Serum ferritin level and morbidity risk in transfusion-independent patients with β-thalassemia intermedia: the ORIENT study.

Similar to other forms of non-transfusion-dependent thalassemia, the diagnosis of β-thalassemia intermedia is associated with a state of iron overload. This occurs in the absence of regular transfusion therapy and is primarily attributed to increased intestinal iron absorption signaled by ineffective erythropoiesis and low serum hepcidin levels. Although iron accumulation in transfusion-independent β-thalassemia intermedia patients is slower than in regularly-transfused β-thalassemia major, recent evidence highlights that a considerable proportion of patients ultimately reach clinically significant levels that can cause serious morbidities after the age of ten years. Accordingly, current management guidelines recommend initiating iron chelation therapy in β-thalassemia intermedia patients over ten years of age and in whom liver iron concentration has reached 5 mg Fe/g dry weight (dw) or over. This threshold was primarily selected in the light of its established association with morbidity in β-thalassemia intermedia patients, as well as recent evidence on the efficacy and safety of iron chelation therapy in non-transfusion-dependent thalassemia (including β-thalassemia intermedia) patients for whom treatment was started at 5 mg Fe/g dw or over (THALASSA trial). A liver iron concentration of 3 mg Fe/g dw was also used and this was the recommended threshold at which to interrupt iron chelation therapy and avoid overchelation. When liver iron concentration measurement is unavailable, serum ferritin levels of 800 and 300 ng/mL can be used as an alternative to the 5 and 3 mg Fe/g dw liver iron concentration values, respectively, as established in the THALASSA trial through correlation analysis between both iron overload indices. With this background in mind, the aims of this study were 3-fold. 1) To evaluate the association between serum ferritin levels (and the relevant thresholds of 300 and 800 ng/mL) and morbidity risk in chelation-naive patients with β-thalassemia intermedia since, unlike for liver iron concentration, such data for serum ferritin level are lacking. This could further support the use of such thresholds to guide management, especially when liver iron concentration measurement is not available. 2) To evaluate such an association in a longitudinal fashion and over an extended period of observation time as current evidence on the relationship between iron overload and morbidity in β-thalassemia intermedia primarily stems from cross-sectional studies. 3) To evaluate whether such an association is independent through proper adjustment for potential confounders. This was a retrospective cohort study using data from five comprehensive care centers in the Middle East (Egypt, Iran, Lebanon, and Oman) and Italy. Age at diagnosis of at least two years and hemoglobin values maintained between 7 and 9 g/dL without the need for a regular transfusional regimen, with or without splenomegaly, were the main criteria to define the β-thalassemia intermedia phenotype at presentation. All patients had pure β-globin gene mutations [IVS-I-6 (T>C), IVS-I-5 (G>C), IVS-II-1 (G>A), or Codon 39 (C>T)]. The current study utilized a completely de-identified dataset. Data were collected as part of now