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Iron overload in Myelodysplastic Syndrome (MDS). Is there a rationale for treatment?

June 2007

Eliezer A. Rachmilewitz. Head Hematology Department, The Edith Wolfson Medical Center, Holon, Israel.

Low risk myelodysplastic syndrome (MDS) is characterized by decrease in all blood cells – red cells, platelets and white cells, due to their ineffective production in the bone marrow. The production of red blood cells is usually most affected in the early stages of the disease, resulting in anemia with all the clinical consequences, tiredness, shortness of breath etc... In cases with severe anemia (hemoglobin level less than 9 grams/dl), therapeutic blood transfusions are indicated and result in the accumulation of large quantities of iron which is defined as iron overload. For instance, a patient receiving two blood units per month, will receive about 100 units every 4 years. Although transfusion therapy is the main cause for iron overload in MDS, it is not the only contributing factor. This could be in part due to increased intestinal iron absorption, either by ineffective production and consequent destruction of red blood cells, less oxygen, or due to low levels of a protein - hepcidin that have been documented in MDS, which is the protein regulating iron absorption from the intestines.

Another measurable parameter resulting from iron overload are circulating forms of free iron, termed “non-transferring bound iron” (NTBI) which were found to be increased in MDS, and are taken up more readily by tissues. This fraction of free iron is toxic by promoting formation of oxygen radicals which are very toxic, since they oxidize major components in the cells, mainly the membranes and result in ineffective production of red blood cells and premature death resulting in iron accumulation in several tissues including liver and heart. Following these observations, it has been shown that in patients with MDS, generation of free oxygen radicals were found in red cells, platelets and leukocytes, concomitant with decrease in the enzymes which protect them from damage induced by the oxygen radicals.

It has been shown that drugs which are capable to get rid of the excess iron known as iron chelators were also capable of neutralizing the toxic effects of free oxygen radicals

Cardiovascular T2* magnetic resonance imaging (MRI)is a new imaging technique which allows estimation of iron in the heart and liver and is now used to measure and monitor iron overload in patients with MDS. Surprisingly, when this method was applied to measure degree of iron overload in 10 transfused MDS patients who received an average of 90 blood units, iron overload was found in the liver of all of them, but not in the heart, unlike in other diseases associated with iron overload. It is possible that in MDS more time and more transfusions are required to induce iron accumulation in the myocard.

However, even without excess amounts of iron in the heart measured by T2* MRI, treatment with drugs to eliminate excess of iron and the consequent generation of oxygen radicals might be justified in order to get rid of the toxic species of iron. A new oral iron chelator (Exjade) is now available, which is much more convenient for the patient compared with a previous drug which was administered through a needle. In any case, scanning the heart in more MDS patients is required since it may show iron deposition especially in those receiving more transfusions for a longer period of time.