Transcript:David P. Steensma, MD: In patients with congenital anemias, like severe beta thalassemia, it’s clear that iron is a major contributor to morbidity and mortality. If you don’t adequately chelate patients with severe transfusion-defendant thalassemia, most of them will die in their teenage years or 20’s or 30’s of complications of cirrhosis of the liver, or liver cancer induced by iron overload, and cardiac defects of cardiomyopathy and electrical conduction problems. And less commonly, iron can also affect other tissues like the pituitary gland or the joints.

But in MDS, it’s not clear how those risks of iron overload compare with other risks of the disease, like disease progression due to increased blasts, or infection, which is the most common cause of death in patients with MDS. Although a low white count is the main driver of infection, iron could potentially contribute to infection in some situations. Many organisms are what’s called, siderophoric, which means that they grow well in an iron-rich environment. So, somebody with iron overload would be more likely to have certain types of fungal infections or bacterial infections. But balancing all of those risks is somewhat challenging. And so, MDS, because it is a cancer, it is a neoplasm. It’s a different situation from the inherited condition, the congenital beta thalassemia.

I think the difference between MDS and a disease like thalassemia, or some of the other inherited inborn anemias, is really two-fold. One is that these other disorders are not neoplasms. They’re not clonal disorders. The anemia and the iron are the major complications of the disease. So, you’re not thinking about, how does this fit in with the other potential problems that my patient could have. Those patients tend to be much younger as well, so they often don’t have a lot of other medical problems the way that our patients with MDS, whose median age is about 71 years, have.

The other difference is that in thalassemia in particular, there seems to be an innate drive of the gut to absorb iron due to the ineffective erythropoiesis in the bone marrow. And that seems to be a little bit less so in MDS. Most of the iron overload in MDS is things that we do to the patient, such as atherogenic from blood transfusions. Not all of it. There is some overlap certainly in the pathophysiology, but it is a little bit distinct from thalassemia. Some of those strategies that might be effective for thalassemia to turn that drive off are going to be less helpful in MDS.

The evidence for iron as a risk in MDS is strongest for the lower-risk disease types. That’s partly because they tend to live longer, so they have more chance over time to accumulate excess iron. And also, it’s a matter of competing risks. In the high-risk disease in the patients with refractory anemia with excess blasts or complex chromosomes, the disease itself moves so swiftly that patients don’t really have time to develop some of the complications of iron overload that may transpire only over years. And so, this is primarily a risk for patients with lower-risk disease. In fact, nobody’s been able to show that iron at least measured by serum ferritin levels matters in higher risk disease.

So, we’re mostly talking about patients with refractory anemia. Interestingly you’d expect patients with the MDS subtype refractory anemia with ring sideroblasts, or RARS, to run into the biggest problem with iron because they have an intrinsic defect in how their red blood cells process iron. However, the RARS population seems to be a little bit special in that people have not been able to show consistently that serum ferritin predicts outcomes in those patients. And iron overload seems to develop at a little bit of a different rate than we might expect.

There’s lots of other factors that determine how quickly iron accumulates in a patient. It’s very common, especially in people of Irish or other Northern European decent, to have a mutation in a gene called HFE, which contributes to hereditary hemochromatosis and promotes iron loading. It promotes accumulation of iron such that somebody who has one of these mutations in HFE is going to start at the time of diagnosis already with mild or moderate overload, or at least predisposed to get that. Whereas if you have someone who is iron deficient because they bleed-in or because in a woman she’s only recently stopped menstruating, then it’s going to take longer for such a person to accumulate iron.

The rate, at which transfusions are given, matters, too. So, if you’re someone who gets a transfusion once every 6 to 8 weeks, you’re much slower to accumulate iron than someone who’s getting 2 units of blood every week. There is a general correlation with the total number of red blood cell units administered, but it’s not perfect. There are people who have had 15 to 20 units of blood who already have substantial iron overload. There are people who have had 150 units of red cells who have minimal iron overload. So, everybody is a little bit different, which makes it challenging for us to think about who would be candidates for chelation therapy.

Transcript Edited for Clarity