Impact of iron overload and potential benefit from iron chelation in low-risk myelodysplastic syndrome

Abstract

Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron’s adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism–driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population.

Observational Monitoring of Patients with Aplastic Anemia and Low/Intermediate-1 Risk of Myelodysplastic Syndromes Complicated with Iron Overload

“…Repeated RBC transfusions or ineffective erythropoiesis, which can cause hemosiderosis in the absence of transfusion, can lead to rapid iron loading in patients with refractory AA or low/int-1 risk MDS [14,15]. Initially, liver parenchymal cells absorb excess iron, followed by absorption in other tissues.…”

Iron overload in patients with myelodysplastic syndromes: An updated overview

“…In addition, the authors documented a positive correlation between hepcidin and parameters of iron metabolism including ferritin and transferrin saturation when measured using an improved enzyme-linked immunoadsorbent assay, with a negative correlation with hemoglobin and transferrin. 35 Additional factors that exacerbate iron overload in specific MDS subtypes include the identification of concurrent HFE gene polymorphisms that affect up to 21% of patients with MDS-SLD-RS. 31 Thus, hepcidin is dominantly regulated by erythropoiesis, but is affected by the iron content in those patients with low transfusion requirements.…”

“…47 However, the most commonly adopted mechanism is the reduction in oxidative stress resulting from the decrease in iron content. Recent data have reported that patients with MDS have elevated levels of growth differentiation factor-11 (GDF11), a member of the transforming growth factor b (TGF-b) family that activates the SMAD pathway, 35 and has a suggested inhibitory role in late-stage erythroid maturation and differentiation. 48 The effect of iron chelation on oxidative stress measures such as LPI has been shown to precede the reduction in serum ferritin.…”

New insights into iron regulation and erythropoiesis

“…Improvements in hematological parameters in thalassemic mice were observed with transgenic overexpression of hepcidin [35], administration of minihepcidins [36], Tmprss6 ablation [37] or administration of Tmprss6 siRNAs [38 ■ ] or antisense oligos [39 ■ ]. A subset of myelodysplastic syndromes (MDS) is also characterized by ineffective erythropoiesis and iron overload toxicities, which can be attenuated with the use of chelating therapies [40]. It remains to be seen to what extent hepcidin suppression contributes to the iron overload and ineffective erythropoiesis in MDS.…”