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MDS: Iron Chelating Options

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: Friday, Nov 04, 2016


Transcript:

Thomas Prebet, MD, PhD:
The question of the benefit of iron chelation therapy in myelodysplastic syndromes is an important question. Basically, for the moment, we don’t have any prospective data potentially showing that iron chelation therapy improves survival in patients with myelodysplastic syndromes.

Most of the data that we have to assess the benefit-risk ratio of iron chelation therapy in myelodysplastic syndromes are based on retrospective studies and registry studies. We know that iron accumulation in the body and high ferritin levels are associated with a shorter survival. And we know from this registry data that iron chelation therapy can potentially reverse the iron accumulation and potentially have some benefit in survival. They are just retrospective data. So, that’s a question that some of the patients are asking us. How are we having the decision and the evaluation of the benefit-risk ratio based on these data, and what is the proof that we have? We need to be honest with them, telling them we don’t have any prospective data showing that evidence. But, interestingly, we have several independent registries and studies showing that we have potential benefit on survival of iron chelation therapy. And maybe more than that, we also have our own clinical experience for some patients, where we have some improvement in not only just ferritin levels, because treating a number is not what we need, we need to improve the survival of patients. For some patients, with clinical experience, we can see the reversal, for example, of iron accumulation in the heart or in the liver for some patients. That’s also the big driver for decision.

Heather Leitch, MD, PhD: Deferoxamine was the first iron chelation therapy agent that was available, and it’s been shown very clearly in the congenital anemias that compliance with deferoxamine infusions impact significantly on survival. So, for patients who took their deferoxamine infusions on 75 days or less, the median survival was in the early 20’s. Whereas for patients who were fully compliant with deferoxamine infusions and took it on most days, the life expectancy was normal. And so, as a former colleague of mine used to say, what other tools do we have in medicine that improve life expectancy from the early 20s to normal? There are very few interventions that have that kind of an impact. Those are the congenital anemias.

Deferoxamine is cumbersome. Because of its short half-life, it has to be given by continuous subcutaneous infusion for at least 5 days per week for at least 12 hours per day. And so, the patients have to carry around a pump with them. In adolescent patients, that can be a real significant factor. I’ve actually found that in my MDS patients, who, of course, are usually older adults, that it’s not such a factor when they can’t have the oral chelators for various different reasons. Once they’ve made up their mind to do iron chelation therapy and that it’s important, then the idea of the pump doesn’t bother them so much.

With deferoxamine, there is an increased incidence of ophthalmologic toxicity and ototoxicity at a ferritin level less than 1000. And for that reason, that’s where the ferritin threshold of 1000 in the guidelines really originated. So, we do chelate patients and stop. Or we don’t stop chelation, but don’t want to go under 1000 because of this increased risk of toxicity. The therapeutic index is used to try to keep patients at a safe level where they won’t experience side effects of deferoxamine.

Deferiprone is the next chelator that became available. It is an oral formulation. It’s not approved for use in MDS in Canada. It may be available in some other countries. It has been used extensively in the congenital anemias. It’s given three times a day. The starting dose of deferiprone is 75 mg/kg/day in three divided doses. The reason it’s not used so much in MDS is because of its potential for exacerbating neutropenia and for causing a granular cytosis.

There are case reports and case series in the literature of MDS patients being treated with deferiprone. The largest case series is from the Czech Republic. They treated 48 MDS patients with lower-risk disease with deferiprone, and the incidence of a granular cytosis in that study was about 4%. So, I think that deferiprone may be useful in MDS, but we need much more experience with this on clinical trials before we use it regularly in MDS patients. About 10 years ago, deferasirox became available, which, of course, is also an oral chelator. First, it came out in its dispersible form, and, more recently, it came out as the film-coated tablet.

Thomas Prebet, MD, PhD: The new formulation of deferasirox (or Jadenu) potentially brings a better tolerance profile for the patients. And, nowadays, most of the patients treated with myelodysplastic syndromes, and for whom I consider the introduction of an iron chelation agent, are now treated with Jadenu. Because we know that tolerance is a key to observance, and observance is a key to potentially efficient iron chelation therapy.

Transcript Edited for Clarity
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Transcript:

Thomas Prebet, MD, PhD:
The question of the benefit of iron chelation therapy in myelodysplastic syndromes is an important question. Basically, for the moment, we don’t have any prospective data potentially showing that iron chelation therapy improves survival in patients with myelodysplastic syndromes.

Most of the data that we have to assess the benefit-risk ratio of iron chelation therapy in myelodysplastic syndromes are based on retrospective studies and registry studies. We know that iron accumulation in the body and high ferritin levels are associated with a shorter survival. And we know from this registry data that iron chelation therapy can potentially reverse the iron accumulation and potentially have some benefit in survival. They are just retrospective data. So, that’s a question that some of the patients are asking us. How are we having the decision and the evaluation of the benefit-risk ratio based on these data, and what is the proof that we have? We need to be honest with them, telling them we don’t have any prospective data showing that evidence. But, interestingly, we have several independent registries and studies showing that we have potential benefit on survival of iron chelation therapy. And maybe more than that, we also have our own clinical experience for some patients, where we have some improvement in not only just ferritin levels, because treating a number is not what we need, we need to improve the survival of patients. For some patients, with clinical experience, we can see the reversal, for example, of iron accumulation in the heart or in the liver for some patients. That’s also the big driver for decision.

Heather Leitch, MD, PhD: Deferoxamine was the first iron chelation therapy agent that was available, and it’s been shown very clearly in the congenital anemias that compliance with deferoxamine infusions impact significantly on survival. So, for patients who took their deferoxamine infusions on 75 days or less, the median survival was in the early 20’s. Whereas for patients who were fully compliant with deferoxamine infusions and took it on most days, the life expectancy was normal. And so, as a former colleague of mine used to say, what other tools do we have in medicine that improve life expectancy from the early 20s to normal? There are very few interventions that have that kind of an impact. Those are the congenital anemias.

Deferoxamine is cumbersome. Because of its short half-life, it has to be given by continuous subcutaneous infusion for at least 5 days per week for at least 12 hours per day. And so, the patients have to carry around a pump with them. In adolescent patients, that can be a real significant factor. I’ve actually found that in my MDS patients, who, of course, are usually older adults, that it’s not such a factor when they can’t have the oral chelators for various different reasons. Once they’ve made up their mind to do iron chelation therapy and that it’s important, then the idea of the pump doesn’t bother them so much.

With deferoxamine, there is an increased incidence of ophthalmologic toxicity and ototoxicity at a ferritin level less than 1000. And for that reason, that’s where the ferritin threshold of 1000 in the guidelines really originated. So, we do chelate patients and stop. Or we don’t stop chelation, but don’t want to go under 1000 because of this increased risk of toxicity. The therapeutic index is used to try to keep patients at a safe level where they won’t experience side effects of deferoxamine.

Deferiprone is the next chelator that became available. It is an oral formulation. It’s not approved for use in MDS in Canada. It may be available in some other countries. It has been used extensively in the congenital anemias. It’s given three times a day. The starting dose of deferiprone is 75 mg/kg/day in three divided doses. The reason it’s not used so much in MDS is because of its potential for exacerbating neutropenia and for causing a granular cytosis.

There are case reports and case series in the literature of MDS patients being treated with deferiprone. The largest case series is from the Czech Republic. They treated 48 MDS patients with lower-risk disease with deferiprone, and the incidence of a granular cytosis in that study was about 4%. So, I think that deferiprone may be useful in MDS, but we need much more experience with this on clinical trials before we use it regularly in MDS patients. About 10 years ago, deferasirox became available, which, of course, is also an oral chelator. First, it came out in its dispersible form, and, more recently, it came out as the film-coated tablet.

Thomas Prebet, MD, PhD: The new formulation of deferasirox (or Jadenu) potentially brings a better tolerance profile for the patients. And, nowadays, most of the patients treated with myelodysplastic syndromes, and for whom I consider the introduction of an iron chelation agent, are now treated with Jadenu. Because we know that tolerance is a key to observance, and observance is a key to potentially efficient iron chelation therapy.

Transcript Edited for Clarity
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