social, and school functioning) compared with the healthy population (P0.01). The univariate analysis indicated that the total HRQoL score for children's self-reports was negatively predicted by high ferritin levels and the presence of any complication. The only negative predictor of the total HRQoL score in multivariate analyses was a high ferritin level (1800 ng/dL).This study showed that thalassemia has a negative impact on HRQoL when compared with a healthy population. For a better quality of life, intensive treatment should be applied for complications and high ferritin levels.

This was a prospective observational study to evaluate abnormalities in lipid profile in 50 children with transfusion dependent thalassemia. Dyslipidemia characterized by high triglycerides, low high density lipoprotein (HDL), and high total cholesterol: HDL ratio was noted. These pro atherogenic risk factors may be lead to significant cardiovascular morbidity in these patients.