Controversies on the Consequences of Iron Overload and Chelation in MDS

Abstract

Many patients with MDS are prone to develop systemic and tissue iron overload in part as a consequence of disease-immanent ineffective erythropoiesis. However, chronic red blood cell transfusions, which are part of the supportive care regimen to correct anemia, are the major source of iron overload in MDS. Increased systemic iron levels eventually lead to the saturation of the physiological systemic iron carrier transferrin and the occurrence of non-transferrin-bound iron (NTBI) together with its reactive fraction, the labile plasma iron (LPI). NTBI/LPI-mediated toxicity and tissue iron overload may exert multiple detrimental effects that contribute to the pathogenesis, complications and eventually evolution of MDS. Until recently, the evidence supporting the use of iron chelation in MDS was based on anecdotal reports, uncontrolled clinical trials or prospective registries. Despite not fully conclusive, these and more recent studies, including the TELESTO trial, unravel an overall adverse action of iron overload and therapeutic benefit of chelation, ranging from improved hematological outcome, reduced transfusion dependence and superior survival of iron-loaded MDS patients. The still limited and somehow controversial experimental and clinical data available from preclinical studies and randomized trials highlight the need for further investigation to fully elucidate the mechanisms underlying the pathological impact of iron overload-mediated toxicity as well as the effect of classic and novel iron restriction approaches in MDS. This review aims at providing an overview of the current clinical and translational debated landscape about the consequences of iron overload and chelation in the setting of MDS.

The Clinical Significance of Iron Overload and Iron Metabolism in Myelodysplastic Syndrome and Acute Myeloid Leukemia

“…Iron deficiency resulting in microcytic anemia due to impaired hemoglobin production is a common nutritional deficiency disorder affecting especially women and children worldwide. As a consequence of iron overload, dysplastic changes and detrimental effects on erythroblast differentiation and maturation resulting in a reduction of the proliferative capacity of erythropoiesis and of erythroblast apoptosis in vitro have been described (3,23). Additionally, iron overload has been shown to induce growth arrest and cell death due to oxidative stress via ROS-mediated activation of p38MAPK, JNK and p53 pathways in immature hematopoietic cells (24,25).…”

“…MDS and AML patients may develop primary iron overload arising from insufficient erythropoiesis (3). Repeated transfusions, which aim at ameliorating the symptoms of anemia, often lead to secondary iron overload.…”

EnvIRONmental Aspects in Myelodysplastic Syndrome

“…However, some of these studies draw their conclusions based on the effects and outcome after therapy with iron chelation. Considering the potential effects of iron chelation besides iron-binding, these results must be interpreted with caution, and prospective trials are needed to better clarify this issue [ 44 , 85 ].…”

“…In the last decade, the understanding that iron overload is not just a bystander due to multiple RBC transfusions but also has multiple implications for the disease has steadily increased. Many reviews exist on the clinical outcome and implication of iron overload in MDS, on which we will only touch superficially in this review [ 2 , 43 , 44 ]. Herein we particularly focus on molecular aspects related to iron metabolism in MDS and discuss relevant, partly yet unanswered questions related to iron overload and MDS.…”

Eltrombopag and its iron chelating properties in pediatric acute myeloid leukemia

“…In particular, in literature it is reported a strong correlation between iron excess and cancer onset and progression [ 9 ], since the great request showed from cancer cells to sustain their metabolic processes. In AML iron overload is very frequent and could be defined as “primary”, due to deficit in erythropoiesis, or “secondary”, related to the repeated red blood cells transfusions principally aimed to counteract anemia [ 10 ]. Anyway, this condition has been seen to worsen AML symptoms, contributing to bone marrow failure [ 11 ] and to immune response decrease [ 12 ].…”