BackgroundMyocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM.Methods and ResultsWe analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients ≤10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload.ConclusionsThe TM patients under follow-up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly-chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old.

Aim: This study aimed to evaluate the imbalance of erythropoiesis and iron metabolism in patients with thalassemia.Methods: 192 patients with non-transfusion-dependent thalassemia (NTDT), 94 patients with transfusion-dependent thalassemia (TDT) and 101 healthy controls were recruited between June 2013 and December 2016 in the Hematology Department, the First Affiliated Hospital of Guangxi Medical University. The groups were compared in terms of levels of erythropoiesis biomarkers [growth differentiation factor 15 (GDF15), erythropoietin (EPO) and soluble transferrin receptor (sTfR)] and of iron overload biomarkers [serum ferritin (SF), liver iron concentration (LIC) and cardiac T2*] and hepcidin.Results: The levels of GDF15, EPO, sTfR, LIC and SF were significantly higher in patients with thalassemia. The levels of GDF15 and EPO were significantly higher in patients with TDT compared to NTDT. Those with iron overload had higher EPO, GDF15, SF and sTfR levels compared with non-iron overload patients. Hepcidin levels and ratios of hepcidin to erythropoietic activity and to iron biomarker levels were lower in patients with β-thalassemia intermedia or hemoglobin (Hb) E/β-thalassemia than in patients with HbH disease. The hepcidin levels were correlated negatively with the levels of EPO, GDF15 and sTfR in patients with NTDT and TDT, but correlated positively with SF and Hb levels only in patients with TDT.Conclusions: Patients with thalassemia showed iron overload, reduced hepcidin levels, and a greater extent of ineffective erythropoiesis. The hepcidin levels were more strongly related to ineffective erythropoiesis compared with iron overload. The imbalance between erythropoiesis and iron metabolism differed across different thalassemia types.

At present, the main therapies for ß-thalassemia patients include regular blood transfusion and iron chelation, associating with a number of limitations. Thalidomide, a fetal hemoglobin (HbF) inducer that promotes γ-globin gene expression, has been reported to be effective for ß-thalassemia. Thus, this meta-analysis was conducted to assess the efficacy and safety of thalidomide for treating patients with ß-thalassemia. We searched the related studies from eight databases published from inception until December 1, 2021. The R 4.0.5 language programming was used to perform meta-analysis. After screening of retrieved articles, 12 articles were included that enrolled a total of 451 patients. The Cochrane Collaboration risk assessment tool was used to evaluate the quality and the bias risk of the randomized controlled trials (RCTs), and non randomized trials were assessed using Newcastle-Ottawa Scale (NOS). After treatment with thalidomide, the pooled overall response rate (ORR) was 85% (95% confidence interval (CI): 80–90%), and the pooled complete response rate (CRR) was 54% (95% confidence interval: 31–76%). Compared with the placebo group, the thalidomide group had higher odds of overall response rate (odds ratio = 20.4; 95% CI: 6.75–61.64) and complete response rate (odds ratio = 20.4; 95% CI: 6.75–61.64). A statistically significant increase in hemoglobin level and HbF level after treatment, while there was no statistically significant difference in adult hemoglobin (HbA) level, spleen size, and serum ferritin. According to the results of ORR and CRR, transfusion-dependent thalassemia (TDT) patients showed remarkable efficacy of thalidomide, 83 and 52% respectively. So we analyzed 30 transfusion-dependent thalassemia patients from three studies and found that the most frequent ß-globin gene mutations were CD41-42 (-TCTT), while response to thalidomide did not show any statistically significant relationship with XmnI polymorphism or CD41-42 (-TCTT) mutation. About 30% of patients experienced mild adverse effects of thalidomide. Collectively, thalidomide is a relatively safe and effective therapy to reduce the blood transfusion requirements and to increase Hb level in patients with ß-thalassemia.

Background. Extramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH. Materials and Methods. 52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed. Results. EMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity. Conclusions. GDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.

Background: Early detection of liver fibrosis in thalassemia patients and rapid initiation of treatment to interfere with its progression are extremely important. Objective: This study aimed to find a sensitive, easy-to-detect and noninvasive method other than liver biopsy for early detection of liver fibrosis in thalassemia patients. Methods: A total of 244 Chinese Thalassemia patients with non-transfusion-dependent thalassemia (NTDT, n ¼ 105) or thalassemia major (TM, n ¼ 139) and 120 healthy individuals were recruited into the present study, and blood collagen type IV (C IV), precollagen type III (PIIINPC) and hyaluronic acid (HA), aspartate aminotransferase (AST), alanine aminotransferase (ALT) and ferritin were measured. Liver iron concentration was determined by MRI. The correlation of serum markers with liver iron load and liver function was evaluated. Results: Serum C IV, PIIINPC and HA were significantly elevated in Chinese patients with NTDT and further elevated in TM patients. Moreover, C IV, PIIINPC and HA were also positively correlated to serum ferritin and liver iron concentration and further elevated during the progression to multi-organ damage in NTDT patients. Finally, serum ferritin and liver iron concentration were significantly correlated with liver dysfunction determined by AST and ALT. Conclusion: Taken together, our results indicate that monitoring serum C IV, PIIINPC and HA is a potentially sensitive method to predict the risks for iron overload-related liver fibrosis in Chinese thalassemia patients.

b-Thalassemia is one of the most prevalent genetic diseases worldwide. The current treatment for b-thalassemia is allogeneic hematopoietic stem cell transplantation, which is limited due to lack of matched donors. Gene therapy has been developed as an alternative therapeutic option for transfusion-dependent b-thalassemia (TDT). However, successful gene therapy for b-thalassemia patients in China has not been reported. Here, we present the results of preclinical studies of an optimally designed lentiviral vector (LV) named LentiHBB T87Q in hematopoietic stem and progenitor cells (HSPCs) derived from Chinese TDT patients. LentiHBB T87Q was selected from a series of LVs with optimized backbone and de novo cloning strategy. It contains an exogenous T87Q b-globin gene (HBB T87Q ) driven by a specific reconstituted locus control region, and efficiently expresses HBB mRNA and HBB protein in erythroblasts derived from cord blood HSPCs. To facilitate clinical transformation, we manufactured clinical-grade LentiHBB T87Q (cLentiHBB T87Q ) and optimized its transduction procedure. Importantly, transduction of cLentiHBB T87Q restored expression of HBB monomer and adult hemoglobin tetramer to relatively normal level in erythroblasts from bone marrow HSPCs of Chinese TDT patients that carry the most common mutation types and cover various genotypes, including b0/b0. Furthermore, viral integration sites (VISs) of cLentiHBB T87Q were similar to other LVs safely used in previous clinical trials, and geneontology (term) analysis of VIS targeted genes suggests that no tumor-associated pathways were enriched in treated samples. Taken together, we have engineered the cLentiHBB T87Q that can restore b-globin expression in the HSPCsderived erythroblasts of Chinese TDT patients with minimal risk of tumorigenesis, providing a favorable starting point for future clinical application.

Background The clinical outcome of hematopoietic stem cell transplantation (HSCT) in those with severe beta‐thalassemia (β‐TM) is closely related to post‐transplantation immune reconstitution (IR). However, the data on the IR in these settings are scarce. Methods A prospective analysis of the clinical outcome and IR in 47 children with severe β‐TM who underwent in vivo T‐cell depletion myeloablative conditioning and matched sibling donor HSCT was performed. Immune reconstitution, including immune cell subset counts, as well as the generation of new T and B cells assays after HSCT, was measured. Results In the first year after HSCT, bacterial infections and cytomegalovirus (CMV) reactivation were observed in 70.2% and 36.2% of the patients, respectively. In the same period, poor CD4+ T‐cell recovery was observed. The B cells recovered within 6 months. Natural killer (NK) cells recovered as early as 1 month, but their function was defective. Cord blood and bone marrow (CB + BM) group had slower T‐cell recovery, and higher B cells and NK cells in comparison with peripheral blood and bone marrow (PB + BM) group. Conclusions The high incidence of infection within 1 year after in vivo T‐cell depletion myeloablative conditioning HSCT in severe β‐TM was consistent with poor IR.

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.