Improvement of Oxidative Stress Parameters in MDS Patients with Iron Overload Treated with Deferasirox

Abstract

Introduction: Using flourescence markers, evidence for oxidative stress has been documented by flow cytometry in red cells (RBC) and other blood cells of patients with congenital and acquired hemolytic anemias (e.g. thalassemia, sickle cell anemia, hereditary spherocytosis and paroxysmal nocturnal hemoglobinuria) as well as in myelodysplatic syndrome (MDS) (Eur. J. Hematol. 79:463,2008). These data included increased generation of reactive oxygen species (ROS) concomittant with a decrease in the cellular content of the major antioxidant reduced gluthatione (GSH), and increased membrane lipid peroxidation. Oxidative stress in these anemias is thought to be mainly due to the accumulation of non-transferrin-bound iron (NTBI) which affects iron homeostasis and results in excess extra-cellular and intra-cellular labile pools: labile plasma iron (LPI) and cellular labile iron pool (LIP) (Cytometry 73:22,2008), respectively, catalyzing ROS generation. The presence of these free iron components is correlated with the severity of hemolysis and the subsequent repetitive blood transfusions, resulting in iron-overload. The purpose of the present study was to measure changes in parameters of iron-overload and oxidative stress in iron-overloaded patients with MDS following treatment with the oral iron-chelator Deferasirox.Patients and Methods: Fifteen patients–5 males and 10 females-(mean age 66 ± 13 years) with “low risk” MDS (IPSS < 1.0) received Deferasirox 20 mg/kg/day (12 patients) or 4–6 mg/kg/day (3 patients) due to side effects mainly gastrointestinal, increased creatinine and rash, for an average period of 95 days (63–163 days). All of them had evidence of iron-overload. Their mean number of transfusions was 65 ± 62, and mean ferritin levels before treatment was 3008 ± 1797 ng/ml. ROS, GSH, lipid peroxidation, LIP and LPI were measured every 3–4 weeks, in RBC, platelets and polymorphonuclear leukocytes (PMN). Blood cell counts, hemoglobin levels and serum ferritin were assayed simulteneously.Results: There was a statistically significant decrease in ROS (28%, p=0.006), lipid peroxidation (138%, p=0.008) and the LIP (23%, p=0.004) of RBC, concomittant with an increase in GSH (123%, p=0.001). GSH was also increased in platelets (48%, p=0.008) and PMN (72%, p=0.001), and LIP decreased in platelets (23%, p=0.004). In 8 patients the mean initial LPI levels of 0.39 units decreased to 0.12 units (p=0.028). There were no significant changes in hemoglobin levels or in any of the other types of blood cells. Mean serum ferritin levels increased in 8 patients by 964 ± 927 ng/ml and decreased in the rest by 1432 ± 1267 ng/ml.Discussion: The results clearly demonstrate that administration of Deferasirox to iron-overloaded MDS patients for a mean period of 3 months resulted in a significant decrease in parameters of oxidative stress mainly in RBC and platelets and in intra-(LIP) and extra-cellular (LPI) species of free iron. Serum ferritin, a major parameter in the assessment of the severity of iron-overload, was increased in 8 patients in the present study, similar to previously reported findings of increased ferritin levels at 12 months following iron chelation with Deferasirox (Am. J. Hematol. 83:611–3, 2008). However, unlike iron stored in ferritin, the major risk of iron-overload is the presence of excess extra and intracellular iron species (LPI and LIP) which are playing an important role in ROS generation and consequent membrane damage in blood cels and in other major organs.. These preliminary data suggest that treatment with Deferasirox, a once-a-day oral iron chelator, reduced the toxic iron species and several parameters of oxidative stress in iron overloaded MDS patients. Furthermore, the novel methodologies applied in this study may be useful for evaluating the severity of the iron-overload and for monitoring the efficacy of iron chelation therapy. Additional studies assessing the correlation of these changes to the long-term morbidity, mortality, and quality of life are definitely warranted in this patient population.