Controversies on the Consequences of Iron Overload and Chelation in MDS.

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.