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LETTERS TO THE EDITOR
Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia
Non-transfusion-dependent β-thalassemia (NTDT) is a broad term encompassing patients who do not require lifelong transfusion therapy for survival. NTDT patients commonly, but not exclusively, present to medical care later in childhood (commonly >2 years of age) and with milder anemia and clinical symptoms compared to patients with transfusion-dependent forms. Our under- standing of the disease process in NTDT has evolved sig- nificantly over the past two decades and it is now estab- lished that a diagnosis of NTDT can be associated with greater morbidity than previously recognized.1 Ineffective erythropoiesis and peripheral hemolysis lead to a state of chronic anemia, which can impact organ function in the long-term. There is a significant correlation between the degree of anemia and morbidity development in this NTDT patient population.2 Ineffective erythropoiesis is also linked to other pathogeneses manifesting as extramedullary hematopoiesis, bone disease, hypercoag- ulability and vascular disease, as well as primary iron overload due to increased intestinal iron absorption.1 Iron overload can be cumulative and leads to end-organ dam- age, especially in the liver.3,4 Despite advances in realizing risk factors and morbidity in NTDT, data on mortality and causes of death remain limited.5
There are currently no approved drugs for the manage- ment of ineffective erythropoiesis, or anemia, in NTDT. Thus, despite the terminology, many patients are given sporadic transfusions or are even placed on regular trans- fusion programs later in their disease course. This is com- monly undertaken in situations of acute stress (during pregnancy, surgery, or infection), in the context of sup- porting growth and development, or for the management and prevention of complications in adulthood.6 Decisions are often based on the physician’s judgement, since man- agement guidelines have only become available since
2013 and do not necessarily provide specific recommen- dations for transfusion therapy or for other erythro- poiesis modulators when data from clinical trials is absent.7 Iron chelation therapy has been used in patients with NTDT for decades, but this have primarily based on expert opinion since data from dedicated clinical trials and management guidelines have only become available in the last 10 years.8,9
Against this background, the aim of the current study was to evaluate survival and causes of death in a large cohort of patients with NTDT. Considering the high vari- ability in management practices, the impacts of transfu- sion and iron chelation therapy on mortality outcomes were also examined.
Data were retrieved from an International Health Repository (IHR) established and approved on 25 May 2017 by the Italian Ethical Committee (EudraCT and Sponsor’s Protocol Code Numbers: 2017-004457-17 and 143AOR2017). All data were anonymized and added to the repository following informed consent by patients, or their legal representatives in case of death. The database included all β-thalassemia patients attending participat- ing centers from 1 January 1997 onwards, and historic data were retrieved for all patients from birth up to 31 December 2020, in case of death, or loss to follow-up. The database included 13 international thalassemia cen- ters of excellence from eight countries: Italy, Iran, Pakistan, USA, Oman, Egypt, Greece, and Saudi Arabia. For the current analysis, we gathered data on 2,033 patients identified by the centers as NTDT; a β-tha- lassemia diagnosis was confirmed by clinical and molec- ular studies at all participating centers. The definition of NTDT was based on the absence of dependence on transfusions for survival, delayed presentation, mild- moderate anemia, and clinician’s judgement of disease severity at diagnosis and during follow-up. Patients had homozygous or compound heterozygous β-thalassemia mutations, or heterozygous β-thalassemia mutations combined with α-globin gene duplications (and hence an
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Table 1. Causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia.
Cause n
Cardiovascular disease 41 (iron-related cardiomyopathy, n = 2;
other cardiomyopathy, n = 14;
myocardial infarction, n = 1;
valvular disease, n = 1;
pulmonary hypertension,
thrombosis or peripheral
vascular disease, n = 23)
Hepatic disease 23 (fibrosis or cirrhosis, n = 10; HCC, n = 13)
Cancer 14 (solid or hematologic
malignancy excluding HCC)
Infection 13 Unclassified thalassemia-related complications 17 Non-thalassemia related causes 5
% of deaths (n = 113)
36.3
20.4 12.4
11.5 15.0 4.4
% of population (n = 2,033)
2.0
1.1 0.7
0.6 0.8 0.2
Median age at death (min-max), years
34.2 (19-85)
55.4 (26-76) 54.0 (12-85)
44.1 (12-68) 19.8 (7-64) 62.0 (27-73)
HCC: hepatocellular carcinoma.