Non-transfusion-dependent Thalassemia Patients Research Articles

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.

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 & 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>G (ß0), -29nt A>G (ß+), Promoter -88nt G>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 >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.

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.

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 < 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 (> 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 > 9.5 g/dL per established guidelines. Criteria included fatigue (all patients), extramedullary hematopoiesis (32%), Hgb < 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.

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.

Metformin as a Fetal Hemoglobin Inducer in Non-transfusion Dependent Thalassemia Patients

Non-transfusion dependent thalassemia (NTDT) refers to a group of thalassemic disorders who do not need regular transfusions for survival, however it may be needed in certain conditions. Metformin was reported as a potential fetal hemoglobin (HbF) inducing agent in vitro but its efficacy and safety in vivo was not fully studied. This is a prospective interventional study aimed at studying the effect of metformin on HbF change in NTDT. Methods: Patients with established diagnosis of NTDT were enrolled. They were receiving a stable fixed dose of Hydroxyurea over the last 3 months. Patients were divided into two groups: a group that received Metformin for 6 months (Metformin group) and a control group. Complete blood picture, reticulocytic count, hemoglobin electrophoresis, liver enzymes, bilirubin, kidney functions, LDH and random blood sugar were performed at onset, 3 and 6 months of the study. All adverse events were recorded. Results: Forty two patients aged 12–23 years were enrolled. Metformin intake over 6 months did not show any statistically significant difference in clinical or the laboratory variables of efficacy when compared to the control group apart from reticulocytic count which was higher in Metformin group throughout the study. Conclusion: Metformin intake, in addition to hydroxyurea, did not yield any extra benefit among patients with NTDT.

5589252 SYSTEMATIC LITERATURE REVIEW OF HEALTH-RELATED QUALITY OF LIFE BURDEN IN PATIENTS ACROSS THE SPECTRUM OF THALASSEMIA

Background: Recent systematic literature reviews (SLRs) have highlighted the health-related quality of life (HRQoL) burden in transfusion-dependent thalassemia (TDT), particularly β-thalassemia (β-thal). However, less is known about HRQoL in non–transfusion-dependent thalassemia (NTDT) and alpha-thalassemia (α-thal). Aims: To conduct an SLR on the real-world HRQoL burden across the spectrum of thalassemia and report evidence gaps. Methods: Searches (Jan 2010 to Sep 2021) were conducted in MEDLINE, Embase, Cochrane Database of Systematic Reviews, Health Technology Assessment Database, NHS Economic Evaluation Database, and EconLit for real-world studies reporting on HRQoL and utilities in adult and pediatric patients with thalassemia. Conference abstracts from Jan 2017 to Sep 2021 were also searched. References were screened by two independent reviewers, and HRQoL data were extracted by one reviewer and validated by another. Results were grouped by genotype (β-thal/α-thal) and transfusion phenotype (TDT/NTDT). Results: A total of 2,548 records were screened at title/abstract and 448 at full text. 126 publications from 116 unique studies were included and data extracted. Most evidence was published since 2015 (95/126) and sample sizes of study populations ranged from 22 to 1240. Most TDT/NTDT studies were conducted in β-thal (84/126); 10 were in mixed α-thal and β-thal, of which 2 reported data separately for Hemoglobin H disease (HbH) pediatric patients; the remaining studies did not specify the thalassemia genotype. HRQoL was significantly poorer in TD β-thal adult or adult/pediatric patients compared with healthy controls across the majority of domains. Among TDT patients, HRQoL also tended to decrease with increasing age. The burden associated with pediatric TD β-thal also impacts caregivers, with one study reporting significantly reduced HRQoL compared with healthy controls (p<0.001). In NTD β-thal patients, 2 studies identified significantly worse PedsQL scores in nearly all domains compared with healthy controls. Across studies in adult or mixed adult/pediatric patients, HRQoL (as measured by SF-36) tended to be poorer among NTDT (β-thal intermedia) compared with TDT (β-thal major) patients. For example, a prospective study found significantly lower SF-36 mental component scores at baseline in adult NTDT vs. TDT (mean [standard deviation (SD)]: 47.4 [8.4] vs. 51.6 [7.2]; p=0.009). While in pediatric patients, there was a pattern for poorer HRQoL burden in TDT vs. NTDT. TD α-thal and β-thal pediatric patients had similar total and subdomains of PedsQL scores, except for physical functioning, whereby homozygous β-thal patients had the best HRQoL, followed by HbH patients, with β-thal/Hb E patients demonstrating the greatest HRQoL burden (mean [SD]: 76.52 [15.23] vs. 61.16 [18.39] vs. 56.88 [17.17], p=0.008). Another study did not find differences in any PedsQL subdomain between HbH, β-thal, and homozygous β-thal (TDT and NTDT, patients 5-18 years; N=315). Conclusion: This SLR highlights the negative impact on HRQoL across the spectrum of thalassemia. Adding to previous SLRs, it shows limited evidence is available for NTDT patients; however, studies suggest that HRQoL burden may be worse in NTDT than TDT adult patients. Characterizing the HRQoL burden of α-thal is a clear evidence gap. High-quality, real-world studies in NTDT and α-thal are needed to better understand the HRQoL burden and the potential impact of new treatments on HRQoL.

PB2233: SYSTEMATIC LITERATURE REVIEW OF HEALTH-RELATED QUALITY OF LIFE BURDEN IN PATIENTS ACROSS THE SPECTRUM OF THALASSEMIA

Background: Recent systematic literature reviews (SLRs) have highlighted the health-related quality of life (HRQoL) burden in transfusion-dependent thalassemia (TDT), particularly β-thalassemia (β-thal). However, less is known about HRQoL in non–transfusion-dependent thalassemia (NTDT) and alpha-thalassemia (α-thal). Aims: To conduct an SLR on the real-world HRQoL burden across the entire spectrum of thalassemia and report evidence gaps. Methods: Searches (2010 to September 2021) were conducted in MEDLINE, Embase, Cochrane Database of Systematic Reviews, Health Technology Assessment Database, NHS Economic Evaluation Database, and EconLit for real-world studies reporting on HRQoL, utilities, and patient-reported outcomes in adult and pediatric patients with thalassemia. Conference abstracts from 2017 to September 2021 were also searched. References were screened at title/abstract and then full text by two independent reviewers. Data extraction was undertaken by one reviewer and validated by a second independent reviewer. Results were grouped by genotype (β-thal/α-thal) and transfusion phenotype (TDT/NTDT) to support comparisons. Results: A total of 2,541 records were screened at title/abstract, 441 at full-text and 7 references were identified through other sources. A total of 126 publications reporting on 116 study populations were included. Most evidence was published since 2015 (n=95) and sample sizes ranged from 22 to 1240. The number of publications by transfusion phenotype (TDT/NTDT) and thalassemia genotype (β-thal/α-thal) is shown in Table 1. Overall, most TDT/NTDT studies were conducted in β-thal or did not report genotype. Four studies included patients with α-thal but did not report HRQoL results separately for this subgroup. Across 52 studies reporting on TD β-thal, most showed that both adult and pediatric patients have reduced HRQoL. One study found EQ-VAS utility values to be poorer in adults than in children with TDT (mean [SD]: 75.04 [17.86] for >18 years vs. 84.97 [15.16] for ≤18 years; P<0.001). Four studies in pediatric patients noted the negative impact of TDT on caregivers’ HRQoL. Very few studies assessed HRQoL for NTDT patients vs healthy controls, and none were in adult population. One pediatric study found NTDT patients had worse total and domain PedsQOL scores (all P<=0.05) than healthy controls. Several studies compared NTDT and TDT patients. Using the SF-36, one study found significantly poorer HRQoL in NTDT than in TDT adults (mean total score [SD]: 66.5 [16.1] vs. 75.8 [18.8]; P=0.021). A prospective, non-interventional study found significantly lower SF-36 mental component scores at baseline in NTDT compared to TDT adults (mean [SD]: 47.4 [8.4] vs. 51.6 [7.2]; P <0.01), and NTDT patients had worse HRQoL change from baseline at 24 weeks than TDT patients. In pediatric patients, one study found poorer HRQoL in TDT compared to NTDT (mean PedsQL total score [SD]: 42.25 [20.61] vs. 67.76 [18.31]; P=0.0001). However, both NTDT and TDT patients had poorer HRQoL than healthy controls (83.45 [15.6]); P<0.0001). Image:Summary/Conclusion: This SLR highlights the negative impact of thalassemia on HRQoL. Adding to previously published SLRs, it shows limited evidence is available for NTDT patients; however, studies suggest that HRQoL burden may be worse in NTDT than TDT patients, particularly in adults. Characterizing the HRQoL burden of α-thal is a clear evidence gap. High-quality, real-world studies in NTDT and α-thal are needed to better understand the HRQoL burden and the potential impact of new treatments on HRQoL.

The use of hydroxyurea in the real life of MIOT network: an observational study

ABSTRACT Background Hydroxyurea (HU) has been widely used in clinical practice to manage patients with non-transfusion dependent thalassemia (NTDT). Few data are available about the effects of its administration in Italian patients. We assessed hematological and non-hematological outcomes following short- and long-term exposure to HU. Research design and methods We considered 71 NTDT patients (30 females) enrolled in the Myocardial Iron Overload in Thalassemia Network and treated for >12 months with HU. Results The mean duration of HU treatment was 8.23±5.79 years, starting at a mean age of 37.02±12.06 years. A significant increase in hemoglobin and mean corpuscular volume values and a down-regulation of all erythropoietic and/or hemolysis indices were detected after at least 12 months of treatment. In 28 patients the hemoglobin increase was ≥1.0 g/dl, associated with a higher HU dose. The hematological response dropped in long-term treatment. A favorable impact of HU treatment in limiting the progression of several complications typical of NTDT syndrome was observed. Conclusion Our findings seemed to suggest that in several NTDT patients HU could be still a valid option to limit the advance in overall disease clinical burden without carrying significant adverse events and increase in mortality.

Cardio-protective effect of regular transfusion in children with non-transfusion dependent thalassemia (NTDT): A cohort study.

Background and aim of the work:Cardiac complications occur in patients with non-transfusion dependent thalassemia (NTDT). The study aimed to evaluate transfusion effect on systolic and diastolic cardiac function in young NTDT patients.Methods:Study design: Cohort study. Seventeen regularly-transfused patients with NTDT (12.5±5.3 years; group 1) and 15 none/minimally transfused patients (13.2±4.8 years; group 2) were followed up for 5 years and compared as regards their clinical parameters, echocardiographic and Tissue-Doppler-Imaging.Results:Group 2 patients had significantly higher peak late-diastolic velocity of the left-ventricular-inflow Doppler (Am). Mitral-valve A-wave duration/pulmonary-veins, A-wave duration-ratio and pulmonary-vein S/D velocities-ratio were larger in group 2 as well (p = ≤ 0.01). The diameters of right and left outflow-tract were larger with a higher cardiac-index in patients of group 2. Systolic-function was similar in the 2 studied groups.Conclusion:Diastolic function assessment revealed indicators of an abnormal relaxation of left-ventricle in non-transfused patients, which suggests a diastolic dysfunction. An increase in the diameter of the outflow-tract is likely attributed to high cardiac-output status in non-transfused NTDT patients as they have a higher cardiac index. Early start of regular transfusion for NTDT patients might prevent serious long-term cardiac complications. (www.actabiomedica.it)

The The use of oral glucose-lowering agents (GLAs) in β-thalassemia patients with diabetes: Preliminary data from a retrospective study of ICET-A Network.

Objective:The management of prediabetes and hyperglycemia is an increasingly important aspect of care in patients with thalassemia. In light of the limited evidence about the management of GD (glucose dysregulation) with glucose-lowering agents (GLAs), we have conducted a retrospective survey in TDT and NTDT patients with diabetes mellitus to collect more detailed information on GLA use in order to make preliminary recommendations.Study design and method:A questionnaire was prepared and distributed to the tertiary thalassemia care Centers of ICET-A Network.Results:Eight thalassemia care Centers [Bulgaria, Greece, Iran, Italy (4 Centers) and Qatar], following 1.554 with transfusion-dependent thalassemia (TDT), 132 (8.4%) with diabetes and 687 with non-transfusion-dependent thalassemia (NTDT), 27 (3.9%) with diabetes, participated in the retrospective survey. The records of 117 TDT patients and 9 NTDT patients with diabetes treated with GLAs were analyzed. Metformin, a biguanide, was the most frequently used drug (47.6 %), followed by alpha-glucosidase inhibitors (5.5 %), incretins (4.7%) and insulin secretagogues (3.1%). In 68 (61.2) patients GLAs was prescribed as monotherapy, while the remaining 49 (38.8%), who had inadequate glucose control with metformin, were treated with combination treatment. Fifty-one patients of 126 (40.4%) initially treated with oral GLA, for a mean duration of 61.0 ± 35.6 months (range: 12- 120 months), required insulin therapy for better metabolic control.Conclusion:This retrospective study covers an unexplored area of research in patients with thalassemia and GD. Oral GLAs appear to be safe and effective for the treatment of diabetes mellitus in patients with thalassemia, and can achieve adequate glycemic control for a substantial period of time. (www.actabiomedica.it)

Iron overload status in patients with non-transfusion-dependent thalassemia in China.

Background:Iron overload is one of the main factors that increase morbidity and mortality in patients with non-transfusion dependent thalassemia (NTDT).Aim:This study aimed at investigating the prevalence and severity of iron overload in Chinese NTDT patients.Methods:we analyzed serum ferritin (SF), liver iron concentration (LIC) and cardiac T2* in 178 Chinese NTDT in this cross-sectional study.Results:The median SF level was 996.00(27.15–19704.00) ng/ml and the median LIC value was 8.90(0.60–43.00) mg Fe/g dry weight (dw). The youngest patient with liver iron overload was 5 years old with 5.6 mg Fe/g dw in LIC. The median cardiac T2* was 33.06(7.46–75.08) ms. 6 patients had cardiac T2*⩽20ms. The patients with β thalassemia intermedia and HbE/β thalassemia showed a statistically significant lower Hb and higher values of SF and LIC than those of hemoglobin H disease patients. On multivariate logistic regression analysis, patients in ⩾ age 30-year old had a significant higher risk for iron overload (OR: 77.75, 95% CI: 8.76–690.49) in the age group. The detailed analysis of proportions of different LIC indicate in > 30-year old group, 76.8% patients suffered from moderate and severe LIC.Conclusion:Our study provides a strong support for the novel findings that Chinese NTDT patients have a high prevalence of iron overload. The first assessment of MRI LIC should be performed as early as 5 years old. Then, NTDT patients > 30 years old may suffer with a high burden of iron overload.

Serum GDF15 in β-Thalassemia: A Quantitative Marker of Ineffective Erythropoiesis?

Introduction: Ineffective erythropoiesis (IE) is a crucial hallmark of β-Thalassemia (β-Thal) and sets the goal for treatment of both Transfusion-Dependent (TDT) and Non Transfusion-Dependent Thalassemia (NTDT) patients. The Growth Differentiation Factor (GDF) group has a relevant role in the molecular regulation of IE. Specifically, GDF11 contributes to the inhibition of RBC maturation and it is targeted by activin traps, such as luspatercept. However, its role is still debated; i.e., in a mouse model of β-Thal, the absence of GDF11 alone is not sufficient to mitigate IE (Guerra A et al., Blood, 2019). GDF15 increases from early until late phases of erythroid differentiation and negatively regulates erythroid cell development in-vitro, modulating maturation and apoptosis. (Ranjbaran R et a.l, Exp Cell Res, 2020). A few clinical studies found elevated serum GDF15 levels in β-Thal (Tanno T et al., Nat Med, 2007; Huang Y et al., Int J Med Sci, 2019), but data are sparse and a clear correlation with the severity of the pathology is still missing.Methods: We run an observational study at our institution. At routine checks, patients were asked to consent to a specific blood sample for GDF15, whereas hemoglobin (Hb), serum erythropoietin (Epo), ferritin (Ftn), iron, and transferrin saturation (TSat) were measured as part of clinical practice. In a small subset of patients, a consent for serial sampling was added. Serum GDF15 was measured by ELISA (DuoSet DY957, R&D Systems). Demographics were collected from clinical records. Statistical analysis was performed using Statistica 10 (Statsoft).Results: GDF15 levels were measured in 458 individuals: 267 TDT, 77 NTDT, 45 β-Thal trait carriers (BTC), and 69 healthy (H) subjects. Median (IQR) levels of GDF15 were significantly different among diagnoses (P<0.0001), and specifically measured 0.22 (0.16-0.34) in H, 0.48 (0.28-0.96) in BTC, 1.35 (0.40-5.46) in NTDT and 5.95 (3.19-10.52) ng/mL in TDT. (FIG 1A). In TDT patients, a mild but highly consistent negative correlation was observed between Hb and GDF15 levels (R=-0.31, P=0.002). GDF15 levels correlated positively with Epo (R=0.60, P<0.0001), TSat (R=0.32, P=0.0003) and serum iron (R=0.27, P=0.003). In addition, they correlated with length of transfusion interval in splenectomized patients (R=0.65, P<0.001). In a small subset of longitudinal data in TDT, the transfusion cycle had a strong and uniform effect on GDF15 levels. FIG 1B shows a single individual (female, 38 years old, splenectomized): mean (±SD) GDF15 levels were 5.27 (± 1.99) and 2.10 (±0.97) ng/mL pre-transfusion and 8 days post-transfusion, respectively (P<0.01). After 21 days post-transfusion, they were 3.74 (±0.76), showing a trend of variation opposite to Hb. In another individual with a prenatal diagnosis of severe TDT (homozygous for IVS I:110), GDF15 levels were high at 5 months and showed a progressive decline after the start of regular transfusion therapy. After reaching the 10 mg/dL threshold for pre-transfusion Hb, GDF15 levels were approximately halved compared to 5 months of age (6.2 vs 2.7 ng/mL) (FIG 1C). In NTDT patients, GDF15 correlated positively with TSat (R=0.40, P<0.0001), serum iron (R=0.39, P<0.0001) and Ftn (R=0.25, P=0.01). Among TDT and NTDT patients, 45 and 19 were paediatrics, respectively. No significant differences were observed at different ages. In BTC, GDF15 correlated negatively with Hb levels (R=-0.43, P=0.002) and positively with Epo (R=0.78, P=0.02), TSat (R=0.77, P<0.0001), serum iron (R=0.62, P<0.0001) and Ftn (R=0.59, P<0.0001). No significant correlations were observed for H subjects.Discussion: GDF15 levels correlated with the severity of β-Thal phenotype, showing a 26-fold (TDT), a 6-fold (NTDT) and a 2-fold (BTC) increase compared to controls. In TDT patients, higher GDF15 levels correlated with lower Hb and higher Epo, which are typically observed as a result of IE in thalassemia. In addition, GDF15 correlated with markers of altered iron metabolism, such as TSat and serum iron. In individual patients, GDF15 showed strong and consistent variation with treatment. GDF15 was also associated with quantitative markers of disease in NTDT and BTC patients. This is to our knowledge the larger sample of patients carrying β-thal mutations in which GDF15 levels were measured and correlated with the severity of the disease. These results show that GDF15 may be a suitable and useful quantitative marker of IE. [Display omitted] DisclosuresPiga: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Research Funding. Longo: Bristol Myers Squibb: Honoraria; BlueBird Bio: Honoraria.

Non-transfusion dependent thalassemia is independently associated with higher alloimmunization risk than transfusion dependent thalassemia and would benefit the most from extended red cell antigen-matching.

Alloimmunization prevalence is conventionally used to identify RBCs alloimmunization risk factors among thalassemia patients, but it may be confounded by differences in transfusion exposure especially between non-transfusion dependent thalassemia (NTDT) and transfusion dependent thalassemia (TDT) patients. To better identify thalassemia patients with high alloimmunization risks, we used cumulative incidence of first alloimmunization as a function of RBCs transfused to compare alloimmunization risks between TDT and NTDT and to evaluate other risk factors. We also proposed practical strategies to prevent alloimmunization in thalassemia. Adult TDT and NTDT patients who had received ≥2 transfusions and no alloimmunization before their first transfusion were included. Alloimmunization was defined as the development of clinically significant alloantibodies. We estimated the first alloimmunization incidence from transfusion by Kaplan-Meier analysis with the horizontal axis expressed as cumulative non-antigen-matched RBC units transfused. We compared this incidence between TDT and NTDT, and analyzed for other alloimmunization risk factors and the alloantibody specificities/frequencies. The alloimmunization prevalence was similar between TDT and NTDT (27% vs. 30% respectively, p= .726). However, for the same transfusion exposure, NTDT had higher alloimmunization incidence than TDT (hazard ratio 8.59, 95% confidence interval [2.25-32.74], p= .002), independent of age at first transfusion and last follow-up, gender, and splenectomy. Anti-E, anti-c, anti-Mia , and anti-Jka were most frequent. NTDT has the highest alloimmunization risk and would benefit the most from extended RBC antigen-matching, especially C, c, E, and e. Other blood group antigen-matching should be guided by the patient/donor disparities and alloantibody frequencies in different populations.

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

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

Measurement of Liver Iron Concentration in a Population of Non-Transfusion Dependent Thalassemia Patients Using a Trained Artificial Neural Network to Analyse Magnetic Resonance Images

Background: Measurements of liver iron concentration (LIC) by magnetic resonance imaging (MRI) have become established and validated in several research intensive centers. However, challenges remain with translating these measurement methodologies for routine clinical use. Current methods involve many steps presenting multiple opportunities for human error and can lead to systematic severe measurement error. Artificial neural networks (ANNs) can be trained to replace human input into image processing and may have a role in providing a simple, robust, and low cost solution for LIC measurement.Aims: The aim of the study wasto determine the limits of agreement between measurements of LIC by a reference standard spin-density-projection-assisted (SDPA) R2-MRI method (FerriScan) and a method using trained ANNs to analyse image data. MR image datasets (400) previously acquired from Siemens scanners were pre-processed and then, together with their corresponding SDPA R2-MRI LIC values, were filtered through publically available ANNs. The ANNs had been pre-trained on large image sets (ImageNet). Relevant features were extracted and then used to train a machine learning (gradient boosting) algorithm to predict LIC values from previously unseen MR image datasets.Methods: Thalassemia patients (N=100) referred by the National Institute of Haematology and Blood Transfusion, Hanoi, Vietnam for routine LIC measurement by MRI were prospectively recruited with informed consent. Patients were randomised to be scanned in either a Philips Ingenia or a Siemens Avanto 1.5T scanner. Image data were acquired using the FerriScan protocol. Images were then processed (1) using a quality controlled core laboratory data analysis service using the SDPA R2-MRI method and (2) by a non-radiologically-trained technician using the trained artificial neural network to generate LIC values. The technician was required to trace the outline of the torso and then click a mouse button. The technician using the ANN was blinded from the SDPA R2-MRI results and the analysts generating the SDPA R2-MRI results were blinded from the ANN results. Reported data were analysed using the statistical methods of Bland and Altman.Results: A plot of the ANN-predicted LIC values against the SDPA R2-MRI LIC values (Figure) shows the data scattered about the line of equivalence indicating that the ANN method is generating results that correlate with the validated SDPA R2-MRI reference standard. The geometric mean ratio of ANN LIC to SDPA R2-MRI LIC was 0.93 (95% CI 0.91 -0.96) indicating a small but statistically significant systematic underestimation of LIC by the ANN. The geometric mean ratios of the two LIC measurements were significantly different for the two scanners (0.98 for Philips and 0.90 for Siemens, p = 0.006) indicating that the bias of the ANN method against the reference standard is not universal but is dependent on scanner. Bland Altman analysis indicates that 95% of pairs of measurements are predicted to have ratios between 1.23 and 0.69 indicating a modest random variability between the ANN method and the reference standard that is better than that between biopsy and the reference standard. The performance of the ANN method in predicting SDPA R2-MRI LIC values above the clinically relevant thresholds of 7 and 15 mg Fe/g dw is characterized in Table 1 showing positive predictive values (PPVs) and negative predictive values (NPVs) together with their 95% CIs.Conclusion: The data indicate that the ANN method of measurement of LIC has potential to be used as a fast and robust method of analysing MR image data to generate LIC values. Further testing is required on a wider range of scanner types and with more patients with lower LICs. The performance of the ANN will also likely be improved through training on a larger number of datasets. [Display omitted] DisclosuresSt Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Speakers Bureau. Cooper:Resonance Health Ltd: Consultancy. Boulos:Resonance Health Ltd: Employment. House:Resonance Health Ltd: Employment. Pang:Resonance Health Ltd: Employment. Bangma:Resonance Health Ltd: Employment. Taher:Novartis Pharmaceuticals: Honoraria, Research Funding; Celgene: Research Funding.

Intermittent Transfusions for Treatment of Thalassemia in the State of Georgia, 2007-2016

Background: Individuals with Non-Transfusion Dependent Thalassemia (NTDT) may require infrequent transfusions. Knowing transfusion history, while important, can be challenging in this subgroup. Study Design: Hospital discharge data in Georgia (2007-2016) was reviewed. Thalassemia patients were defined as ≥3 encounters with a thalassemia diagnosis code. Transfusion was defined by the presence of a diagnosis, CPT, revenue, or HCPCS code for red cell transfusion. Results: There were 428 patients identified; 57 received multi-site transfusions. Conclusion: Georgia hospitals provide intermittent transfusions to low volumes of probable NTDT patients. Patient and provider education may help assure adherence to best practices, avoiding serious transfusion complications.

The association between pre-transfusion hemoglobin levels and thalassemia complications

ABSTRACT 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.

Diagnostic Work-up of Pulmonary Hypertension in Non Transfusion Dependent Thalassemia Patients: Pathophysiologichal Mechanisms and Clinical Implications

INTRODUCTION: Pulmonary hypertension (PH) is a well documented clinical complication in Non-Transfusion Dependent Thalassemia (NTDT) patients, and it is associated with poor outcome [1]. PH prevalence is extremely variable among studied cohorts, ranging from 4.8% to 59% [2, 3]. Nevertheless, in the majority of the studies, the diagnosis is based on echocardiography, whereas the gold standard for PH definition is right heart catheterization (RHC). Thus, PH real prevalence, its pathophysiological mechanisms and risk factors still need to be elucidated. AIM:The aim of this study is to define the prevalence of PH in a cohort of NTDT patients through the application of the PH diagnostic work-up of the European Society of Cardiology Guidelines (ESC) [4]. We also aimed to investigate the involved pathophysiological mechanisms, to define risk factors, and to identify a potential role for cardiopulmonary exercise testing (CPET) in the risk stratification. MATERIALS AND METHODS: We planned a screening program for all NTDT patients referring to Rare Disease Center, in collaboration with the Dyspnea Lab of the Cardiology Unit, at Fondazione IRCCS Ca' Granda Policlinico in Milan. Following the systematic approach of ESC PH algorithm, together with an echocardiogram and cardiological evaluation, our patients underwent cardiopulmonary exercise testing (CPET) and the dosage of NT-proBNP. Patients were stratified according to PH probability (low vs intermediate-high) and further investigations (including V/Q lung scan and RHC) to confirm PH were performed in those with intermediate-high risk. RESULTS AND DISCUSSION:48 NTDT patients (18 females and 30 males) were consecutively enrolled over a period of 10 months. The mean age at enrollment was 46±12 years (median 45, range 25-72 years) and a wide spectrum of thalassemia genotypes was observed. 38 out of 48 (79%) had a low PH probability according to NYHA class and echocardiogram, thus they were addressed to regular follow-up. 10 patients presented intermediate-high PH probability and underwent further tests. So far, 6 out of 10 intermediate-high risk underwent RHC: PH was confirmed in 5 cases, allowing to identify 2 post-capillary PH, 1 pre-capillary PH (due to pulmonary embolism detected with V/Q scan) and 2 forms of PH due to high cardiac output (CO). The sixth patient showed a condition of high CO but with a mean arterial pulmonary pressure just below the value needed to diagnose PH. Thus, PH was confirmed in 5 out of 48 patients, with a prevalence of 10.4%. The four remaining patients with high PH probability are planned to be tested. Comparing those with high and low PH probability, the first were older (58.4 ±8.9 vs 42.6 ±10.7 years, p=0.0002) and presented higher NT-proBNP (450±442 vs 92±99 ng/mL, p=0.0001). Hemoglobin, erythroblasts, and platelet count were similar. Patients with high PH probability on CPET reached a lower maximal workload (87.9 W ±32.1 vs 126.9 ±41.6W) and lower O2 consumption (1207.7 ±284.5 vs 1594 ±454.8 mL/min), together with worse ventilation efficiency (VE/VCO2 slope 40.9 ±6.9 vs 29.4 ±3.85). CONCLUSIONS: In our cohort, according to these preliminary data, PH prevalence in NTDT is 10.4% and older patients seem to be at higher risk. Thus, cardiac evaluation programs are required, considering the increased life span. RHC is mandatory to confirm the diagnosis, to identify the underlying mechanisms and consequently a proper treatment. CPET may have an essential role in detecting predictive and prognostic parameters of PH and in defining different hemodynamic mechanisms (pre- or post-capillary) to select patients requiring RHC. Together with pulmonary embolism, which needs to be excluded with imaging, high CO due to chronic anemia seems to play an important role. This hypothesis could have significant treatment implications, giving more importance to increase Hb levels, either with blood transfusions or new therapies. Sleiman J, Int J Mol Sci 2018 2 Derchi G, Circulation 2014 3 Aessopos E., Blood 2001 4 Galiè N, Eur Heart J 2016 Disclosures Motta: Sanofi Genzyme:Honoraria.Cappellini:Genzyme/Sanofi:Honoraria, Membership on an entity's Board of Directors or advisory committees;CRISPR Therapeutics, Novartis, Vifor Pharma:Membership on an entity's Board of Directors or advisory committees;BMS:Honoraria.

Association of Exon 14 of the SOX6 Gene Sequence Variations with Response to Hydroxyurea Therapy in Patients Carrying Non Transfusion-Dependent Thalassemia

Hydroxyurea (HU) activates the γ-globin gene, resulting in increased Hb F synthesis. The SOX6 gene is a member of the Sox (Sry-type HMG box) family of transcription factors, characterized by minor groove binding domain. The DNA binding domain of this gene is encoded by exon 14. We assessed the relationship between response to HU and exon 14 of the SOX6 gene sequence variations in patients with non transfusion-dependent thalassemia (NTDT). One hundred NTDT patients from southern Iran underwent HU therapy randomly participated in this cross-sectional study between February 2013 and October 2014. Based on response to HU therapy, the patients were divided into two groups: good and poor responder. Sequence variations of exon 14 of the SOX6 gene was assayed by the Sanger sequencing technique. From all evaluated single nucleotide polymorphisms (SNPs) as above, we found no significant association between sequence variations of exon 14 of the SOX6 gene and response to HU therapy (p > 0.05). It seems that no SNPs in exon 14 of the SOX6 gene is associated with response to HU in NTDT patients, but more studies are needed for further evaluation.