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Excess Iron in MDS

Insights From:Thomas Prebet, MD, PhD, Yale Cancer Center; Heather Leitch, MD, PhD, St. Paul’s Hospital;Vinod Pullarkat, MD, City of Hope Medical Center
Published: Tuesday, Oct 18, 2016


Transcript:

Heather Leitch, MD, PhD:
One of the things that’s difficult for patients to understand about iron is there really aren’t any acute adverse effects of iron overloads. So, it’s not something they can feel that’s adversely affecting them until we know things are really out of control. The long-term effects, however, are inevitable. And so, these include not only iron overload in the organs such as the liver and the heart, which can lead to organ failure, it also can be detrimental to the endocrine organs and the bone marrow, leading to worsening of bone marrow failure. But other long-term effects that we think are relevant in MDS with iron overload, besides affecting the organs and bone marrow failure, include a possible effect on infections risk, possible acceleration of AML development, and a possible decrease in overall survival. This has been shown in multiple analyses, although these analyses are noncontrolled and we’re waiting for results from randomized trials.

Vinod Pullarkat, MD: The acute toxicity of iron overload is cardiac toxicity, and, fortunately, in MDS patients, cardiac iron is rare. It only occurs in patients who have had a lot of transfusions, typically age 75 or more. So, heart failure is one of the acute manifestations. I think one of the under recognized manifestations of iron overload is infection, and there are various studies in other iron overloaded states that show that iron overload does predispose those patients to infection. And MDS patients have abnormalities in their immune system; they have low white count. So, this is not a well-studied complication, but I would consider infection as an acute complication of iron overload. The chronic toxicity of iron overload is, again, in the heart and endocrine glands. Endocrine dysfunction can occur if the patients live long enough to experience those side effects. And cardiac toxicity, like I say, when they require a lot of transfusions, can be a manifestation of iron overload.

Thomas Prebet, MD, PhD: It is important to talk about iron overload, but we need to discuss, what are the consequences of iron overload. It has some negative consequences for the patients. What has been shown basically for myelodysplastic syndromes is that an increased ferritin level is associated with an increased mortality. And this increased ferritin level, obviously, is associated with an increased transfusion rate for most of the patients.

The question that comes now is what are the patients dying from? And basically what has been shown is most of these patients are dying of complications of the cytopenias, but also have an increased risk of cardiac events. So, that’s one of the potential direct consequences that we can associate with iron overload in transfusion. Both anemia and transfusion in that case can increase the risk of having cardiac events for these patients.

Obviously, iron deposition is not limited to the heart. We also have some potential consequences for the liver, for example, and we can have some signs of hepatic dysfunction because of the iron overload. What we can see for patients with primary hemochromatosis, we can also have some other depositions of iron; for example, the skin, thyroid, etc.

Heather Leitch, MD, PhD: I think we can learn a lot from the hereditary anemias in terms of iron overload, and this is, of course, where the iron overload was first described and addressed. But there are differences between hereditary iron overload and acquired anemias. And so, in thalassemia for example, we don’t have the underlying genomic instability that we do in MDS and other acquired anemias. These patients are not prone to AML evolution, for example, from iron overload, or from other factors. But the organ toxicity and the effect on survival is very well documented in thalassemia patients. Thalassemia patients, or with other acquired anemias, are also prone to increased GI iron absorption. In thalassemia intermedia, for example, patients do develop significant iron overload despite not being transfusion-dependent because they have decreased hepcidin levels, which allow increased GI absorption of iron over time.

Historically, I think there’s a bit of disconnect between hematologists who treat benign conditions and hematologists who treat malignant conditions. And so the hematologists that treat the congenital anemias know a lot about iron overload and managing iron chelation therapy. But for hematologists like myself that trained mostly in malignancy hematology, our experience with that and our comfort level with iron overload in iron chelation therapy may not be as great.

I think it’s very important to think about iron overload in our MDS patients. It’s a bit of a learning curve, maybe, for this generation of hematologists, myself included. I think we do have a responsibility not only to our patients, but also for the generation of hematologists that we’re training to learn how to manage iron overload appropriately in patients with acquired anemias.

Transcript Edited for Clarity
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Transcript:

Heather Leitch, MD, PhD:
One of the things that’s difficult for patients to understand about iron is there really aren’t any acute adverse effects of iron overloads. So, it’s not something they can feel that’s adversely affecting them until we know things are really out of control. The long-term effects, however, are inevitable. And so, these include not only iron overload in the organs such as the liver and the heart, which can lead to organ failure, it also can be detrimental to the endocrine organs and the bone marrow, leading to worsening of bone marrow failure. But other long-term effects that we think are relevant in MDS with iron overload, besides affecting the organs and bone marrow failure, include a possible effect on infections risk, possible acceleration of AML development, and a possible decrease in overall survival. This has been shown in multiple analyses, although these analyses are noncontrolled and we’re waiting for results from randomized trials.

Vinod Pullarkat, MD: The acute toxicity of iron overload is cardiac toxicity, and, fortunately, in MDS patients, cardiac iron is rare. It only occurs in patients who have had a lot of transfusions, typically age 75 or more. So, heart failure is one of the acute manifestations. I think one of the under recognized manifestations of iron overload is infection, and there are various studies in other iron overloaded states that show that iron overload does predispose those patients to infection. And MDS patients have abnormalities in their immune system; they have low white count. So, this is not a well-studied complication, but I would consider infection as an acute complication of iron overload. The chronic toxicity of iron overload is, again, in the heart and endocrine glands. Endocrine dysfunction can occur if the patients live long enough to experience those side effects. And cardiac toxicity, like I say, when they require a lot of transfusions, can be a manifestation of iron overload.

Thomas Prebet, MD, PhD: It is important to talk about iron overload, but we need to discuss, what are the consequences of iron overload. It has some negative consequences for the patients. What has been shown basically for myelodysplastic syndromes is that an increased ferritin level is associated with an increased mortality. And this increased ferritin level, obviously, is associated with an increased transfusion rate for most of the patients.

The question that comes now is what are the patients dying from? And basically what has been shown is most of these patients are dying of complications of the cytopenias, but also have an increased risk of cardiac events. So, that’s one of the potential direct consequences that we can associate with iron overload in transfusion. Both anemia and transfusion in that case can increase the risk of having cardiac events for these patients.

Obviously, iron deposition is not limited to the heart. We also have some potential consequences for the liver, for example, and we can have some signs of hepatic dysfunction because of the iron overload. What we can see for patients with primary hemochromatosis, we can also have some other depositions of iron; for example, the skin, thyroid, etc.

Heather Leitch, MD, PhD: I think we can learn a lot from the hereditary anemias in terms of iron overload, and this is, of course, where the iron overload was first described and addressed. But there are differences between hereditary iron overload and acquired anemias. And so, in thalassemia for example, we don’t have the underlying genomic instability that we do in MDS and other acquired anemias. These patients are not prone to AML evolution, for example, from iron overload, or from other factors. But the organ toxicity and the effect on survival is very well documented in thalassemia patients. Thalassemia patients, or with other acquired anemias, are also prone to increased GI iron absorption. In thalassemia intermedia, for example, patients do develop significant iron overload despite not being transfusion-dependent because they have decreased hepcidin levels, which allow increased GI absorption of iron over time.

Historically, I think there’s a bit of disconnect between hematologists who treat benign conditions and hematologists who treat malignant conditions. And so the hematologists that treat the congenital anemias know a lot about iron overload and managing iron chelation therapy. But for hematologists like myself that trained mostly in malignancy hematology, our experience with that and our comfort level with iron overload in iron chelation therapy may not be as great.

I think it’s very important to think about iron overload in our MDS patients. It’s a bit of a learning curve, maybe, for this generation of hematologists, myself included. I think we do have a responsibility not only to our patients, but also for the generation of hematologists that we’re training to learn how to manage iron overload appropriately in patients with acquired anemias.

Transcript Edited for Clarity
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