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MDS and Iron Overload: An Argument for Iron Chelation Therapy

Panelists:James M. Foran, MD, FRCPC, Mayo Clinic Cancer Center; Azra Raza, MD, Columbia University Medical Center; David P. Steensma, MD, Dana-Farber Cancer Institute
Published: Monday, May 23, 2016


Transcript:

James M. Foran, MD, FRCPC:
Do you think that iron overload in MDS differs compared with other diseases like thalassemia?

Azra Raza, MD: Not really, because iron overload is iron overload. It is an additional reason to be more aggressive in MDS, as it can actually affect underlying disease. A third of the patients improve their cytopenias when their ferritin level comes down. That’s very important. A number of patients become transfusion-independent just with iron chelation therapy and no other treatment. So, in other words, iron chelation is actually having an effect on the underlying disease. And James, this should not be frowned upon, that, “Oh, there is no prospective trial to say that.”

Why I say it is because everybody is now beginning to realize that iron metabolism is disturbed in cancers-at-large. In fact, iron chelation is now being proposed for solid tumors where there is no transfusion history because their ferritin levels can be very high. And you need to really think of disturbed iron metabolism now in a larger perspective, rather than just the iatrogenic perspective we have been talking about. But even with the iatrogenic, where we are giving transfusions, causing iron overload, reducing that iron overload improves their underlying cytopenias. And I think that’s how this MDS iron overload differs from thalassemia and sickle cell, where iron chelation is not going to improve their disease because they have genetic diseases.

James M. Foran, MD, FRCPC: Yes. I’ve heard it said that iron overload in a young person or a developing body may have a more deleterious effect, but I think we have a lot of evidence in the adult population of the deleterious effect. And I think sometimes it’s just the finite lifespan of the patient after diagnosis that makes people not focus upon this and not try to improve the quality of the care or the quality of the outcome.

It’s interesting how the science in MDS has led the way in several fields. I think it was really the first disease that showed that aberrant methylation was common. And now looking at chelation and seeing how that’s spilling into other areas for investigation is fascinating. But we do suffer from a lack of data, and so I hope we’ll be able to get the kind of prospective data that we need to really change practice, because right now, some people would consider it anecdotal. And, unfortunately, there’s a religious aspect to it where some are believers and some are not. But I think it’s an important part of the quality of care.

I don’t know what physicians say to their patients when they’re not chelating them, and how they say, “Well, your ferritin is 3000 but we’re not going to address that.” I think it’s something that has to at least be discussed and addressed with the patient to educate them. Do you start with an oral chelator then? Do you start with deferasirox?

Azra Raza, MD: I mean, that’s a no-brainer. The subcutaneous, intravenous, really doesn’t work as well. The subcutaneous pump is very uncomfortable. Patients can get it. I mean, I used it for so long before these oral chelators became available, so yes. By the way, before I answer this further, I want to say how much I appreciate you saying that MDS can lead the way into understanding many other malignancies. The reason I dedicated myself to studying this disease with complete focus and energy for the rest of my life was because I did feel it is a window on understanding how a pre-leukemia cell becomes a fully malignant, leukemic cell. If we could understand what accounts at the molecular genetic level for that switching, we may be able to understand how a normal cell becomes a malignant cell and understand the underlying basis of many cancers—because nature is parsimonious. It may be the same algorithm, if not universally, for all cancers, for many cancers. So, I’m so glad you have vindicated me today by saying MDS provides the lead into many studies in cancers.

James M. Foran, MD, FRCPC: I think it has, and we’ll come back to that point because I want to talk about some of the evolving science with next-generation sequencing and some of the mutations. To get back to your point about the no-brainer, I agree with you, and I think deferasirox is the obvious first choice. There’s a recent new formulation that was FDA-approved this year for use. Have you changed your practice with that? Are you still giving the Exjade or have you moved over to the Jadenu formulation? Do you have any opinion about that?

Azra Raza, MD: Once again, it’s a no-brainer because the newer formulation is so much easier to take. You can take it with food. You don’t have to starve for 2 hours before you take the medication. It’s much easier on the GI tract. I have patients who are so happy with the switch. So, I think, universally, the switch from Exjade to Jadenu has been very welcomed by the patients and very much recommended by me. And yes, the answer is, I have switched everybody over.

James M. Foran, MD, FRCPC: I’ve heard it said that there’s a concern the toxicity will be ironically, or paradoxically, greater with Jadenu than with the Exjade formulation because patients will actually be able to tolerate it. There actually will be adherence. They will comply with it, and it might ultimately increase the side-effect profile just because they’re able to be on it for a reasonable or extended period of time. So, I would say it matters to manage the other toxicities. If somebody is only on Exjade for 4 months or 6 months and they can’t take it, then you’re not always following for retinopathies, you’re not always following the creatinines closely, or you’re not always tracking for the toxicities. I would say that if people will tolerate the Jadenu better, which I agree is likely, then you have to have a monitoring plan in place to watch for those side effects, because there are toxicities of the drug.

Azra Raza, MD: Yes. This is why my policy is to start early, stop when the ferritin level falls below 500, and then give the patient a break from any chelation for 6 to 12 months. Then when their ferritin rises up again, then you start early again. But if you wait until the ferritin level is 5000 before instituting chelation then, yes, you are going to end up having to give a lot of these drugs and then end up with toxicity. So, I do think it’s very important to emphasize early intervention with chelation and then to try to give it intermittently.

James M. Foran, MD, FRCPC: I heard you say that you start it at a low dose and try to work your way up. That’s not the label to do that.

Azra Raza, MD: I said you can start at a low dose and work up or start at a high dose and dose de-escalate. That’s what I really meant.

James M. Foran, MD, FRCPC: I didn’t mean to put words in your mouth, because that’s something that we’ve done in our practice, as well. We start at a low dose and work our way up, over a couple of months, to tolerability—just while we’re monitoring for side effects—and then look for efficacy afterwards just to increase adherence to therapy. So, we do a similar kind of strategy.

Transcript Edited for Clarity
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Transcript:

James M. Foran, MD, FRCPC:
Do you think that iron overload in MDS differs compared with other diseases like thalassemia?

Azra Raza, MD: Not really, because iron overload is iron overload. It is an additional reason to be more aggressive in MDS, as it can actually affect underlying disease. A third of the patients improve their cytopenias when their ferritin level comes down. That’s very important. A number of patients become transfusion-independent just with iron chelation therapy and no other treatment. So, in other words, iron chelation is actually having an effect on the underlying disease. And James, this should not be frowned upon, that, “Oh, there is no prospective trial to say that.”

Why I say it is because everybody is now beginning to realize that iron metabolism is disturbed in cancers-at-large. In fact, iron chelation is now being proposed for solid tumors where there is no transfusion history because their ferritin levels can be very high. And you need to really think of disturbed iron metabolism now in a larger perspective, rather than just the iatrogenic perspective we have been talking about. But even with the iatrogenic, where we are giving transfusions, causing iron overload, reducing that iron overload improves their underlying cytopenias. And I think that’s how this MDS iron overload differs from thalassemia and sickle cell, where iron chelation is not going to improve their disease because they have genetic diseases.

James M. Foran, MD, FRCPC: Yes. I’ve heard it said that iron overload in a young person or a developing body may have a more deleterious effect, but I think we have a lot of evidence in the adult population of the deleterious effect. And I think sometimes it’s just the finite lifespan of the patient after diagnosis that makes people not focus upon this and not try to improve the quality of the care or the quality of the outcome.

It’s interesting how the science in MDS has led the way in several fields. I think it was really the first disease that showed that aberrant methylation was common. And now looking at chelation and seeing how that’s spilling into other areas for investigation is fascinating. But we do suffer from a lack of data, and so I hope we’ll be able to get the kind of prospective data that we need to really change practice, because right now, some people would consider it anecdotal. And, unfortunately, there’s a religious aspect to it where some are believers and some are not. But I think it’s an important part of the quality of care.

I don’t know what physicians say to their patients when they’re not chelating them, and how they say, “Well, your ferritin is 3000 but we’re not going to address that.” I think it’s something that has to at least be discussed and addressed with the patient to educate them. Do you start with an oral chelator then? Do you start with deferasirox?

Azra Raza, MD: I mean, that’s a no-brainer. The subcutaneous, intravenous, really doesn’t work as well. The subcutaneous pump is very uncomfortable. Patients can get it. I mean, I used it for so long before these oral chelators became available, so yes. By the way, before I answer this further, I want to say how much I appreciate you saying that MDS can lead the way into understanding many other malignancies. The reason I dedicated myself to studying this disease with complete focus and energy for the rest of my life was because I did feel it is a window on understanding how a pre-leukemia cell becomes a fully malignant, leukemic cell. If we could understand what accounts at the molecular genetic level for that switching, we may be able to understand how a normal cell becomes a malignant cell and understand the underlying basis of many cancers—because nature is parsimonious. It may be the same algorithm, if not universally, for all cancers, for many cancers. So, I’m so glad you have vindicated me today by saying MDS provides the lead into many studies in cancers.

James M. Foran, MD, FRCPC: I think it has, and we’ll come back to that point because I want to talk about some of the evolving science with next-generation sequencing and some of the mutations. To get back to your point about the no-brainer, I agree with you, and I think deferasirox is the obvious first choice. There’s a recent new formulation that was FDA-approved this year for use. Have you changed your practice with that? Are you still giving the Exjade or have you moved over to the Jadenu formulation? Do you have any opinion about that?

Azra Raza, MD: Once again, it’s a no-brainer because the newer formulation is so much easier to take. You can take it with food. You don’t have to starve for 2 hours before you take the medication. It’s much easier on the GI tract. I have patients who are so happy with the switch. So, I think, universally, the switch from Exjade to Jadenu has been very welcomed by the patients and very much recommended by me. And yes, the answer is, I have switched everybody over.

James M. Foran, MD, FRCPC: I’ve heard it said that there’s a concern the toxicity will be ironically, or paradoxically, greater with Jadenu than with the Exjade formulation because patients will actually be able to tolerate it. There actually will be adherence. They will comply with it, and it might ultimately increase the side-effect profile just because they’re able to be on it for a reasonable or extended period of time. So, I would say it matters to manage the other toxicities. If somebody is only on Exjade for 4 months or 6 months and they can’t take it, then you’re not always following for retinopathies, you’re not always following the creatinines closely, or you’re not always tracking for the toxicities. I would say that if people will tolerate the Jadenu better, which I agree is likely, then you have to have a monitoring plan in place to watch for those side effects, because there are toxicities of the drug.

Azra Raza, MD: Yes. This is why my policy is to start early, stop when the ferritin level falls below 500, and then give the patient a break from any chelation for 6 to 12 months. Then when their ferritin rises up again, then you start early again. But if you wait until the ferritin level is 5000 before instituting chelation then, yes, you are going to end up having to give a lot of these drugs and then end up with toxicity. So, I do think it’s very important to emphasize early intervention with chelation and then to try to give it intermittently.

James M. Foran, MD, FRCPC: I heard you say that you start it at a low dose and try to work your way up. That’s not the label to do that.

Azra Raza, MD: I said you can start at a low dose and work up or start at a high dose and dose de-escalate. That’s what I really meant.

James M. Foran, MD, FRCPC: I didn’t mean to put words in your mouth, because that’s something that we’ve done in our practice, as well. We start at a low dose and work our way up, over a couple of months, to tolerability—just while we’re monitoring for side effects—and then look for efficacy afterwards just to increase adherence to therapy. So, we do a similar kind of strategy.

Transcript Edited for Clarity
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