Revisiting morbidities and predictors in transfusion-dependent thalassemia: A  cohort study over 10 years from the national registry of hemoglobinopathies in Türkiye

Abstract

Abstract Introduction National registries in hemoglobinopathies are crucial for identifying gaps between research evidence and clinical care in real-world healthcare settings. This study aims to assess morbidity trends over time in a large cohort of transfusion-dependent β-thalassemia (TDT) patients from the National Hemoglobinopathy Registry (NHR) of the Turkish Hematology Association in Türkiye. Methods We conducted a nationwide prospective cohort study over 10 years, from June 2015 to June 2025, involving patients with hemoglobinopathies attending 63 Thalassemia Centers. We standardized the recording of clinical, laboratory, and imaging data across participating centers, utilising an electronic medical record software. Ethics Committee approval was obtained, and written informed consent for data collection and use was received from patients at each centre. This study is a retrospective analysis of patients aged >10 years who received red blood cell (RBC) transfusions (Tx) ≥ 8 times per year over a 10-year observation period. Subjects who died or had undergone stem cell transplantation at initial registration were excluded from the analysis set. For each patient, we retrieved demographic data, which included the age at diagnosis, the age when Tx and chelation began, and whether splenectomy was performed. We collected the mean annual pre-Tx Hb and serum ferritin (SF) levels for each year. We then calculated the average of all documented mean annual pre-Tx Hb and SF values for each patient over a 10-year observation period. We recorded the most recent liver and cardiac iron monitoring by T2* MRI. We assessed the morbidities of each patient, including the age of occurrence and their frequency in the target population. The risk factors that may influence the occurrence of morbidities were evaluated using logistic regression analysis and non-parametric tests. Results The NHR contains data on 4255 patients with thalassemia. Among these, 4129 have β-thalassemia, which includes 89,2% with β-TM. This study focuses on 1,670 eligible TDT patients aged >10 years. The mean age of the cohort was 25,4±11,2 years, (median 23, IQR 16.8-33), in which 41,2% of patients were adolescents (10-20 years old) and 28.9% were young adults (21-30 years old), while 20.1% were between 31-40 and 9.8% were above 40 years. Splenectomy was present in 50.2% of patients with a median age at splenectomy of 11 years (IQR 7-17). All patients (99.5%) were receiving iron chelation therapy. Deferasirox was the most prevalent (74.1%). A total of 54.5% subjects had at least one morbidity, and among these, 58.9% had 2 or more morbidities. The age of the diagnosis did not impact the development of morbidity (p=0.841). However, patients who began the Tx program earlier or started chelation therapy later had a significantly higher risk of developing morbidity with an odds ratio (OR) of 1,003 (95% CI: 1,000-1,006); p=0,027, and OR of 1,004 (95% CI: 1,002-1,006) p<0,001, respectively. In addition, 69.8% of splenectomized patients, while only 30.2% of those with an intact spleen, exhibited morbidities (OR 3,482, 95% CI: 2,840-4,269; p<0,001). Overall, endocrine and skeletal complications were present in 35.4% and 42.4% of the cohort, and emerged since the 2nd decade of life, with rates of 17.7% and 15.6% among their peers, respectively. These rates increased notably during the 3rd decade (35.5% and 48.5%) and continued to rise in the 4th (51.3% and 65.4%) decade, after which the rates appeared to plateau. In contrast, cardiovascular events were observed in only 3% of patients in their 2nd decade. This figure gradually increased, rising to 10.8%, 16.8% and 27.3% in the 3rd, 4th, and 5th decades. Overall, 11.5% of the cohort experienced cardiovascular morbidities. The frequency and age of the cardiac events (CEs) remained constant over 5-year periods, except for the last 5 years during which CEs decreased, and no cardiac death was reported. 18% of patients with CE had a cT2*of <10 ms at last MRI vs. 5.9% of the patients without a CE (p<0.001). 93% of patients with thrombosis and 86.6% of those with pulmonary arterial hypertension have undergone splenectomy. Hepatic morbidities were present in only 3% of the cohort; 32 of 48 events were attributed to chronic liver disease due to HCV infection, and 2 events were hepatocellular carcinoma. Conclusions Insights gained from the registry will illuminate the need to enhance standards of care for the large thalassemia population in Türkiye.