To the Editor: Aplastic anemia (AA) is a rare hematologic disease characterized by immune mediated bone marrow failure with consequent life-threatening cytopenias. Most AA patients are heavily transfusion-dependent of both platelets and red blood cells, and iron overload may become an issue. There is increasing evidence that excess iron may hamper the function of several organs (liver, heart, kidney, and endocrine system), but also have a negative effect on normal hematopoiesis. This is harmful in various diseases, including hemoglobinopaties, myelodysplastic syndromes, and myelofibrosis, but may be particularly detrimental in AA, where residu al normal hematopoiesis is even poorer. The thrombopoietin (TPO) analogue eltrombopag (EPAG) has been shown to improve hematopoiesis in 40% to 45% of patients with both relapsed/refractory and newly diagnosed AA. 1, 2 The trilineage response observed is linked to a direct effect on hematopoietic stem cells expressing TPO-receptor. In addition to bone marrow stimulation, recent reports demonstrated iron-mobilizing activity of the EPAG in vitro. 3 Furthermore, data from two trials of severe and moderate AA cases showed harmonic oscillation of serum ferritin, concomitant to EPAG initiation and discontinuation, indicating an iron mobilization effect also in vivo. 4 Here we report iron status dynamics in a real life series of 10 AA patients treated with EPAG and prospectively followed at our Institution (from August 2000 until May 2019). Furthermore, we describe an emblematic case, where EPAG combined to iron chelation seemed to modify outcome. Figure 1A shows hematologic parameters and iron status at baseline and at various time points during EPAG treatment. At the time of drug initiation, six cases presented severe AA according to Camitta criteria, and transfusion dependence (TD) was recorded in 60% of patients. Three patients were therapy naïve and received EPAG (150 mg/day since day+ 14) together with frontline immunosuppression; seven cases were relapsed/refractory, previously treated with anti-thymocyte globulin (ATG) and cyclosporine (2), cyclosporine alone (2), and steroids only (2). Median age was 43 years (23-91), and male to female ratio 1: 1. Median time from diagnosis to EPAG start was 5.36 months (1-137).

Hb, neutrophils, and platelets values significantly ameliorated from baseline to month+ 3, and during follow up. Mean increase from baseline was 0.7±1.6 g/dL for Hb, 0.3±0.48× 109/L for neutrophils, and 27±38× 109/L for platelets. Of note, transfusion requirement was progressively lost, and overall response rate progressively ameliorated from 56% at month+ 3 to 100% at month+ 6 and thereafter, although complete response was observed in two patients only. Ferritin values increased from baseline to month+ 1 (P=. 04), and iron and transferrin saturation were persistently augmented at month+ 1,+ 3, and+ 6 vs baseline (P=. 01, P=. 03, P=. 04, respectively). Iron chelation was performed in two cases starting from month+ 6, possibly accounting for the decrease of all iron parameters observed at month+ 12. To exclude the confounding effect of iron chelation and transfusions, we separately analyzed TD and non-TD cases excluding the two chelated ones (Figure 1A). Both groups showed the same trend with initial increase of serum iron and transferrin saturation, followed by a progressive decrease. Notably, ferritin levels showed an earlier reduction from month+ 3 onwards, with a delta decline greater than 100%(Figure 1B). These trends are consistent with an effect of EPAG on iron mobilization in both TD and non-TD cases. Figure 1C shows hematologic and iron …