Iron chelation therapy in patients with myelodysplastic syndromes: consensus conference guidelines.

• Vol 10 • May 2008 374 The myelodysplastic syndromes are a group of clonal stem cell disorders, characterized by ineffective hematopoiesis, abnormal differentiation and maturation, qualitative hematopoietic cellular defects, peripheral cytopenias, and high incidence of leukemic transformation [1]. More than 90% of MDS patients have anemia, and many of them are symptomatic enough to require treatment [1,2]. Although, the introduction of recombinant human erythropoietin [3], and more recently thalidomide [4] and lenalidomide [5], have improved our therapeutic armamentarium for symptomatic anemia in MDS, red blood cell transfusion remains the gold standard therapy for most of these patients. From lessons we have learned while treating patients with thalassemia [6], and more recently with MDS patients [7,8], it is becoming clear that multiple blood transfusions − although correcting the hemoglobin and hematocrit, reducing blood transfusion requirements and improving quality of life − lead to iron accumulation and iron overload, eventually causing organ damage, especially in the heart, liver and endocrine glands [9,10]. However, most of the data were obtained from patients with thalassemia, who are younger than the MDS patients. Therefore, the consequences of iron overload might be somewhat different. A unit of packed RBC contains 250–300 mg iron. The iron assimilated by a single transfusion of two units of packed RBC is thus equal to a 1 to 2 year intake of iron. Iron accumulates in chronically transfused patients because the human body lacks an effective mechanism for increased iron excretion [11]. As iron loading progresses, the capacity of serum transferrin, the main transport protein of iron, to bind and detoxify iron may be exceeded. Consequently, the non-transferrin-bound fraction of iron and labile plasma iron within the plasma, which can be measured, may lead to the generation of free hydroxyl radicals, propagators of oxygen-related damage [12-14]. The effectiveness of an iron-chelating agent depends in part on its ability to bind NTBI over sustained periods, thereby ameliorating iron-catalyzed toxicity of free radicals [9]. In a retrospective analysis of 46 MDS patients who had received 50 units or more (range 50–150, mean 79) of RBC, 20 patients (43%) had cardiac hemosiderosis, 9 (20%) had arrhythmias, and 14 (30%) died of heart failure. In addition, 12 patients (26%) suffered from hepatic dysfunction, and 5 (11%) developed diabetes mellitus [15]. Taking into consideration that evidence-based medicine on this topic is limited, The MDS Foundation has initiated an international project and several parallel roundtable discussions were organized in different countries. The summarized consensus guidelines will be written and published by the MDS Foundation. Here, the summary of the Israeli panel is presented. In Israel, the consensus committee included experts in thalassemia (H.T., E.R.) having a broad experience with iron chelation therapy, iron experts (C.H.) and others interested in MDS (G.L., D.M., N.S., M.M., and E.R.). The conference was recorded and audio-taped (supported by an unrestricted grant from Novartis, Israel). The issues and relevant questions raised by The MDS Foundation and addressed by the expert panel are presented below.