Anemia, having low number of red blood cells (RBC), affects 80% of patients with MDS, with a substantial majority becoming dependent on transfusions to keep their counts up during their disease course. While RBC transfusions help improve anemia-related symptoms and quality of life for MDS patients, it can come at a price of iron deposition in the body over a short period of time. The amount of iron in a single RBC transfusion is the same as 1,280 cups of cooked spinach. The buildup of iron in the body begins early on in the disease process, even before there is need for RBC transfusions. It is thought that the bone marrow diseased with MDS decreases the liver’s production of a hormone called hepcidin. This then leads to an increase in absorption of iron in the small intestine. However, this way of building up iron is tiny in comparison to the amount of iron deposited through multiple RBC transfusions over time.
Iron overload (IO) can lead to organ damage. Several research studies have shown that MDS patients who need frequent RBC transfusions have a higher rate of heart failure, diabetes, shortness of breath, and infections when compared to MDS patients not requiring regular transfusions. The problem of IO is more important in patients with lower-risk MDS who are more dependent on regular RBC transfusions for anemia-related symptoms. While the total amount of iron deposited in the tissues play a role in tissue injury, the free and unbound form of iron (non-transferrin-bound iron or NTBI), particularly labile plasma iron (LPI), is thought to be the most toxic as it can enter cells and make damaging substances called reactive oxygen species. When taking care of MDS patients, ferritin levels in the blood have been used to estimate total amount of iron in the body. If a patient has a ferritin more than 1000 ng/ml, they are considered overloaded with iron. However, high ferritin levels can be misleading because any infection or inflammation in the body can make the number go up as well. More recently, magnetic resonance imaging (MRI) has been shown to be a more accurate and reliable way of measuring IO in organs such as the heart and liver.
Many researchers have asked if toxicity from IO in MDS patients affects their survival. Several studies, all looking back over many patients, have shown that a higher number of RBC transfusions and serum ferritin is related to worse survival. Whether or not this is a direct consequence of IO is a matter of intense debate. While some say the IO is damaging, others argue that anemia, leading to regular transfusions, and then IO, really just indicates a more aggressive MDS. Since many patients have other medical conditions with MDS, the excess deaths reported in these studies could be more of an effect of the transfusion-related IO making these other medical problems, such as heart failure, worse. The way to prove that iron is the culprit is to see if removing the excess iron makes patients with MDS live longer. Iron is removed by medications called iron chelators. Small studies looking back over patients have suggested that lower-risk MDS patients receiving iron chelators lived longer than those who did not. While at present we do not have rigorous data to confirm this reported benefit of iron chelation therapy in MDS, the prospective TELESTO trial (ClinicalTrials.gov Identifier: NCT00940602), is currently underway and will hopefully provide the answer to this question.
In summary, the “true” risk of iron-related complications, including worse survival, in MDS patients who receive regular RBC transfusions remain unclear. In absence of any prospective clinical trial data, careful judgment needs to be exercised by the treating physicians regarding the potential risks versus benefits of starting iron chelation medications in heavily transfused MDS patients.
Update: This review also includes the follow two projects as well as the one listed.