Non-transfusion-dependent Thalassemia Research Articles

Organ-Specific Iron Overload in Non-Transfusion-Dependent Thalassemia Patients: Insights from Quantitative MRI Evaluation

ObjectiveTo elucidate the iron load in different organs of non-transfusion-dependent thalassemia (NTDT) patients using magnetic resonance imaging (MRI) T2* scan. MethodsThirty-four NTDT patients, including 28 NTDT iron chelation without and 6 NTDT with iron chelation, together with 15 normal controls, underwent MRI examination between December 2022 and July 2024 were enrolled in the study. Measured T2* of the pituitary gland, kidney cortex, heart, liver, pancreas, spleen. Liver and spleen volumes were evaluated. ResultsOf the 28 patients in NTDT without iron chelation group, 19 patients with iron overload in the liver, 9 patients with iron overload in the kidneys, and 4 patients with iron overload in the spleen. Most patients with abnormal kidney and spleen iron (76.9 %) had liver iron overload. Compared with the control group, NTDT without iron chelation patients had lower T2* in the liver, kidney, and spleen (p < 0.05). And heart T2* was correlated with kidney T2* (r = 0.480, p = 0.010) and pancreas (r = 0.411, p = 0.037). Liver T2* was correlated with spleen T2* (r = 0.479, p = 0.011). Pancreas T2* was correlated with pituitary T2* (r = -0.433, p = 0.031). ConclusionsNTDT patients exhibit significant organ-specific iron overload, particularly in the liver, kidneys, and spleen. The correlations between iron levels in different organs suggest interconnected mechanisms of iron accumulation. These findings highlight the importance of regular MRI screening to monitor and manage iron overload in NTDT patients.

Health-Related Quality of Life of Adolescents With Non-transfusion-Dependent Thalassemia in Basrah, Iraq.

Thalassemia is a chronic inherited disease with the potential for serious clinical and psychological effects. In the case of thalassemia, a cure is not currently accessible, and lifelong treatment is required. Health-related quality of life (HRQoL) is considered a crucial health outcome. This study aims to assess the HRQoL of children and adolescents with non-transfusion-dependent thalassemia (NTDT) and compare it with that of beta-thalassemia major (β-TM) and healthy subjects. This case-control study included 88 patients with NTDT and 153 age- and gender-matched healthy children and adolescents. In addition, we included 70 registered patients with β-TM. We used the short-form health survey questionnaire to assess HRQoL. Of the 88 patients, 41 were diagnosed with alpha-thalassemia intermedia (α-TI; hemoglobin H disease), and 47 were with beta-thalassemia intermedia (β-TI). HRQoL domains were significantly higher in healthy children and adolescents compared to NTDT patients (P<0.001); the role emotion domain was the most affected in NTDT patients (51.92 ± 3.37), followed by general health (52.72 ± 3.05) and role physical (53.59 ± 3.13). α-TI patients had significantly higher HRQoL domains than patients with β-TI. The study also indicated that NTDT patients had significantly better QoL scores compared to β-TM patients (P<0.001) across all domains. NTDT patients have a lower HRQoL compared to healthy controls. However, their HRQoL scores are significantly better than those of patients with β-TM. Among NTDT patients, those with α-TI have significantly better HRQoL scores compared to patients with β-TI.

Clinical efficacy of thalidomide for various genotypes of beta thalassemia

ObjectiveThe objective of this study was to investigate the therapeutic efficacy of thalidomide across various genotype presentations of β-thalassemia so as to facilitate the early screening of thalidomide-sensitive thalassemia cases and to understand the impact of iron overload on thalidomide.MethodsFrom our initial sample of 52 patients, we observed 48 patients with β-thalassemia for two years after administration of thalidomide. This cohort included 34 patients with transfusion-dependent thalassemia (TDT) and 14 patients with non-transfusion-dependent thalassemia (NTDT). We recorded the values of hemoglobin (Hb), fetal hemoglobin (HbF), and serum ferritin (SF) in the baseline period and at 1, 3, 6, 12, 18, and 24 months after enrollment, as well as the pre- and post-treatment blood transfusion volume in all 48 cases. According to the increase in Hb levels from baseline during the 6-month observation period, the response to thalidomide was divided into four levels: main response (MaR), minor response (MiR), slow response (SLR), and no response (NR). A decrease in serum ferritin levels compared to baseline was considered alleviation of iron overload. We calculated the overall response rate (ORR) as follows: ORR = MaR + MiR + SLR/number of observed cases.ResultsThe ORR was 91.7% (44/48 cases), and 72.9% showed MaR (35/48 cases). Among the 34 patients with TDT, 21 patients (61.8%) were free of blood transfusion, and the remaining 13 patients still required blood transfusion, but their total blood transfusion volume reduced by 31.3% when compared to the baseline. We found a total of 33 cases with 10 combinations of advantageous genes, which included 5 cases with βCD41-42/βCD17 and 6 cases with βCD41-42/β-28. Based on the treatment outcomes among the 48 cases in the observation group, there were 33 cases in the MaR group and 15 cases in the SLR/NR group. There was a difference in HbF between the two groups at baseline (P = 0.041). There were significant differences between the two groups in Hb and HbF at the time points of 6 and 12 months, respectively (P < 0.001). Compared to the baseline measurement, there was a significant decrease in the level of SF at months 12 and 24 (P < 0.001).ConclusionIn this study, we identified 10 β-thalassemia gene combinations that were sensitive to thalidomide. These gene combinations can be used for initial screening and to predict the therapeutic effect of thalidomide in clinical practice. We examined the therapeutic response to thalidomide and found that the administration of thalidomide in combination with standardized iron removal was more beneficial in reducing iron overload.

Anemia Heart Disease in a Patient with Suspected Non-Transfusion Dependent Thalassemia, a Case Report

Anemia Heart Disease in a Patient with Suspected Non-Transfusion Dependent Thalassemia, a Case Report

Brain perfusion changes in beta-thalassemia

BackgroundBrain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce.AimsWe investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity.MethodsWe performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded.ResultsBoth TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found.ConclusionRelative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment.

Health-related quality of life with standard and curative therapies in thalassemia: A narrative literature review.

Health-related quality of life (HRQOL) is a patient-reported outcome that assesses the impact of a disease or illness on different domains of a patient's life. Different general and disease-specific measures can be used to evaluate HRQOL. This article aimed to summarize the evidence for HRQOL among patients with transfusion-dependent (TDT) and non-transfusion-dependent thalassemia (NTDT). We included HRQOL data related to standard therapy with blood transfusions, iron chelation, and/or luspatercept in TDT and NTDT, as well as curative therapies for TDT, including hematopoietic stem cell transplant (HSCT) and gene therapy. Patients with thalassemia had worse HRQOL scores compared to the general population, and chronic pain was seen to increase in frequency and severity over time with age. NTDT patients reported worse physical health and functioning, mental health, general health, and vitality than TDT patients. However, TDT patients reported worse pain, change in health, and social support than NTDT. Most therapies improved overall HRQOL among thalassemia patients. Deferasirox, an oral iron chelator, was associated with more HRQOL benefits compared to deferoxamine, an intravenous iron chelator. Luspatercept showed clinically meaningful improvement in physical functioning among TDT and NTDT. Furthermore, HSCT and gene therapy were associated with better physical, emotional, and mental domains scores.

Two risk factors for hypozincemia in diabetic β-thalassemia patients: Hepatitis C and deferasirox.

Hypozincemia is a prevalent adverse consequence in diabetes mellitus (DM) and β-Thalassemia patients. We aimed to evaluate the level of serum zinc in β-thalassemia patients with DM and a risk assessment for hypozincemia. The study population included transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT) with overt DM (fasting plasma glucose (FPG) ≥126 mg/dL, and/or 2-h plasma glucose≥200 mg/dL). Serum zinc concentration was measured by the colorimetric method, and the values below 70 μg/dL were defined as hypozincemia. Myocardial and liver T2*-weighted magnetic resonance imaging (MRI T2*, millisecond [ms]) were valued by a free contrast MRI. The demographic, clinical, paraclinical, and laboratory data were also recorded. The data belonged to the period from December 2018 until December 2020. Of 64 diabetic β-thalassemia patients, 41 cases had zinc data in their medical files (aged 38 ± 9 years, 48.8% female). 78.05% of patients (n = 32) were TDT, and 21.95% were NTDT (n = 9). The mean ± standard deviation of zinc level was 110.2 ± 127.6 μg/dL. The prevalence of hypozincemia was 9.76%, 95% confidence interval [CI] 0.27 to 19.24 (four cases). After controlling age, the odds of hypozincemia for using deferasirox (DFX) was 8.77, 95% CI 0.60 to 127.1. In β-thalassemia patients, the age-adjusted risk of hypozincemia was calculated at 15.85, 95% CI 0.47 to 529.3 for hepatitis C. The adjusted risk of hypozincemia based on age for antacid use was 6.34, 95% CI 0.39 to 102.7. In light of this study, as well as hepatitis C, using DFX and antacids is associated with a high risk of hypozincemia amid diabetic β-thalassemia cases. However, upward bias should be taken into consideration.

Non-transfusion dependent HbE/βO-thalassemia as the results of co-existent SEA-αO thalassemia, Hb Constant Spring, and XmnI-Gγ site: Thai family studies

Background: Four university students of northern Thai descent were found to be HbE/βO-thalassemia. However, they all had a mild form of this disease, categorized as Non-Transfusion Dependent Thalassemia. Objectives: To analyze involvement of types of β-globin mutations, α-thalassemia, and XmnI-Gγ site in mild clinical symptoms observed in four Thai non-transfusion dependent HbE/βO-thalassemia cases. Materials and methods: EDTA blood samples were collected from the patients and their family members after signing the informed consent. Automated complete blood count with blood smear examination, hemoglobin typing, molecular analysis for α and β-globin mutations, β-globin gene haplotypes, and XmnI-Gγ site were performed on all blood samples. In addition, nucleotide sequencing of β-globin gene and globin chain separation were performed for patient#3 and their parents. Results: The first three patients had hemoglobin levels ranging 8.5-11.2 g/dL, while the fourth patient had hemoglobin level of 6.7 g/dL. The first and fourth patients were compound heterozygote for βE (HBB:c.79G&gt;A) and β17 (HBB:c.52A&gt;T) alleles with typical hemoglobin pattern of EF. The second patient was compound heterozygote for βE and β41/42 (HBB:c.126_129delCTTT) alleles also with typical hemoglobin pattern of EF. The third patient was compound heterozygote of βE and βIVS1-1(HBB:c.92+1G&gt;T), however, with atypical hemoglobin pattern of EE. Family analysis found co-inheritance of Hb Constant Spring (HBA2:c.427T&gt;C) and the XmnI-Gγ site (T at rs7482144) in the first two patients, of SEA-αO thalassemia (NG_000006.1:g.26264_45564del19301) and XmnI-Gγ site in the third patient, and of only XmnI-Gγ site in the fourth patient. Conclusion: These family studies proved the fact that co-existence of SEA-αO thalassemia and Hb Constant Spring in HbE/βO-thalassemia could lead to mild clinical severity. Minimal effect of XmnI-Gγ site on clinical symptoms of this disease was emphasized. This information should be useful in prenatal diagnosis of HbE/β-thalassemia.

Association of Hemoglobin Levels with Healthcare Resource Utilization and Costs in Non-Transfusion-Dependent α- and β-Thalassemia: A Retrospective Observational Study Using Real-World Data

Introduction: Alpha (α)- and beta (β)-thalassemia result from reduced synthesis of α- or β-globin, respectively, leading to ineffective erythropoiesis, chronic hemolytic anemia (HA), and related complications. Thalassemia can also be characterized phenotypically as transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT). Decrease in hemoglobin (Hb) has been linked to increased risk of comorbidities and number of comorbidities in NTD β-thalassemia. Healthcare resource utilization (HCRU) has been analyzed in TDT in the US, but there is limited research on the association of Hb levels with HCRU and costs in α- and β-NTDT. Objective: To assess the association of average Hb levels with HCRU and costs in adult patients with α- and β-NTDT using retrospective claims data. Methods: This study analyzed data from the Merative ® MarketScan ® Commercial, Medicare, and Lab Results Databases for patients with thalassemia and no evidence of other HAs who were ≥18 years of age on the index date (date of the first observed diagnosis code for α- or β-thalassemia). Patients were stratified by type of thalassemia (α- or β-thalassemia) and by transfusion dependence (NTDT or TDT). NTDT was defined as &amp;lt;8 transfusions within 12 months of follow-up or with &amp;gt;42 days between any 2 adjacent transfusions. To evaluate if the results in NTDT were driven by patients with β-NTDT, patients with α-NTDT were also analyzed separately. Hb levels, HCRU (inpatient [IP] admissions, outpatient [OP] visits, and emergency room [ER] visits), and costs were assessed during a variable-length follow-up period (at least 12 months from the index date to end of plan enrollment, end of study, or IP death, whichever occurred first). Available Hb levels were averaged across the follow-up period for each patient. HCRU (number and type of service) and costs (US dollars) were converted to per-patient per-year values. All dollar estimates were inflated to 2020 (using Medical Care Component of Consumer Price Index). To assess the association of Hb levels with HCRU and cost outcomes, univariate regression analyses with negative binomial models were conducted. Percent changes in cost and incidence rate ratios of HCRU associated with 1 g/dL decrease in Hb level and corresponding 95% confidence intervals and p values (with significance level set to 0.05) were reported. Results: In the Commercial/Medicare database, 4077 adult patients with thalassemia and a variable length follow-up of at least 12 months were identified (median length of follow-up: 943 days). Of these, 909/4077 (22.3%) had at least 1 Hb value during the follow-up period in the Lab Results database, including 400 patients (44.0%) with α-thalassemia, 509 (56.6%) with β-thalassemia, 898 (98.8%) with NTDT (α or β), and 11 (1.2%) with TDT (α or β). The average Hb value per patient with NTDT (α and β; N=898) was 11.3 g/dL (11.5 g/dL for α-NTDT; N=400). In the NTDT group, 4.1% had at least 1 transfusion in first 12 months of follow up (3.6% had 1-3 transfusions and 0.5% had 4-7). For all patients with NTDT, with each 1 g/dL decrease in Hb, the number of IP admissions increased by 17%, OP visits by 8%, and ER visits by 11% (all p&amp;lt;0.001). For patients with α-NTDT, with each 1 g/dL decrease in Hb, the number of IP admissions increased by 15%, OP visits by 6%, and ER visits by 16% (all p&amp;lt;0.01; Table 1). Regarding costs for all patients with NTDT, with each 1 g/dL decrease in Hb, total healthcare costs increased by 15% (p&amp;lt;0.001), IP costs by 56% (p&amp;lt;0.001), OP costs by 12% (p&amp;lt;0.001), ER costs by 20% (p&amp;lt;0.003), and prescription costs by 12% (p=0.061). For patients with α-NTDT, with each 1 g/dL decrease in Hb, total healthcare costs increased by 14% (p&amp;lt;0.001), IP costs by 47% (p&amp;lt;0.001), OP costs by 10% (p&amp;lt;0.001), ER costs by 30% (p&amp;lt;0.003), and prescription costs by 9% (p=0.322). It is possible that because of incorrect/incomplete coding, some patients with thalassemia minor may have been included in the analyses, which may account for the higher-than-expected Hb levels in the NTDT cohorts. This may, in turn, underestimate the impact of Hb level on HCRU and costs. Conclusion: In this study, each 1 g/dL decrease in Hb was associated with significantly higher HCRU and costs. This association was seen in both the NTDT group and α-NTDT subgroup suggesting that both α-NTDT and β-NTDT experience this burden. This analysis indicates that raising Hb levels in patients with both α- and β-NTDT could result in reduced HCRU and costs.

Oxidative Stress Damage of Iron Overload on Bone Marrow Erythropoiesis, Heart and Liver in Non-Transfusion Dependent Thalassemia

Background: Non-transfusion-dependent thalassemia (NTDT) characterized by ineffective hematopoiesis and increased intestinal iron absorption, and excessive iron deposits in the bone marrow, heart, and liver, causing progressive organ damage. It has been reported that oxidative stress damage caused by iron overload could induce apoptosis or ferroptosis. However, the related studies and mechanisms are not well unknown in NTDT disorders. Aims: To investigate the effects of iron overload on bone marrow erythropoiesis, heart and liver in NTDT patients and Hbb th3(th3/+) mice. Methods: Patients (19-47 y of age) and 12-month-old Hbb th3(th3/+) mice with NTDT were selected as thalassemia group, healthy human and normal mice were selected as control group. Iron overload related indexes, bone marrow erythropoiesis, oxidative stress, apoptosis and ferroptosis of each sample were detected by Elisa, flow cytometry, RT-PCR and Weston blot methods, respectively. Results: Compared with the control group, Serum ferritin is significantly increased in NTDT group, and there is imbalance of iron metabolism. And in NTDT patients, liver and myocardial iron deposition was assessed by MRI analysis, resonance results suggest that the degree of iron overload in liver is more significant than that in heart. The damage of erythropoiesis in NTDT group was more severe than that in control group, which showed active erythropoiesis, and the differentiation of erythroid precursor cells stagnated in early stage of erythroid precursor cells, and there were maturation disorders. The oxidative stress-related indexes reactive oxygen species (ROS), lipid peroxidation and malondialdehyde (MDA) induced by iron overload were also significantly increased in the NTDT group. However, significant signs of apoptosis were observed in the bone marrow of the NTDT group, including increased proportion of apoptotic cells, signs of apoptosis were mainly observed in the mitochondria of erythroid colony electron microscopy, and the level of GPX4 that is a key indicator of ferroptosis, was increased. But the expression of GPX4, VDAC2 and SLC7A11 of ferroptosis was decreased in the heart and liver with heavy iron deposition, and the signs of ferroptosis were also observed under electron microscopy. Summary/Conclusion: Our study found that there are differences in iron overload and injury performance among different organs in NTDT. Oxidative stress caused by iron overload in the bone marrow impairs erythropoiesis mainly through apoptosis, whereas signs of ferroptosis were observed in the liver and heart of Hbb th3(th3/+) mice.These results suggest that with the gradual accumulation of iron circulation, the damage is a dynamic process, and different organs show different signs of damage, which may be related to the different mechanisms of damage, tolerance and compensation of organs, but further studies are needed to confirm.

Evaluation of Couples at Risk for Hemoglobin Disorders in Italy: The Results of an 18-Month Retrospective Observational Single-Center Study

Background: Hemoglobinopathies are genetic disorders caused by mutations in the genes encoding globin chains. These conditions are the most common monogenic disorders worldwide, resulting in significant morbidity and mortality among those affected by the most severe forms. Antenatal evaluation for thalassemia and sickle cell disease (SCD) enables couples to know their reproductive risk, thus allowing an informed reproductive choice. However, in certain areas, couples do not often receive the appropriate counseling at the appropriate time. Aim: The aim of this study is to describe the characteristics of couples referred to our tertiary referral center in Milan, Italy, for evaluation of hemoglobinopathy risk and their management. Methods: in our Institution, a diagnostic-therapeutic pathway involving the Hemoglobinopathies unit, the Medical Genetic unit, and the central laboratory has been implemented. Subjects referred to the Institution, and their partner, underwent the following laboratory tests: complete blood count, hemolysis and iron parameters, vitamin pattern, and hemoglobin (Hb) pattern by high-performance liquid chromatography (HPLC). The couples were then evaluated by a hemoglobinopathy expert, and those at risk for Hb disorders were offered a molecular analysis. Couples were then referred to the geneticist to receive the results of the molecular analysis, discuss the genetic risk for the fetus and, in case of high risk, discuss possible reproductive choices (i.e., prenatal diagnosis, pre-implantation diagnosis). We retrospectively collected and analyzed couples' data referred to our center from the 1 st of July 2021 to the 31 st of December 2022. Results: Three hundred and fifty-one couples were evaluated for hemoglobinopathies over 18 months. The median age was 34 years, with a tendency for younger age in female partners; 67% (234/351) of the women were already pregnant at the time of evaluation (median gestational age 18 weeks, range 7-37), while 33% (117/351) were referred for preconception counseling. Individuals from more than 48 different countries were screened, and the most represented countries of origin included: Italy (50%), Nigeria (6%), Bangladesh (4%), and Ivory Coast (4%), underpinning a vastly diverse genomic background. The referral was triggered by either evidence of microcytic anemia (58%) or HPLC anomalies (42%), including Hb variants, HbA2 anomalies, or elevated HbF in at least one partner. 55% of the referrals did not require additional testing. The remaining 45% (158/351) underwent advanced molecular tests to determine the nature of the Hb defect, guided by the results of the first-level panel. Among these, 33 couples (12% of the total) were found to be at risk for transmission of severe clinical forms of β-thalassemia, sickle cell anemia, or compound β-disorder heterozygosity (HbS/β-thal, HbC/HbS). One additional couple (0.4%) was at risk for HbH disease. In addition, 4 couples (1.5%) were found to be at risk for thalassemia intermedia combining a β-thalassemia mutation and α-gene triplication. Of the above, all 34 couples underwent invasive fetal evaluation: 24 women underwent chorionic villous sampling, while 10 received amniocentesis. A diagnosis of thalassemia in the fetus was reported in 6/34 (18%) cases and 3 (9%) of SCD. Interestingly, during the 18 months of observation, among the evaluated adult subjects, we found 4 cases of non-transfusion dependent thalassemia (NTDT) and 1 of HbS/β-thal in otherwise healthy subjects. All 4 cases of NTDT resulted from α-gene triplication paired with a β-thalassemia heterozygous defect. Furthermore, α triplication was found alone in 4 subjects without additional Hb gene defects. Overall, α triplication was detected in 9 out of 154 (5.8%) individuals who underwent HBA gene analysis. Conclusion: The median gestational age at presentation was high, leading to a limited time for couples to receive the appropriate counseling to make an informed reproductive choice. Increasing awareness across all involved specialists remains the mainstay for an effective prevention program to promptly identify at-risk couples and offer counseling at the right time. In addition, the relatively high incidence of α triplication in our population of asymptomatic and hematologically normal subjects and the new diagnosis of 4 NTDT warrants further studies to confirm the prevalence of α triplication in the general population.

Case Series of Paraspinal Extramedullary Hematopoiesis in Transfusion-Dependent Thalassemia Treated with Luspatercept

Introduction: Extramedullary hematopoietic (EMH) pseudo-tumors are commonly seen in patients with non-transfusion dependent thalassemia but rare in transfusion-dependent beta thalassemia (TDT). Paraspinal EMH is more prevalent in older patients with severe ineffective erythropoiesis and low fetal hemoglobin levels. Luspatercept, an inhibitor of the TGF-beta pathway, has been shown to reduce transfusion requirements and improving iron overload in TDT. Emerging data report risk of EMH in patients receiving luspatercept, resulting in updated safety labeling, yet there is scarce data on the optimal management of EMH. In this case series, we present four cases of paraspinal EMH in TDT patients in their twenties treated with Luspatercept, and report management approaches and treatment response. Methods: We conducted a retrospective analysis of adult patients with TDT receiving luspatercept in the Northern Alberta hemoglobinopathy program and identified those who developed EMH. Clinical, laboratory and imaging data were collected, including transfusion requirements, clinical presentation, management strategies, and response to treatment. Results: From June 2021-June 2023, 9 patients with TDT received luspatercept therapy. Three discontinued therapy early, median 2 months (range 1-4), due to side effects (2 severe headache, 1 erratic Hb). Six patients (2F, 4M) continued for long term use. One had baseline MR spine, and 1 had small thoracic EMH noted on cardiac MR; 5/6 underwent MR spine post luspatercept therapy, 1 for neurologic symptoms, 4 for EMH screening. We identified 4 cases of EMH. Luspatercept treatment median 17 months (range 14-20). All 4 patients were males, median age 24 years (range 20-29). All 4 patients had documented history of massive splenomegaly, 2 requiring splenectomy, 1 requiring partial splenic embolization. All 4 cases had significant elevations in reticulocyte count, nRBC, and 2/4 had thrombocytosis (Table 1). Case 1 presented with progressive leg weakness with resultant hemiplegia. Cases 2 and 3 were asymptomatic and found on screening MRI. Case 4 had pre-existing, asymptomatic paraspinal EMH first noted 4 years prior, had enlarged prior to luspatercept, and then enlarged further on CT chest 16 months post luspatercept. Treatment varied according to severity of EMH. Case 1 was hospitalized for 2 months, treated with 18 Gy radiation, dexamethasone for 2 months, hydroxyurea 2000 mg (24 mg/kg), hypertransfusion (goal Hb &amp;gt; 110 g/L) and luspatercept discontinuation. He regained mobility after therapy. Case 3 had impending spinal cord compression. Luspatercept was stopped, and he received radiation therapy 18 Gy, followed by hydroxyurea 1000 mg (16 mg/kg). Case 2, asymptomatic, continued luspatercept, hydroxyurea was added, with planned increased surveillance MR and physical examination. Case 4, initially asymptomatic, continued luspatercept, with increased transfusion threshold. Later he developed symptoms, luspatercept discontinued, and hydroxyurea initiated. Discussion: Paraspinal EMH is uncommon in TDT. However, our case series highlights the occurrence of paraspinal EMH in younger TDT patients treated with luspatercept. All four patients were male, with risk factors for EMH including massive splenomegaly and brisk reticulocytosis. Management options for paraspinal EMH include increased transfusions, hydroxyurea, radiotherapy, surgical decompression, or a combination thereof. Low-dose radiation has shown promising results although access in resource-limited settings and recurrence remain a concern. Limitations of this review include the retrospective nature and small number of patients; a causal relationship cannot be established. Further, given the lack of prior surveillance MRI spine, it is not clear the exact timing of EMH development. Further studies are needed to establish the long-term efficacy and safety of luspatercept in patients with TDT. Conclusion: Paraspinal EMH is a rare complication in TDT patients, but its occurrence should be considered, especially with the increasing use of luspatercept. Screening guidelines for EMH should be established to detect and manage this potentially debilitating condition promptly. In the absence of guidelines, based on the high rate of EMH noted in our cohort, we propose screening MRI spine as a baseline prior to luspatercept, with consideration of regular surveillance MRI post therapy.

Increased Proportion of Black Transfusion Dependent Thalassemia Patients in a Single Southeast U.S. Center

Thalassemia is a common disorder worldwide but remains relatively rare in the United States (U.S). Over the past decade, there has been a significant demographic shift as more patients are entering care as either international adoptees or refugees from under-resourced countries. We analyzed our own center's demographic evolution from 2014 to 2023. Only transfusion dependent thalassemia (TDT) patients fully managed within our pediatric center are represented in Table 1. We did not include non-transfusion dependent thalassemia (NTDT) patients nor TDT patients who have graduated to adult care, relocated, or those who travel to our center only for comprehensive visits from out of state. When compared to the national data collected by the Cooley's Anemia Foundation (CAF), we saw a similar increase in patients from China and Southeast Asia (SEA), reflecting the increased number of adoptees in the period from 2014-2019 (Tables 1 &amp; 2). Since that time, we have seen an increase in patients from South Asia (SA) and the Middle East (ME). These patients are mostly refugees from regional conflicts (Syria, Afghanistan, Myanmar, etc.). This trend is similar to other centers, according to the CAF (unpublished communication). Interestingly, however, our center has a significantly larger proportion of Black TDT patients compared to the national data (Table 2 ). As can be seen in the tables below, we have nearly 20x more Black patients (20-22.9% vs. 0.9-1.2%) when compared to the national data. This may be in part due to our center's location in Atlanta, Georgia. However, according to the latest U.S. Census data, Georgia's population is 33.1% Black, compared to 13.6% in the U.S population as a whole. Based on this, we would expect a 2.4x increase, as opposed to a 20x increase. Vichinsky et al published a study in Pediatr Blood Cancer in 2017 using data collected from 4 Comprehensive Thalassemia Treatment Centers (CTTC) in the Northeast, Midwest and West coast of the U.S. looking at the racial distribution and changes of NTDT patients. They also found a higher-than-expected proportion of Black patients, about 17%. Of our 65 NTDT patients, 26% are Black and an additional 5% are mixed race, Black and Asian. The majority (60%) have Hemoglobin H disease. We looked to see if our TDT patients were relatives of sickle cell disease (SCD) patients, since our center has the largest pediatric SCD population in the U.S. However, only 20% (2/10) report family members with any form of SCD. The majority (8/10) of the patients identify as African American, whereas the remaining 2 are 1st generation Somalian and Ghanaian. Genotype data is available for 9/10 patients, with three ß0/ß0 and six ß+/ß0. The most common mutations seen were IVS II-849 A&amp;gt;G (ß0), -29nt A&amp;gt;G (ß+), Promoter -88nt G&amp;gt;T (ß+) and Codon 5 (-CT) frameshift (ß0). All are mutations predominantly found in Blacks. Clinically, as a group, they had a high rate of splenomegaly (8/10) and skull changes (6/10) before transfusions began. Transfusions began ages 6mos-9 yrs. with 50% occurring after age 3 yrs. Black TDT patients may face unique challenges in the U.S. where there are &amp;gt;50 SCD patients for every thalassemia patient. Indications for transfusion and overall clinical management are vastly different for these two diseases, but providers with little experience in the treatment of Thalassemia may inappropriately treat them like SCD patients.

Efficacy of Low Dose Vs Standard Dose of Thalidomide in Patients with Transfusion-Dependent Thalassemia (TDT): A Non-Inferiority Trial

Background Thalidomide has been demonstrated to induce global gene expression hereby increasing the proliferation of erythroid cells. Recent studies have revealed encouraging data regarding the efficacy and safety of thalidomide in both transfusion dependent (TDT) and non-transfusion dependent (NTDT) thalassemia. However, the optimal dose of thalidomide remains unclear. The study was designed to compare the efficacy and safety of thalidomide at low-dose (1 mg/kg/d) vs standard-dose (2 mg/kg/d). Methods Patients with TDT &amp;gt; 12 years of age with no recent (previous 6 months) intake of Hb enhancers were enrolled in a non-inferiority trial across 4 sites in India. Patients with hypersplenism, prior history of thromboembolism, HIV, active hepatitis B/C infection, or any other known systemic illness like neurological, renal, significant hepatopathy, and sexually-active females unwilling to use contraceptives/undergo medical termination of pregnancy in case of accidental pregnancy while on the drug were excluded. Patients were randomised to receive low-dose or standard-dose thalidomide for 6 months. Pre-transfusion Hb, transfusion frequency and volumes, and adverse effects were recorded at each visit. Response was graded based on reduction in transfusion requirement at 24 weeks: Good (&amp;gt; 50 %), moderate (25-50 %), or minimal (&amp;lt;25%). Results: A total of 188 patients with mean age of 18.1 ± 5.2 years and M:F ratio of 2.1:1 were enrolled. 85.6% (80 in low-dose and 81 in standard-dose) participants completed the study period. 14.4% discontinued thalidomide due to various reasons. The mean Hb and baseline transfusion requirement were 8.6 ± 0.98 g/dl and 35.91 ml/kg in the preceding 12 weeks. The overall response rate was 55.9%. There was no statistically significant difference in the response rates in 2 groups (63% in low-dose vs 48% in standard-dose) (p:0.135). Good, moderate, and minimal responses were seen in 19.3%, 36.6 %, and 44.1% of the participants respectively. Response rate was not affected by age, sex, transfusion requirement or serum ferritin at baseline. The commonest adverse events were somnolence (n=40), constipation (n=29), weight gain (n=25), reversible cytopenia's (n=22), and peripheral neuropathy (n=14). 3.7% participants experienced Grade 2/3 events. There were no grade 4 events. Conclusions: The low-dose thalidomide was as efficacious as the standard dose in reducing transfusion requirements. Thalidomide is well tolerated and can be considered as an adjunct to optimal transfusion-chelation regimen under close monitoring in a resource constrained setting.

Erythrocyte labile iron pool indicating concealed iron overload in non-transfusion-dependent β-thalassemia

Abstract Objectives Not only do transfusion-dependent thalassemia (TDT) patients have a risk of clinical consequences arising from iron overload, non-transfusion-dependent thalassemia (NTDT) patients may encounter it also. In this study, we demonstrated the usefulness of intra-erythrocyte labile iron pool (LIP) measurement in NTDT patients with HbE/β-thalassemia in revealing a concealed iron overload and the resultant oxidative cell damage. Methods LIP and ferritin levels were assayed in 20 HbE/β-thalassemia patients, comprising 10 NTDT and 10 TDT patients and 10 healthy individuals. Erythrocyte oxidative stress parameters (intraerythrocyte reactive oxygen species (ROS) levels, numbers of erythrocyte vesicles, and cell apoptosis) were also determined and their correlations to LIP and ferritin levels were analyzed. Results LIP levels (based on different mean fluorescence intensity (MFI) values obtained by flow cytometry) were high in both the NTDT (54 [42–90]) and TDT (71 [68–77]) patients compared to the healthy individuals (43 [31–61]). The ferritin level observed in the NTDT group (2,149 [781–4,071] ng/mL) was lower than that of the TDT group (4,885 [2,343–7,826] ng/mL). The LIP level was significantly correlated with the NTDT patients’ age and all oxidative stress parameters, but the ferritin level was not. Correlation analysis predicted that NTDT patients without receiving any therapy aged 32.5 years old or over are likely at risk of iron overload status and oxidative cell damage. Conclusions The results indicate that LIP may be a helpful alternative parameter for defining the risk of iron overload.

Patients with Non-Transfusion-Dependent Thalassemia May Evolve to Transfusion-Dependent Thalassemia in Adulthood

Introduction: Non-transfusion-dependent thalassemia (NTDT) describes a prevalent and clinically heterogeneous group of patients in the United States. Adults with significant forms of NTDT display progressive age-related complications due to chronic anemia and ineffective erythropoiesis. While the importance of early diagnosis and close monitoring in pediatric patients with NTDT is well-established, the characteristics and complications of adults with NTDT in the United States is poorly described. Many adult patients with NTDT are managed by community providers who often have limited experience with this condition.This single-center observational study describes the clinical characteristics of patients with NTDT during their initial presentation to an adult thalassemia treatment center and identifies intervenable complications related to NTDT. Methods: We evaluated patients referred to the Penn Comprehensive Adult Thalassemia Program between 2013 and 2023 who carried a diagnosis of NTDT (defined as alpha or beta thalassemia and requiring fewer than 8 units of red cells in the 12 months preceding their initial visit). Data was collected via manual chart review. Clinical complications were defined as symptoms at presentation, history of splenectomy, hepatosplenomegaly, paraspinal masses, pulmonary hypertension, cardiac arrhythmia, endocrine complications (hypothyroidism, hypogonadism, diabetes, decreased bone mineral density), thrombotic events, and iron overload requiring chelation. Laboratory markers of disease severity included hemoglobin (Hgb), markers of hemolysis, nucleated red blood cells, serum ferritin and MRI quantitation of liver and cardiac iron. Results: Of the 94 patients with thalassemia referred to the Penn Comprehensive Adult Thalassemia Program, 34 carried a diagnosis of NTDT. Of these, 13 had α- thalassemia (deletional and non-deletional HbH), 19 had β-thalassemia variants (homozygous or double heterozygous β-globin gene mutations), and 2 had hemoglobin E/β-thalassemia. The median age at referral was 37.5 years (range 20-74); 71% were female. In general, patients with β-thalassemia had a larger number of significant complications than those with α-thalassemia. Overall, 11 patients (32%, all with β-thalassemia) had a history of splenectomy, 21 (62%) had evidence of extramedullary hematopoiesis with hepatosplenomegaly, and 7 (21%) had paraspinal masses. Pulmonary hypertension was seen in 5 of 21 patients with β-thalassemia and hemoglobin E/β-thalassemia (24%) while 4 patients overall (11%) had a history of thrombosis. The most common endocrinopathy was decreased bone mineral density (32%). Mean Hgb was 9.1 g/dL, however, 53% had a Hgb &amp;lt; 9 g/dL. Seven patients had an increase in nucleated red blood cells (range 161-1522 %) as a marker of ineffective erythropoiesis. Serum ferritin exceeded international NTDT guidelines for tissue evaluation (&amp;gt; 800 ng/mL) in 32% of patients; the mean ferritin for all patients was 897 ng/mL (range 45-7601 ng/mL). A liver MRI was obtained in 56% of patients with mean iron content of 25 mg/g dry weight (range 1.5 - 41.2 mg/g dry weight). No patients had evidence of cardiac iron overload. Of the 34 patients referred for NTDT, 14 (41%) met criteria to initiate a chronic transfusion regimen to maintain a pre-transfusion Hgb &amp;gt; 9.5 g/dL per established guidelines. Criteria included fatigue (all patients), extramedullary hematopoiesis (32%), Hgb &amp;lt; 7 g/dL (8%), and pulmonary hypertension (15%). Several patients had more than one indication for chronic transfusion. Conclusions: This is the first report of patients with NTDT in the United States that highlights clinically significant complications that accumulate in adults. Our results demonstrate a previously unknown high prevalence of conditions that warrant close monitoring, screening and intervention. Clinically, 41% of adult NTDT patients referred to our comprehensive adult thalassemia program met criteria to initiate a chronic transfusion program, a number that is significantly higher than previously published rates outside of the USA. These findings indicate a critical need for thalassemia education of adult providers that emphasizes the importance of monitoring for early complications of NTDT, as well as criteria for initiating a chronic transfusion program to mitigate complications and provide meaningful impacts in clinical outcomes.

Burden of Illness of Alpha- and Beta-Thalassemia: A Qualitative Study

CONCLUSION Alpha (α)- and beta (β)-thalassemia are inherited red blood cell disorders with a wide spectrum of symptoms, functional manifestations, and disease burden. The standard of care for α- and -β-thalassemia major is regular transfusions and iron chelation therapy. However, symptoms may persist despite treatment. Patients with non-transfusion dependent (NTD) thalassemia are historically considered to have less severe disease than patients who are transfusion-dependent (TD), yet they may experience considerable disease burden negatively affecting their health-related quality of life (HRQoL). Additionally, little is known about the HRQoL of α- thalassemia patients, of whom a majority are NTD. This qualitative research study sought to understand the patient perspective of disease burden experienced with these disorders and explore any differences that might be related to genotype of thalassemia (α or β) or transfusion requirements. Twenty-six adult participants (13 α, 13 β) who have made no changes to their thalassemia treatment for at least 6 months were interviewed about symptoms, impact, quality of life, and transfusion-dependence in a cross-sectional, non-interventional qualitative study. There were 8 males and 18 females; 18 were TD (5 α and 13 β) and 8 were NTD (all α). Symptoms and their impact were elicited via open-ended, semi-structured interviews. Symptom severity and bothersomeness were rated by participants on a 0-10 numerical rating scale (NRS) with 0 meaning no severity or bothersomeness, and 10 meaning extreme severity or bothersomeness. Frequency of participants reporting each symptom during the interview were calculated as a percent of the total participants in each group. Mean symptom severity and bothersomeness among participants reporting the symptom were calculated from responses to the 0-10 NRS. The results were then presented for α- and β-thalassemia, and for TD and NTD groupings of the 26 participants.All participants provided informed consent and all interviews were audio recorded and transcribed for analysis. The most frequently reported symptoms among all participants were fatigue (100%), weakness (73%), shortness of breath (69%) and difficulty focusing (73%). Mean severity and bothersomeness scores for these 4 symptoms were generally similar across genotype and transfusion status, with mean severity scores for all participants ranging from 6.6 to 7.8, and mean bothersomeness scores ranging from 6.9 to 8.0 (Figures 1 and 2). Pain was reported by all groups but more frequently by TD than NTD (72% vs 50%) and β- compared to α-thalassemia participants (77% vs 54%). Pain bothersome ratings ranged from 6.4 to 8.7 indicating many of these patients are bothered or distressed by the symptom. Other frequently described and bothersome symptoms included difficulty with focused attention and memory (6 to 7.5 across all subgroups), as well as headaches (&amp;gt;6 across all subgroups) Nearly half of the participants (12/26, 46%) reported considerable impact on their function and daily activities regardless of transfusion status or genotype, and a majority (14/26, 54%) reported having to make lifestyle changes because of their thalassemia. The most frequently reported limitations were physical activities, along with interference in sport and leisure activities. More than half of participants (18/26, 69%) reported emotional challenges (including being stigmatized) and having difficulty getting quality sleep. Patients with α-NTDT and α-TD reported a similar degree of symptoms and impact on their HRQoL as patients with β-TDT, despite a historical perception of α-thalassemia as a more benign disease. The fact that many symptoms were commonly reported and were similarly severe and bothersome in both NTDT and TDT, and in both α- and β-thalassemia, suggests that patients with thalassemia are negatively impacted by their disease, regardless of transfusion dependency and genotype. Although the small sample size of this qualitative study precludes any statistical inference, the findings describe the patient experience of thalassemia and helps to inform the development of patient-relevant endpoints for future clinical trials. Additional research is needed to explore the relationship between these symptoms/HRQoL impact and clinical/pathophysiologic correlates.

Durable Symptom Improvement for Patients with Non-Transfusion Dependent Thalassemia Treated with Luspatercept: Patient-Reported Outcomes from the BEYOND Study

Background: Patients with non-transfusion dependent beta-thalassemia (NTDT) suffer from chronic anemia due to ineffective erythropoiesis. The phase 2, randomized, placebo-controlled BEYOND study demonstrated that luspatercept increased hemoglobin (Hb), reduced transfusion burden, and improved NTDT-related symptoms based on the data with 48 weeks of follow-up (Taher A, et al. Lancet Haematol. 2022;9(10):E733). Objective: The purpose of this analysis was to investigate the long-term effect of luspatercept + best supportive care (BSC) vs placebo + BSC on NTDT-related symptoms through 96 weeks using data collected in the BEYOND study. Methods: 145 patients with NTDT were randomized 2:1 to luspatercept (Q3W) + BSC or placebo + BSC. BSC included red blood cell (RBC) transfusions and iron chelation therapy as deemed necessary by investigators. Patients completed the NTDT Patient Reported Outcome (NTDT-PRO) and Patient Global Impression of Severity (PGI-S) in a daily electronic diary starting 7 days prior to the first dosing day until Week 24, and thereafter over the 7 days prior to dosing at every other dosing visit. The Patient Global Impression of Change (PGI-C) was administered at every other dosing visit, starting with the first dosing day. The NTDT-PRO consists of 6 questions measuring 2 NTDT anemia-related symptom domains: Tiredness/Weakness (T/W) and Shortness of Breath (SoB), each with a score range of 0 (no symptoms) to 10 (extreme symptoms). The PGI-S asks patients to rate the overall severity of their NTDT-related symptoms (range of 0 to 10, with a higher score indicating greater severity), whereas the PGI-C asks patients to rate the overall change in their NTDT-related symptoms since the start of the study (7-level verbal rating scale ranging from “a great deal better” to “a great deal worse”). Least squares (LS) mean changes from baseline at each visit (up to Week 96) in NTDT-PRO T/W and SoB scores, as well as the PGI-S score, were estimated using a mixed model for repeated measures (MMRM). Responses to the PGI-C were descriptively summarized by treatment group. All analyses were performed in the health-related quality of life (HRQoL)-evaluable population, defined as all randomized patients with a valid QoL assessment and at least 1 post-baseline assessment. All p-values reported from the analyses were nominal. Results: The HRQoL-evaluable population consisted of 95 of the 96 patients randomized to the luspatercept arm and all 49 patients randomized to the placebo arm. LS mean changes from baseline in both the NTDT-PRO T/W and SoB scores for the luspatercept arm consistently demonstrated greater improvement (i.e., lower scores) than the placebo arm across visits. Improvement in both T/W and SoB domains were more pronounced starting at Week 24 and sustained through Week 96, with differences in LS mean changes from baseline ranging from -0.89 to -0.21 in the T/W domain and from -0.80 to -0.45 in the SoB domain over this time period (both domains on a 0 to 10 scale). Between-treatment differences were significant (p&amp;lt;0.05) at Week 30 (between-treatment difference in LS mean change from baseline, 95% confidence interval: -0.76, -1.42 to -0.10), Week 36 (-0.89, -1.55 to -0.22), and Week 72 (-0.81, -1.54 to -0.09) in the T/W domain and at Week 30 (-0.71, -1.36 to -0.06), Week 48 (-0.77, -1.43 to -0.10), and Week 72 (-0.80, -1.51 to -0.10) in the SoB domain. LS mean changes from baseline in the severity of overall NTDT-related symptoms, assessed by the PGI-S, showed a marked improvement through Week 96 in the luspatercept arm ( Figure 1), whereas patients receiving placebo tended to worsen over time. The between-treatment difference was statistically significant (p&amp;lt;0.05) across most assessment visits from Weeks 18 to 96. For the PGI-C, most patients treated with luspatercept reported “a little better” or more on their overall NTDT-related symptoms at Weeks 72 (89%) and 96 (87%), whereas most patients receiving placebo reported no change at either Week 72 (61%) or 96 (75%) ( Figure 2). Conclusions: Analysis of the PRO data collected in BEYOND suggests that, in addition to improvements in Hb, patients with NTDT treated with luspatercept experienced durable improvement in NTDT-related symptoms, from a patient perspective, through at least 96 weeks of treatment.

SAT545 Erythropoietic Thyroid Nodule in the Setting of Myelofibrosis

Abstract Disclosure: L.M. Vasquez: None. J.M. Bruder: None. M. Koops: None. J. Trejo: None. Background: Extramedullary hematopoiesis is frequently seen in non-osseous locations but not endocrine organs, this is a case of hematopoesis in a thyroid nodule. Clinical Case: A 79-year-old man with myelofibrosis diagnosed at age 66, CAD post CABG, atrial fibrillation on anticoagulation and HFrEF was referred to the endocrinology clinic due to enlarging left lobe thyroid nodule. He was diagnosed with a goiter at age 72 but denied compressive symptoms. He had no history of radiation to his neck or family history of thyroid cancer. On physical exam, the left thyroid lobe was visibly enlarged with slight right tracheal deviation without lymphadenopathy. TSH level was normal. Thyroid ultrasound demonstrated a 6.4 x 4.0 x 4.8 cm, complex cystic-solid, taller than wide nodule in the left lobe and a sub-centimeter cystic nodule in the right lobe. FNA showed hematopoietic elements, including maturing cells in three lineages of hematopoiesis. On repeat ultrasound 5 years later. The left nodule increased in size to 7.3 x 5.4 x 4.4 cm and highly suspicious (TR4 and TR3) by Ti-RADS criteria. Repeat FNA of the nodule showed many red blood cells with few hematopoietic cells, flow cytometry did not show any abnormal populations. No thyroid follicular cells were reported. Myelofibrosis was diagnosed by bone marrow biopsy many years prior. He had maintained a stable CBC without palpable spleen or hepatomegaly. Given this history without thyroid dysfunction or reported symptoms, surgery was not pursued. External beam radiation was a treatment option should the nodule cause symptoms. He continued to have mild anemia not requiring blood transfusions. He passed away 2 years later in hospice care after hospitalization for severe heart failure decompensation. Conclusion: Extramedullary hematopoiesis involving the thyroid is rare but has been reported(1). This type of extramedullary hematopoiesis. can be treated with surgery or low-dose radiation because of the radiosensitivity of hematopoietic tissue (2). This was a potential treatment modality if compressive symptoms arose, but they did not. This case illustrates a situation in which surgical intervention on highly suspicious nodules would not have been the optimal treatment choice. Reference: 1. Jan I., Weng M., Wang C., et al. Extramedullary hematopoiesis involving the thyroid: A rare cytologic finding in otherwise healthy patients and review of literature. Journal of the Formosan Medical Association. (2018) 117, 1108-1114. 2. Taher A, Vichinsky E, Musallam K et al., authors; Weatherall D, editor. Guidelines for the Management of Non-Transfusion Dependent Thalassaemia (NTDT) [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2013. Chapter 11, EXTRAMEDULLARY HEMATOPOIESIS. Available from: https://www.ncbi.nlm.nih.gov/books/NBK190455/ Presentation Date: Saturday, June 17, 2023

When a synonymous mutation breaks the silence in a thalassaemia patient.

Synonymous mutations were considered to lack functional roles in human diseases; however, distinguishing deleterious synonymous mutations from benign ones is still a challenge. In this article, we identified a deleterious synonymous mutation β-codon 16 (C>T). HBB: c.51C>T, in compound heterozygous form with known β-thalassaemia mutation patients who clinically presented as non-transfusion-dependent thalassaemia (NTDT). A total of 9 families with 11 compound heterozygous index cases were reported. In the heterozygous state, codon 16 (C>T) mutation results in borderline HbA2 (3.18 ± 0.36%) and slightly reduced RBC indices (RBCs: 4.73 ± 0.75 × 106 /μL, Hb: 12.26 ± 2.60 g/dL, MCV: 79.48 ± 8.40 fL, MCH: 25.95 ± 4.15 pg). The compound heterozygous patients showed elevated HbA2 (5.98 ± 1.17%) and HbF (12.75 ± 7.51%) and presented clinically as NTDT with a mean Hb of 6.95 ± 1.29 g/dL. Many of them were dependent on few transfusions and had mild splenomegaly. Of the 11 patients, 5 (45.4%) were treated with hydroxyurea. This study highlights the clinical significance of synonymous mutation, when inherited with other β-thalassaemia mutations leading to the phenotype of NTDT. Thus, the study would help to improve screening protocols for β-thalassaemia carriers, which will ultimately improve the prevention programme.