Iron Overload in Myelodysplastic Syndromes: Pathophysiology, Consequences, Diagnosis, and Treatment

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms varying in severity affecting one or more lines of hematopoiesis. Ineffective erythropoiesis results in dysregulation of iron metabolism. Most MDS patients have anemia, and some require regular red blood cell transfusions. These transfusions, in addition to factors of the disease itself, can result in iron overload (IO). Retrospective analyses suggest that MDS patients with IO have reduced overall survival and poorer outcomes following allogeneic stem cell transplant vs. those without IO. Iron chelation therapy (ICT; deferoxamine, deferasirox, or deferiprone) has been used to alleviate IO in other transfusiondependent hematologic conditions (e.g., thalassemia), but its role in MDS has not been firmly established. A growing body of evidence suggests that ICT in MDS patients is an effective means for reducing transfusional IO and may significantly improve outcomes such as survival. The orally administered iron chelator deferasirox has been widely studied in MDS, and available studies have shown it to be generally well tolerated and effective in reducing IO in this population. The pathophysiology and clinical consequences of IO in MDS, as well as current methods for diagnosing and treating IO in these patients, are discussed.

Understanding iron homeostasis in MDS: the role of erythroferrone

“…ERFE expression was increased in all MDS subtypes compared to healthy controls, but was specifically pronounced in cases with ring sideroblasts (MDS-RS-SLD and MDS-RS-MLD). This data is in line with the observation that MDS-RS patients already present with elevated levels of ferritin before they become transfusion dependent ( 16 ).…”

Bone marrow transplantation reduces FGF-23 levels and restores bone formation in myelodysplastic neoplasms

“…Therefore, other signals or cells within the bone microenvironment or beyond may participate in this regulation. In line with this, it has been shown that FGF-23 production/cleavage can be triggered by erythropoietin, iron deficiency, anemia, and inflammation [8][9][10], factors that also play a role in MDS [11,12]. While iron serum levels are unchanged in NHD13 mice, erythropoietin is upregulated.…”

Controversies on the Consequences of Iron Overload and Chelation in MDS

“…Blood transfusions remain the dominant cause of iron overload in MDS patients. 44,45 Especially for patients suffering from lowrisk or intermediate-1-risk MDS, the improvement of anemia through RBC transfusions is a central point of supportive care. 7 Iron overload can develop rapidly as every unit of transfused blood contains about 200 to 250 mg of iron, whereas natural iron losses reach only 1 to 2 mg daily.…”

“…Blood transfusions remain the dominant cause of iron overload in MDS patients 44,45 . Especially for patients suffering from low‐risk or intermediate‐1‐risk MDS, the improvement of anemia through RBC transfusions is a central point of supportive care 7 .…”

“…Importantly, several studies have now shown that iron chelation improves survival in transfusion‐dependent MDS. (Table 1) 44 Besides an ameliorated erythropoietic response, the therapeutic benefit of iron chelation in MDS might be mediated by substantial improvements in the functions of tissue which are significantly affected by iron overload, as described in the next sections.…”