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Factors to Consider in 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: Friday, Jun 17, 2016


Transcript:

David P. Steensma, MD:
We’ve known for about 20 years now that there are some patients who are chelated—who then are able to produce blood cells more effectively—and it seems likely that toxic iron species in the bone marrow are causing injury to blood cell precursors and making the bone marrow less effective at making blood cells. And there are a couple of different studies in the more modern chelation era that have shown that with chelation, a subset of patients—as many as 20%—will have an improvement in their blood counts. Usually modest improvements, but we’ll take whatever we can get.

I think the real problem people have with iron chelation is not that they believe having a lot of iron on board is a good thing, because it’s clearly not, it’s clearly harmful. It’s just a matter of degree. But the chelators are expensive, and they’re not entirely benign. One-third of patients who go on deferasirox will have an increase in their creatinine by more than 33% and above the normal range.

Even in the studies where patients were carefully selected, such as in the USO3 Study and the European EPIC Study, half of the patients who started on deferasirox had dropped out by the end of the first year. And most of them had dropped out and stopped taking the chelator by the end of the second year because of gastrointestinal side effects, renal insufficiency, other rare side effects, and then because of just disease progression—such that chelation became less critical in the big picture with other more intense treatments that were needing to be considered.

So, I think that’s a big challenge with the chelators. Deferasirox is more than $10,000 a month, and if people have even a 10% or a 20% co-pay, that’s a substantial amount of money. And if it’s something that you knew could help you live X months longer, then maybe that’s worth it. But we don’t know that yet. And so I think that’s the real conundrum with iron chelation and MDS.

We know that iron is a problem. We know that it’s a bigger problem for some patients than others. But we don’t know that the benefits of chelation outweigh the risks yet. They probably do for certain patients—the low-risk, heavily transfusion-dependent patient who otherwise has a good prognosis. But for many other patients—higher-risk disease—those that don’t tolerate the chelator well, the risks probably do outweigh the benefits of chelating. That’s the art of trying to figure out who truly are good candidates.

One important point is that all of the studies that have shown benefit from chelation therapy, in terms of survival, have been retrospective studies where the investigators have tried to balance the chelated patients and the controls for disease features. But there’s lots of things that go into chelation that aren’t so easy to capture. So, for instance, somebody who has better access to their doctor, better insurance, is seen more frequently and is more likely to be chelated. That patient, because they have better access, may do a little bit better anyway. The doctors may offer chelation to the patients who, just looking at them, seem to be more functional, more active, and therefore somebody who’s going to live a little bit longer anyway. There’s all sorts of confounding that goes into retrospective studies of chelation versus no chelation. And, again, that’s why TELESTO is such an important study because it’s the first prospective, randomized, placebo-controlled trial. I just hope that gives us a useful answer.

Transcript Edited for Clarity
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Transcript:

David P. Steensma, MD:
We’ve known for about 20 years now that there are some patients who are chelated—who then are able to produce blood cells more effectively—and it seems likely that toxic iron species in the bone marrow are causing injury to blood cell precursors and making the bone marrow less effective at making blood cells. And there are a couple of different studies in the more modern chelation era that have shown that with chelation, a subset of patients—as many as 20%—will have an improvement in their blood counts. Usually modest improvements, but we’ll take whatever we can get.

I think the real problem people have with iron chelation is not that they believe having a lot of iron on board is a good thing, because it’s clearly not, it’s clearly harmful. It’s just a matter of degree. But the chelators are expensive, and they’re not entirely benign. One-third of patients who go on deferasirox will have an increase in their creatinine by more than 33% and above the normal range.

Even in the studies where patients were carefully selected, such as in the USO3 Study and the European EPIC Study, half of the patients who started on deferasirox had dropped out by the end of the first year. And most of them had dropped out and stopped taking the chelator by the end of the second year because of gastrointestinal side effects, renal insufficiency, other rare side effects, and then because of just disease progression—such that chelation became less critical in the big picture with other more intense treatments that were needing to be considered.

So, I think that’s a big challenge with the chelators. Deferasirox is more than $10,000 a month, and if people have even a 10% or a 20% co-pay, that’s a substantial amount of money. And if it’s something that you knew could help you live X months longer, then maybe that’s worth it. But we don’t know that yet. And so I think that’s the real conundrum with iron chelation and MDS.

We know that iron is a problem. We know that it’s a bigger problem for some patients than others. But we don’t know that the benefits of chelation outweigh the risks yet. They probably do for certain patients—the low-risk, heavily transfusion-dependent patient who otherwise has a good prognosis. But for many other patients—higher-risk disease—those that don’t tolerate the chelator well, the risks probably do outweigh the benefits of chelating. That’s the art of trying to figure out who truly are good candidates.

One important point is that all of the studies that have shown benefit from chelation therapy, in terms of survival, have been retrospective studies where the investigators have tried to balance the chelated patients and the controls for disease features. But there’s lots of things that go into chelation that aren’t so easy to capture. So, for instance, somebody who has better access to their doctor, better insurance, is seen more frequently and is more likely to be chelated. That patient, because they have better access, may do a little bit better anyway. The doctors may offer chelation to the patients who, just looking at them, seem to be more functional, more active, and therefore somebody who’s going to live a little bit longer anyway. There’s all sorts of confounding that goes into retrospective studies of chelation versus no chelation. And, again, that’s why TELESTO is such an important study because it’s the first prospective, randomized, placebo-controlled trial. I just hope that gives us a useful answer.

Transcript Edited for Clarity
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