The Effect of Treatment With the Oral Iron Chelator Deferiprone on the Oxidative Stress of Blood Cells and on Iron Overload Status in Transfusion Dependent, Iron-overloaded Patients With Low Risk Myelodysplastic Syndrome

INTRODUCTION 1.1 Background Myelodysplastic syndrome (MDS) is characterized by deficiencies in blood cell production that can lead to anemia, which may necessitate regular transfusions of red blood cells (RBCs) as supportive therapy. While this treatment can be life-saving, since the body has no natural means of removing the excess iron introduced through the intake of RBCs, a consequence can be accumulation of excess iron, including labile iron, in the plasma (as labile plasma iron, LPI, the pathological form of non-transferrin-bound iron) and in cells. The cellular labile iron pool (LIP) is known to participate in biochemical reactions that generate free oxygen radicals, resulting in oxidative stress and cell and tissue damage. A certain percentage of patients with MDS develop signs and symptoms resulting from iron overload، and oxidative stress markers have been observed in the blood cells of such patients. Progressive iron overload can lead to organ toxicity and cardiac disease. Reduction of LIP would reduce the generation of tissue-damaging free oxygen radicals and thereby help prevent morbidity and mortality; however, iron chelation therapy has not been part of the standard of care for this population. It should be noted that While the LPI level provide a momentarily "snapshot" of the iron status and it rapidly changes due to nutrition, transfusion or chelation, the LIP represent long-term accumulation. Both parameters complement each other in analogy to hemoglobin A1C and glucose measurements in patients with Diabetes mellitus).

There has been some exploration of the use of the oral iron chelators deferasirox and deferiprone in MDS patients , with indications of efficacy as assessed by iron reduction, decreased need for transfusions, or increased survival. However, it is difficult to draw clear conclusions from the literature as there was high variability in these investigations, not only in type of chelator but in study design, severity of disease, and endpoints studied. The safety profiles reported in the literature for MDS patients are similar to those seen in thalassemia patients. However, for patients at later stages of the disease who are at high risk of death from AML or other causes within 5 years, the benefit of chelation may be minimal. What emerges from the literature is that because of the progression of the disease, iron chelation is likelier to be of more benefit to patients with a less severe form of MDS who have an expectation of 5 years or more of survival but who also have the likelihood of long-term RBC transfusion dependency, with the accompanying risk of iron overload.

1.2 Deferiprone Deferiprone (active ingredient 3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate iron chelator that preferentially binds trivalent iron (Fe3+) in a 3:1 (deferiprone : iron) complex. Its effectiveness in the treatment of patients with iron overload has been assessed by urinary iron excretion, sequential measurements of serum ferritin levels, iron concentration in the liver and in the heart, and clinical outcomes such as the ability to prevent iron-induced cardiac disease and prolong survival in transfused patients with thalassemia.

1.2.1 Side effects of Deferiprone The safety profile of deferiprone in patients with thalassemia has been extensively characterized in clinical trials. Based on the Summary of Product Characteristics,apart from chromaturia, which is due to iron excretion and is harmless, the most commonly reported adverse events seen in clinical trials have been nausea, vomiting, abdominal pain, increased alanine aminotransferase, arthralgia, and neutropenia, defined as a confirmed absolute neutrophil count (ANC) less than 1.5×109/L. The most significant serious adverse event (SAE) associated with deferiprone use is severe neutropenia, also known as agranulocytosis, which is defined as a confirmed ANC less than 0.5×109/L.

In a clinical trial in which 19 multi-transfused MDS patients were treated with the oral iron chelator deferasirox for 3 months, a significant decrease in free iron species was observed in the plasma and cells, which was associated with amelioration of the parameters of oxidative stress. Another finding was a gradual increase in the levels of the iron regulatory hormone hepcidin, which could also reflect amelioration of oxidative stress. However, many MDS patients, particularly older ones, are unable to tolerate treatment with deferasirox, mainly due to renal and/or gastrointestinal side effects. The proposed clinical trial is a similar study that will look at the safety and efficacy of deferiprone in iron overloaded, blood dependent MDS patients.