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Evidence With Iron Chelation Therapy in MDS

Panelists: Vinod Pullarkat, MD, City of Hope Medical Center; Jamile Shammo, MD, Rush University Medical Center; Rami S. Komrokji, MD, Moffitt Cancer Center; Thomas Prebet, MD, PhD, Yale Cancer Center; Ellen K. Ritchie, MD, New York Presbyterian Hospital
Published: Wednesday, Jan 25, 2017


Transcript:

Rami S. Komrokji, MD:
To set the stage, I’m going to also talk about the iron chelation role, in general, in MDS patients, because obviously, there is a school of thought. Some are believers in the role of iron chelation, some are not. You built a nice story, that patients who are blood-transfusion–dependent, they don’t do as well. Serum ferritin levels correlate with worse outcome. But the question is, does iron chelation make a difference? And, obviously, we don’t have a randomized clinical trial, so you have to make some conclusions. There have been several retrospective studies.

Vinod Pullarkat, MD: Including at this meeting—you saw that registry data from Europe.

Rami S. Komrokji, MD: Right. Those suggest that patients who get iron chelation, do better. And then, there are studies that Jamile alluded to, like the EPIC that showed you can decrease the serum ferritin. Those retrospective studies are obviously criticized by selection bias that the patients who will get iron chelation will live longer. Because they are doing better, they could get iron chelation for a longer duration. There have actually been some observational prospective studies, like the French, that they published a few years ago. They looked at patients who were transfusion dependent, they followed them, and they found out that patients who were on strict iron chelation did better than intermittent, and the intermittent even did better than no iron chelation.

Vinod Pullarkat, MD: Better means survival.

Rami S. Komrokji, MD: And, interestingly, sometimes even leukemia-free survival. When we looked at our experience with oral iron chelators, particularly, we saw that, and even the serum ferritin levels had been correlated to leukemia-free survival. It’s also an observational study, but it’s probably prospective, as well, because this is through the European network looking at patterns of use of therapy in Europe with the introduction of the oral iron chelator. So, we know that, historically, we use subcutaneous deferoxamine, which, in my experience over 10 years, maybe 2 or 3 patients accepted to have the pumps attached all week. Then, we started having the oral iron chelators, the deferasirox, and now the newer formulation. There is another one, deferiprone. That’s probably more myelosuppressive, so we usually don’t use it much in MDS.

In this study, this treatment has not been offered to many patients with lower risk. I think maybe 1 out of 4 or 5 patients will get on iron chelation at one point. But, what was shown was that, basically, patients did better on oral, especially the deferasirox than the deferoxamine. And when you adjust for different factors, it seems, that even in this prospective observational study, that there is a survival advantage for those. Again, the gold standard for all of us is a randomized clinical trial. The TELESTO study has been going on for a while, which is a study that looks at that, but it’s not an easy task to do a randomized clinical trial looking at iron chelation alone without other variables. So, I think at the end, there is substantial evidence to suggest that, and you’re either a believer or non-believer in the subject.

Vinod Pullarkat, MD: You mentioned chelation for the lower-risk patients who are transfusion dependent, and there has been some development in recent years with the development of oral formulations. I think most patients would be on deferasirox. And, in the United States, now, we have the availability of the film-coated tablets. So, you think that’s going to improve the tolerance for patients?

Rami S. Komrokji, MD: As mentioned earlier, I think there are several modalities. Obviously, the oral iron chelators are much more appealing, easier to do. We have the original deferasirox, Exjade, used for those patients, and now we have a newer formulation that’s easier to do, probably more compliance for the patients. It doesn’t have to be mixed. Patients can take it as a tablet. It improves the compliance.

Vinod Pullarkat, MD: From gastrointestinal side effects.

Rami S. Komrokji, MD: Right. So, the data are starting to evolve in other fields, that maybe there is less GI toxicity, and that there is actually better compliance. Anecdotally, in some of the patients that we’ve had, when they shift, they do have less side effects. I always think that with the use of those medications, there are a couple of things, as we were discussing: the benefit and the risk. The benefit needs some time to be seen, so those patients need to be maintained for 1 to 2 years, at least, to see the benefit for iron chelation. You want to make sure that you are managing the toxicities appropriately. What we see is that those patients are sometimes started inappropriately on high doses, they have toxicities early on and you stop, or they are started on low doses, and then they keep going on low doses that we know don’t do anything on the level of iron chelation. I think you have this discussion, you assess the patients, and you follow them closely up front—monitoring kidney functions and liver functions every week or every other week. And, once you get to a point, then you should escalate the dosing. So, the new formulas are making that easier. Patients are more compliant with less side effects, but, again, I think we should always be keeping the toxicity in mind and assessing it closely, especially early on.

Vinod Pullarkat, MD: I think the use of deferasirox requires significant experience, and that’s sometimes challenging. The newer formulation has a different dosing from the dispersible formula. It’s about a 30% less dose, so that’s something to remember. And the monitoring of organ toxicities is particularly important, but I think we should also emphasize the expectations. You would like to achieve a negative iron balance. So, in that transfusion-dependent patient, that would be a downward trend in ferritin. But, even a stable serum ferritin is not necessarily bad in a transfusion-dependent patient.

Rami S. Komrokji, MD: And in a setting of patients where they’re getting blood transfusions, we expect the serum ferritin would continue to go up. I think it’s important that we mention that the approval for the new formulation is based on bioavailability not studied in patients with MDS. So, older data that we talk about are patients that were treated with deferasirox. The Jadenu was shown to be bioavailable and equivalent. As you mentioned, the dosing is one-third, but all the studies done in MDS were with deferasirox.

Vinod Pullarkat, MD: Yes, but I just want to emphasize that the active agent is the same, so one needs to pay particular attention to the side effects when managing these patients. And a common problem is these therapies are often stopped before we have any chance of a patient benefitting from them.

Rami S. Komrokji, MD: Yes. With the deferasirox study, 50% of patients ended up coming off because of side effects, mostly GI and renal. So, if you can improve those, with the new formulation, then you’re definitely going to be able to improve the compliance and, hopefully, have more effective iron chelation.

Vinod Pullarkat, MD: I think my preference is to start low and then work my way up gradually rather than start at full dose and then manage the side effects.

Jamile Shammo, MD: I agree.

Ellen K. Ritchie, MD: Oh, I titrate patients up. I always start low and then go higher.

Rami S. Komrokji, MD: Yes, because if you look at the data, actually there is a difference in meaningful iron chelation. So, if you look at the serum ferritin reduction, it’s usually with the higher doses. You need to go up with the dose at one point to have meaningful chelation. But, to your point, I think I totally agree—start low, and make sure the toxicities are managed.

Vinod Pullarkat, MD: Give it some time, yes.

Rami S. Komrokji, MD: Right, and then escalate. Don’t keep the dose at the low level.

Ellen K. Ritchie, MD: And this has to be a medication that the patient is tolerant to take over time. You don’t want to start at a level where they absolutely are not going to want to be on this medication ever again. You want to be able to adjust it, so that they’re willing to take it over time.

Vinod Pullarkat, MD: Especially when you’re treating a problem that’s not symptomatic.

Ellen K. Ritchie, MD: That’s right. It’s like treating hypertension. People don’t really realize that they have high blood pressure. It’s the same sort of situation.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Rami S. Komrokji, MD:
To set the stage, I’m going to also talk about the iron chelation role, in general, in MDS patients, because obviously, there is a school of thought. Some are believers in the role of iron chelation, some are not. You built a nice story, that patients who are blood-transfusion–dependent, they don’t do as well. Serum ferritin levels correlate with worse outcome. But the question is, does iron chelation make a difference? And, obviously, we don’t have a randomized clinical trial, so you have to make some conclusions. There have been several retrospective studies.

Vinod Pullarkat, MD: Including at this meeting—you saw that registry data from Europe.

Rami S. Komrokji, MD: Right. Those suggest that patients who get iron chelation, do better. And then, there are studies that Jamile alluded to, like the EPIC that showed you can decrease the serum ferritin. Those retrospective studies are obviously criticized by selection bias that the patients who will get iron chelation will live longer. Because they are doing better, they could get iron chelation for a longer duration. There have actually been some observational prospective studies, like the French, that they published a few years ago. They looked at patients who were transfusion dependent, they followed them, and they found out that patients who were on strict iron chelation did better than intermittent, and the intermittent even did better than no iron chelation.

Vinod Pullarkat, MD: Better means survival.

Rami S. Komrokji, MD: And, interestingly, sometimes even leukemia-free survival. When we looked at our experience with oral iron chelators, particularly, we saw that, and even the serum ferritin levels had been correlated to leukemia-free survival. It’s also an observational study, but it’s probably prospective, as well, because this is through the European network looking at patterns of use of therapy in Europe with the introduction of the oral iron chelator. So, we know that, historically, we use subcutaneous deferoxamine, which, in my experience over 10 years, maybe 2 or 3 patients accepted to have the pumps attached all week. Then, we started having the oral iron chelators, the deferasirox, and now the newer formulation. There is another one, deferiprone. That’s probably more myelosuppressive, so we usually don’t use it much in MDS.

In this study, this treatment has not been offered to many patients with lower risk. I think maybe 1 out of 4 or 5 patients will get on iron chelation at one point. But, what was shown was that, basically, patients did better on oral, especially the deferasirox than the deferoxamine. And when you adjust for different factors, it seems, that even in this prospective observational study, that there is a survival advantage for those. Again, the gold standard for all of us is a randomized clinical trial. The TELESTO study has been going on for a while, which is a study that looks at that, but it’s not an easy task to do a randomized clinical trial looking at iron chelation alone without other variables. So, I think at the end, there is substantial evidence to suggest that, and you’re either a believer or non-believer in the subject.

Vinod Pullarkat, MD: You mentioned chelation for the lower-risk patients who are transfusion dependent, and there has been some development in recent years with the development of oral formulations. I think most patients would be on deferasirox. And, in the United States, now, we have the availability of the film-coated tablets. So, you think that’s going to improve the tolerance for patients?

Rami S. Komrokji, MD: As mentioned earlier, I think there are several modalities. Obviously, the oral iron chelators are much more appealing, easier to do. We have the original deferasirox, Exjade, used for those patients, and now we have a newer formulation that’s easier to do, probably more compliance for the patients. It doesn’t have to be mixed. Patients can take it as a tablet. It improves the compliance.

Vinod Pullarkat, MD: From gastrointestinal side effects.

Rami S. Komrokji, MD: Right. So, the data are starting to evolve in other fields, that maybe there is less GI toxicity, and that there is actually better compliance. Anecdotally, in some of the patients that we’ve had, when they shift, they do have less side effects. I always think that with the use of those medications, there are a couple of things, as we were discussing: the benefit and the risk. The benefit needs some time to be seen, so those patients need to be maintained for 1 to 2 years, at least, to see the benefit for iron chelation. You want to make sure that you are managing the toxicities appropriately. What we see is that those patients are sometimes started inappropriately on high doses, they have toxicities early on and you stop, or they are started on low doses, and then they keep going on low doses that we know don’t do anything on the level of iron chelation. I think you have this discussion, you assess the patients, and you follow them closely up front—monitoring kidney functions and liver functions every week or every other week. And, once you get to a point, then you should escalate the dosing. So, the new formulas are making that easier. Patients are more compliant with less side effects, but, again, I think we should always be keeping the toxicity in mind and assessing it closely, especially early on.

Vinod Pullarkat, MD: I think the use of deferasirox requires significant experience, and that’s sometimes challenging. The newer formulation has a different dosing from the dispersible formula. It’s about a 30% less dose, so that’s something to remember. And the monitoring of organ toxicities is particularly important, but I think we should also emphasize the expectations. You would like to achieve a negative iron balance. So, in that transfusion-dependent patient, that would be a downward trend in ferritin. But, even a stable serum ferritin is not necessarily bad in a transfusion-dependent patient.

Rami S. Komrokji, MD: And in a setting of patients where they’re getting blood transfusions, we expect the serum ferritin would continue to go up. I think it’s important that we mention that the approval for the new formulation is based on bioavailability not studied in patients with MDS. So, older data that we talk about are patients that were treated with deferasirox. The Jadenu was shown to be bioavailable and equivalent. As you mentioned, the dosing is one-third, but all the studies done in MDS were with deferasirox.

Vinod Pullarkat, MD: Yes, but I just want to emphasize that the active agent is the same, so one needs to pay particular attention to the side effects when managing these patients. And a common problem is these therapies are often stopped before we have any chance of a patient benefitting from them.

Rami S. Komrokji, MD: Yes. With the deferasirox study, 50% of patients ended up coming off because of side effects, mostly GI and renal. So, if you can improve those, with the new formulation, then you’re definitely going to be able to improve the compliance and, hopefully, have more effective iron chelation.

Vinod Pullarkat, MD: I think my preference is to start low and then work my way up gradually rather than start at full dose and then manage the side effects.

Jamile Shammo, MD: I agree.

Ellen K. Ritchie, MD: Oh, I titrate patients up. I always start low and then go higher.

Rami S. Komrokji, MD: Yes, because if you look at the data, actually there is a difference in meaningful iron chelation. So, if you look at the serum ferritin reduction, it’s usually with the higher doses. You need to go up with the dose at one point to have meaningful chelation. But, to your point, I think I totally agree—start low, and make sure the toxicities are managed.

Vinod Pullarkat, MD: Give it some time, yes.

Rami S. Komrokji, MD: Right, and then escalate. Don’t keep the dose at the low level.

Ellen K. Ritchie, MD: And this has to be a medication that the patient is tolerant to take over time. You don’t want to start at a level where they absolutely are not going to want to be on this medication ever again. You want to be able to adjust it, so that they’re willing to take it over time.

Vinod Pullarkat, MD: Especially when you’re treating a problem that’s not symptomatic.

Ellen K. Ritchie, MD: That’s right. It’s like treating hypertension. People don’t really realize that they have high blood pressure. It’s the same sort of situation.

Transcript Edited for Clarity
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