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Unmet Needs in Severe Aplastic Anemia and Exciting Ongoing Developments

Insights From: Phillip Scheinberg, MD, Hospital Sao Jose
Published: Wednesday, Dec 26, 2018



Transcript: 

Phillip Scheinberg, MD: I think one of the things that still bothers me is I think we have a regimen where the ATG [antithymocyte globulin] cyclosporine, eltrombopag, has hit really high marks in terms of overall and complete response rates. Obviously, we can always improve upon that. But in terms of response rate, I think we’re pretty up there. We would like to see that these patients are having these types of responses without having to be on therapy, which I think is something that is also evolving, and also not having these long-term complications of clonal evolution, for example. That’s something we have worried about and we have monitored. Now, the rates so far of these late events have been around 8% to 10%, which is very much in accordance with several reports, including from the United States but also other places with hundreds of patients. So that doesn’t seem, at least to date, to have gone higher in terms of cumulative incidence, but I would like that number to go to 0. You could probably put that as an unmet need.

Now, we don’t understand all the mechanisms that are involved for clonal evolution, so it’s hard for us to address that. But from a safety point of view, at least to date, we have seen something in accordance with what we have seen historically. The other thing along those lines that I think would be interesting is to incorporate other biological information or markers that could predict a little bit better, more consistently across studies, the patients who will respond who will have these later complications, either doing molecular studies or genetic studies or telomere linking or PNH [paroxysmal nocturnal hemoglobinuria] or some other pieces of information that would help us better define those risks and incorporate them into the treatment algorithms. Because, as I said earlier, we’re still using age and the availability of a donor to make those decisions.

I think the reason we haven’t incorporated those is that the data have not been terribly consistent, so we worry, obviously, about incorporating something that might not be right because we’re making major decisions and advising people to make those decisions based on that information. So you want to make sure that this is pretty tight. I think that my view of the unmet needs would be more in terms of some of these later complications and incorporating more biological information into our treatment decision algorithms.

In terms of new development and ongoing development, I think there are several things ongoing involving these classes of agents like the thrombopoietin receptor agonists. There are several trials that are ongoing, understanding that there are other interests associated with the management of these patients. Let me give you a few examples. These are still open questions. We talked about eltrombopag in refractory patients, right? Somebody failed their immunosuppressive therapy, so you put them on eltrombopag. Would adding cyclosporine to that be better than just giving eltrombopag alone? So we don’t know, but that’s something that people are very, very interested in.

What if somebody failed immunosuppressive therapy, and you want to give eltrombopag with cyclosporine and ATG again? Is that better than just giving eltrombopag alone? These are questions that I think are important. Some other questions would be: Do you need ATG at all? Can you just give the eltrombopag, cyclosporine? Because that benefits some patients. ATG can be a hard drug to give, especially in older populations, comorbid patients. But do you need that in younger patients? Can you get away with ATG? Most places don’t have horse ATG, and sometimes countries that have ATG don’t have it available in their center. So can you get away with doing 2 drugs like an oral patient regimen with cyclosporine, eltrombopag. So we don’t know. That’s being investigated.

What about the role of eltrombopag with rabbit ATG cyclosporine? That’s also a question that’s being answered in the context of a clinical trial. So there are these questions here. There are all these trials worldwide that are being conducted. Romiplostim is the other thrombopoietin receptor agonist that is also being investigated in a much earlier, preliminary fashion. But that would be a question that also would be of interest. Now, there are some preliminary data to suggest that it has activity but in very few patients, only published in abstract form. So far less developed than eltrombopag, but that’s something that is also currently being investigated.

Pediatric patients. Not a lot of pediatric patients are included in these trials. There is activity in that setting, but how active? So there are pediatric dedicated studies that are ongoing in the context of clinical research that will help answer this question. And then there’s a large European study comparing horse ATG cyclosporine versus horse ATG cyclosporine and eltrombopag randomized 1:1 that is about to complete accrual. And that will also give us a lot of answers in terms of the comparativeness between these 2 regimens and also long-term outcomes.

Could other agents be added to this backbone like androgens to eltrombopag and cyclosporine and ATG? These are all ongoing, so there’s a lot still that we would like to have answered. Now, there are many trials addressing these questions, not all these questions but several of these questions. So when you ask me what I will see in terms of development, I think this is a very exciting time because this is worldwide development, with several centers and countries around the world addressing these different questions.

So in 2, 3, 4, maybe 5, years, we’ll definitely have a lot more answers and better have more informed data or data to inform us, actually, how to better incorporate all these different possibilities into our treatment algorithms to provide the best care and outcomes that we can for our patients with this once universally fatal disease. So we can’t forget that aplastic anemia killed almost everybody 4 or 5 decades ago. Now most patients are actually alive. So the natural history of the disease has actually changed dramatically. So this is a success story of modern medicine, but we obviously want to keep continuing that and improving even more.

So I think there are a few important messages. One is that eltrombopag adds to the armamentarium of treatments in the past few years as a single agent with activity in refractory aplastic anemia. So that’s obviously an important addition, more recently with the incorporation of horse ATG cyclosporine with eltrombopag, also an option in up-front therapy. This is something that we’ll have to see how it will be incorporated into people’s day-to-day lives. It’s a very exciting addition to what we had before.

It’s important for the community physician who is actually using these types of therapies to pay attention to some of the important, practical aspects of giving this drug. There are dietary restrictions associated with eltrombopag, so you have to have it 2 hours before or 4 hours after a meal. I say that because I see patients coming to me who are not following that, and I think that this is being affected, their absorption. And monitoring for liver function test abnormalities in about 10% of patients.

So these are more practical, day-to-day considerations for the community hematologist. Most patients can tolerate this regimen. Few patients have to actually have the drug discontinued for a few days. They usually tolerate resumption, but the 40% or 50% response rate and the refractory percent, the refractory setting and the added benefit in the up-front setting I think are the major take-home messages—all these data that we have actually been discussing here for this activity.

Transcript Edited for Clarity 
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Transcript: 

Phillip Scheinberg, MD: I think one of the things that still bothers me is I think we have a regimen where the ATG [antithymocyte globulin] cyclosporine, eltrombopag, has hit really high marks in terms of overall and complete response rates. Obviously, we can always improve upon that. But in terms of response rate, I think we’re pretty up there. We would like to see that these patients are having these types of responses without having to be on therapy, which I think is something that is also evolving, and also not having these long-term complications of clonal evolution, for example. That’s something we have worried about and we have monitored. Now, the rates so far of these late events have been around 8% to 10%, which is very much in accordance with several reports, including from the United States but also other places with hundreds of patients. So that doesn’t seem, at least to date, to have gone higher in terms of cumulative incidence, but I would like that number to go to 0. You could probably put that as an unmet need.

Now, we don’t understand all the mechanisms that are involved for clonal evolution, so it’s hard for us to address that. But from a safety point of view, at least to date, we have seen something in accordance with what we have seen historically. The other thing along those lines that I think would be interesting is to incorporate other biological information or markers that could predict a little bit better, more consistently across studies, the patients who will respond who will have these later complications, either doing molecular studies or genetic studies or telomere linking or PNH [paroxysmal nocturnal hemoglobinuria] or some other pieces of information that would help us better define those risks and incorporate them into the treatment algorithms. Because, as I said earlier, we’re still using age and the availability of a donor to make those decisions.

I think the reason we haven’t incorporated those is that the data have not been terribly consistent, so we worry, obviously, about incorporating something that might not be right because we’re making major decisions and advising people to make those decisions based on that information. So you want to make sure that this is pretty tight. I think that my view of the unmet needs would be more in terms of some of these later complications and incorporating more biological information into our treatment decision algorithms.

In terms of new development and ongoing development, I think there are several things ongoing involving these classes of agents like the thrombopoietin receptor agonists. There are several trials that are ongoing, understanding that there are other interests associated with the management of these patients. Let me give you a few examples. These are still open questions. We talked about eltrombopag in refractory patients, right? Somebody failed their immunosuppressive therapy, so you put them on eltrombopag. Would adding cyclosporine to that be better than just giving eltrombopag alone? So we don’t know, but that’s something that people are very, very interested in.

What if somebody failed immunosuppressive therapy, and you want to give eltrombopag with cyclosporine and ATG again? Is that better than just giving eltrombopag alone? These are questions that I think are important. Some other questions would be: Do you need ATG at all? Can you just give the eltrombopag, cyclosporine? Because that benefits some patients. ATG can be a hard drug to give, especially in older populations, comorbid patients. But do you need that in younger patients? Can you get away with ATG? Most places don’t have horse ATG, and sometimes countries that have ATG don’t have it available in their center. So can you get away with doing 2 drugs like an oral patient regimen with cyclosporine, eltrombopag. So we don’t know. That’s being investigated.

What about the role of eltrombopag with rabbit ATG cyclosporine? That’s also a question that’s being answered in the context of a clinical trial. So there are these questions here. There are all these trials worldwide that are being conducted. Romiplostim is the other thrombopoietin receptor agonist that is also being investigated in a much earlier, preliminary fashion. But that would be a question that also would be of interest. Now, there are some preliminary data to suggest that it has activity but in very few patients, only published in abstract form. So far less developed than eltrombopag, but that’s something that is also currently being investigated.

Pediatric patients. Not a lot of pediatric patients are included in these trials. There is activity in that setting, but how active? So there are pediatric dedicated studies that are ongoing in the context of clinical research that will help answer this question. And then there’s a large European study comparing horse ATG cyclosporine versus horse ATG cyclosporine and eltrombopag randomized 1:1 that is about to complete accrual. And that will also give us a lot of answers in terms of the comparativeness between these 2 regimens and also long-term outcomes.

Could other agents be added to this backbone like androgens to eltrombopag and cyclosporine and ATG? These are all ongoing, so there’s a lot still that we would like to have answered. Now, there are many trials addressing these questions, not all these questions but several of these questions. So when you ask me what I will see in terms of development, I think this is a very exciting time because this is worldwide development, with several centers and countries around the world addressing these different questions.

So in 2, 3, 4, maybe 5, years, we’ll definitely have a lot more answers and better have more informed data or data to inform us, actually, how to better incorporate all these different possibilities into our treatment algorithms to provide the best care and outcomes that we can for our patients with this once universally fatal disease. So we can’t forget that aplastic anemia killed almost everybody 4 or 5 decades ago. Now most patients are actually alive. So the natural history of the disease has actually changed dramatically. So this is a success story of modern medicine, but we obviously want to keep continuing that and improving even more.

So I think there are a few important messages. One is that eltrombopag adds to the armamentarium of treatments in the past few years as a single agent with activity in refractory aplastic anemia. So that’s obviously an important addition, more recently with the incorporation of horse ATG cyclosporine with eltrombopag, also an option in up-front therapy. This is something that we’ll have to see how it will be incorporated into people’s day-to-day lives. It’s a very exciting addition to what we had before.

It’s important for the community physician who is actually using these types of therapies to pay attention to some of the important, practical aspects of giving this drug. There are dietary restrictions associated with eltrombopag, so you have to have it 2 hours before or 4 hours after a meal. I say that because I see patients coming to me who are not following that, and I think that this is being affected, their absorption. And monitoring for liver function test abnormalities in about 10% of patients.

So these are more practical, day-to-day considerations for the community hematologist. Most patients can tolerate this regimen. Few patients have to actually have the drug discontinued for a few days. They usually tolerate resumption, but the 40% or 50% response rate and the refractory percent, the refractory setting and the added benefit in the up-front setting I think are the major take-home messages—all these data that we have actually been discussing here for this activity.

Transcript Edited for Clarity 
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