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Practical Experience with Iron Chelating Agents

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: Wednesday, Nov 16, 2016


Transcript:

Vinod Pullarkat, MD:
For the dispersible tablet of deferasirox, or Exjade, the recommended dose is 20 mg/kg. In my practice, I don’t often start the patients at that dose. I often start lower and give the patients some time, and then titrate the patient up to a therapeutic dose, which ranges from 20 mg/kg to 40 mg/kg. So, I think a lot of patients discontinue iron chelation in the first month of treatment. That is largely due to the fact that they’re often started at a higher dose, then they experience side effects, and then the physicians often stop the drug.

One important thing to remember is that the benefits of iron chelation in some of the large studies, particularly with regard to improvement in transfusion dependency and improvement in blood counts, they have been seen with a median of about 100 days. So, it requires at least about 3 months of therapy to see the full benefits of iron chelation with deferasirox. Prematurely stopping the drug is a problem. That is often due to high dosing to start with and also lack of experience with its side effects. For example, you would expect some elevation in serum creatinine with use of the agent, and that’s a known effect of the drug. That doesn’t necessarily mean you have to discontinue the agent.

Same thing applies to side effects like skin rash or side effects like gastrointestinal toxicity. You can sometimes improve it by taking the drug in a different medium, like for Exjade, or by changing the time of the day when the drug is taken. All of these things can improve the tolerability of the drug. The experience with use of iron chelation is important in order to make sure that the patient is adherent to the agent. One thing to remember about Jadenu is that the bioavailability is more, so the dosing is about 30% less than for Exjade. So, you have to make sure that you make the appropriate dose calculations so that you don’t overdose the patient.

An example of a case where I have used iron chelation prior to transplantation is a patient of mine who was around 30 years of age who had aplastic anemia from childhood. She has had multiple recurrence of response to immunosuppression, has relapsed, and then eventually developed myelodysplastic syndrome. She was classified as an intermediate 1 risk based on her IPSS score, but was very transfusion dependent. The plan was made to take her to get an allogeneic transplant from a match, unrelated donor. But when I saw her, the serum ferritin was very high—if I remember, it was around 5000, with a very high LIC (liver iron concentration). There was no imminent risk of transformation in that patient, so we decided to chelate the patient adequately prior to proceeding to an allogeneic transplant. And within about a year, we could bring the LIC down below 4 mg/g and we could take that patient to a successful allogeneic transplant. So, that’s an example where a patient can wait a little bit before we do the transplant, and there is enough opportunity to do the chelation. In this patient, Jadenu was well tolerated and the patient was able to take it at the therapeutic dose.

Thomas Prebet, MD, PhD: When we discuss good examples of the potential efficacy or interest with iron chelation agents, one example that pops in my mind is maybe not the most classical case. I remember well a young lady who was, in fact, allo-transplanted years ago from myelodysplastic syndromes, but kept some transfusion requirement after the allo-transplantation. Ferritin levels were pretty high. But more than just ferritin levels, when we assessed the iron burden by MRI, she had a pretty significant iron overload, not only in the liver, but also in the heart. After the initiation of iron chelation therapy, we had a significant improvement of both liver and heart MRI. And so, the liver function test abnormalities that we thought were related to graft-versus-host disease, in fact, almost completely corrects with initiation of the treatment. What we thought to be graft-versus-host disease was just symptoms of iron overload in this specific lady.

Another discussion that we have when we talk about iron chelation agents is something brought up by the patient. There’s some description of a case report, in some series of improvement of blood counts, with the use of iron chelation agents out of any other potential disease-modifying treatments. It’s a pretty controversial issue, but there is some report of potential steady improvement of counts over several months with the use of iron chelation. Therapy has been shown as a side evaluation for several international studies. So, there’s a lot of work around this specific question. Why is it something that happens? Is it something real that is happening from both a clinical level and the laboratory science level? That’s one of the potentially exciting questions that we have on the subject of iron chelation agents.

Vinod Pullarkat, MD: The use of our oral iron chelation, using deferasirox or deferoxamine subcutaneously, requires a lot of experience. So, my recommendation for those physicians is to refer the patient to a center where there is expertise in management of these patients, particularly with regard to iron chelation, and manage that patient together with an expert. Because it requires significant expertise with use of these agents to appropriately titrate the dose and manage the side effects.

Heather Leitch, MD, PhD: I think for physicians who don’t have a lot of experience with managing iron overload and iron chelation therapy, if they run into difficulties with side effects or with iron overload control, or any other difficulties, they should have a low threshold for referring to a colleague with more experience. I think that this not only allows the patient to really stay on a therapeutic intervention that we think is very beneficial for them, but it also conveys the message to the patient that this is something that’s important and that we don’t necessarily just stop at the first bump on the road. Patients may not fully appreciate this because, as discussed before, they don’t have acute clinical manifestations of iron overload. It’s more of a matter of developing serious complications once iron overload is significant, and we want to prevent them from getting to that point.

Transcript Edited for Clarity
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Transcript:

Vinod Pullarkat, MD:
For the dispersible tablet of deferasirox, or Exjade, the recommended dose is 20 mg/kg. In my practice, I don’t often start the patients at that dose. I often start lower and give the patients some time, and then titrate the patient up to a therapeutic dose, which ranges from 20 mg/kg to 40 mg/kg. So, I think a lot of patients discontinue iron chelation in the first month of treatment. That is largely due to the fact that they’re often started at a higher dose, then they experience side effects, and then the physicians often stop the drug.

One important thing to remember is that the benefits of iron chelation in some of the large studies, particularly with regard to improvement in transfusion dependency and improvement in blood counts, they have been seen with a median of about 100 days. So, it requires at least about 3 months of therapy to see the full benefits of iron chelation with deferasirox. Prematurely stopping the drug is a problem. That is often due to high dosing to start with and also lack of experience with its side effects. For example, you would expect some elevation in serum creatinine with use of the agent, and that’s a known effect of the drug. That doesn’t necessarily mean you have to discontinue the agent.

Same thing applies to side effects like skin rash or side effects like gastrointestinal toxicity. You can sometimes improve it by taking the drug in a different medium, like for Exjade, or by changing the time of the day when the drug is taken. All of these things can improve the tolerability of the drug. The experience with use of iron chelation is important in order to make sure that the patient is adherent to the agent. One thing to remember about Jadenu is that the bioavailability is more, so the dosing is about 30% less than for Exjade. So, you have to make sure that you make the appropriate dose calculations so that you don’t overdose the patient.

An example of a case where I have used iron chelation prior to transplantation is a patient of mine who was around 30 years of age who had aplastic anemia from childhood. She has had multiple recurrence of response to immunosuppression, has relapsed, and then eventually developed myelodysplastic syndrome. She was classified as an intermediate 1 risk based on her IPSS score, but was very transfusion dependent. The plan was made to take her to get an allogeneic transplant from a match, unrelated donor. But when I saw her, the serum ferritin was very high—if I remember, it was around 5000, with a very high LIC (liver iron concentration). There was no imminent risk of transformation in that patient, so we decided to chelate the patient adequately prior to proceeding to an allogeneic transplant. And within about a year, we could bring the LIC down below 4 mg/g and we could take that patient to a successful allogeneic transplant. So, that’s an example where a patient can wait a little bit before we do the transplant, and there is enough opportunity to do the chelation. In this patient, Jadenu was well tolerated and the patient was able to take it at the therapeutic dose.

Thomas Prebet, MD, PhD: When we discuss good examples of the potential efficacy or interest with iron chelation agents, one example that pops in my mind is maybe not the most classical case. I remember well a young lady who was, in fact, allo-transplanted years ago from myelodysplastic syndromes, but kept some transfusion requirement after the allo-transplantation. Ferritin levels were pretty high. But more than just ferritin levels, when we assessed the iron burden by MRI, she had a pretty significant iron overload, not only in the liver, but also in the heart. After the initiation of iron chelation therapy, we had a significant improvement of both liver and heart MRI. And so, the liver function test abnormalities that we thought were related to graft-versus-host disease, in fact, almost completely corrects with initiation of the treatment. What we thought to be graft-versus-host disease was just symptoms of iron overload in this specific lady.

Another discussion that we have when we talk about iron chelation agents is something brought up by the patient. There’s some description of a case report, in some series of improvement of blood counts, with the use of iron chelation agents out of any other potential disease-modifying treatments. It’s a pretty controversial issue, but there is some report of potential steady improvement of counts over several months with the use of iron chelation. Therapy has been shown as a side evaluation for several international studies. So, there’s a lot of work around this specific question. Why is it something that happens? Is it something real that is happening from both a clinical level and the laboratory science level? That’s one of the potentially exciting questions that we have on the subject of iron chelation agents.

Vinod Pullarkat, MD: The use of our oral iron chelation, using deferasirox or deferoxamine subcutaneously, requires a lot of experience. So, my recommendation for those physicians is to refer the patient to a center where there is expertise in management of these patients, particularly with regard to iron chelation, and manage that patient together with an expert. Because it requires significant expertise with use of these agents to appropriately titrate the dose and manage the side effects.

Heather Leitch, MD, PhD: I think for physicians who don’t have a lot of experience with managing iron overload and iron chelation therapy, if they run into difficulties with side effects or with iron overload control, or any other difficulties, they should have a low threshold for referring to a colleague with more experience. I think that this not only allows the patient to really stay on a therapeutic intervention that we think is very beneficial for them, but it also conveys the message to the patient that this is something that’s important and that we don’t necessarily just stop at the first bump on the road. Patients may not fully appreciate this because, as discussed before, they don’t have acute clinical manifestations of iron overload. It’s more of a matter of developing serious complications once iron overload is significant, and we want to prevent them from getting to that point.

Transcript Edited for Clarity
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