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Transplantation in Patients With Severe Aplastic Anemia

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



Transcript:

Phillip Scheinberg, MD: Age has a lot to do with transplantation eligibility because age and transplantation actually go hand in hand. We know that patients who are younger have better outcomes with stem cell transplantation. That’s true for both the matched related and the matched unrelated settings. So patients up to 20 do far better than those patients who are over 40. So if you look at a survival curve, matched sibling donor up to the age of 20 is about 80%. That number drops to about 60% and 65% between the ages of 20 and 40 and drops even more if you’re over the age of 40. You’re talking about a 50% overall survival. So you’re talking about survival of 80%, about 60%, 65%, to 50%. So this is a very linear, very correlative aspect between age and stem cell transplantation, both in the matched related and in the unrelated settings.

Although advances have been made in transplantation protocols in safety, the older patient is still a challenge. They’re still having a lot of complications from transplantation. Transplantation has also evolved, obviously, not only immunosuppressive therapy with the addition, for example, of eltrombopag. But there is still a drop of 10% or 20% of patients who actually either die from transplantation-related complications, complications of acute and chronic graft versus host disease, and infections. So it deceases with younger age. These tend to be more tolerated, but they can be very limiting in a nonmalignant disease like aplastic anemia.

Doing bone marrow transplantation or stem cell transplantation in patients with aplastic anemia is something that evolved historically, meaning that this was a modality that was developed in the early 1970s, when transplantation was starting to become more feasible. Aplastic anemia, interestingly, was one of the first diseases actually to benefit from stem cell transplantation because, remember, in order for a stem cell transplantation to be successful in aplastic anemia, you need to engraft and not die from the transplantation or not have complications from the transplantation. So you don’t have to have a graft versus tumor effect or graft versus leukemia or graft versus myeloma. You just have to engraft, and if they don’t have complications, you’re pretty much cured of the disease.

The issue is that the only trial that compared transplantation with something else with androgens was in the 1970s, and there’s been no trial comparing immunosuppressive therapy with transplantation frontline. So historically, the transplantation has been incorporated into treatment. So if you’re less than 20 and for sure have had a matched related donor, transplantation should be offered, given that the results long term are pretty good and the increased tolerability of this treatment modality in the up-front setting.

Now, this is also extended to patients between 20 and 40 years of age, given that although the risks are higher, they’re still acceptable. The issue becomes that of unrelated bone marrow transplantation in the up-front setting. Now, if you look at the data in the results, they look, especially in the very young patient population, very similar to those of the matched related donor. The problem is that it takes several months, actually, to find an unrelated donor, and this unrelated donor may not pan out. And now you’re going to have somebody 2, 3, 4 months out not getting any specific therapy, with complications of neutropenia and transfusions increasing their burden. And so that’s very problematic when you have very effective therapy, as in the horse ATG [antithymocyte globulin] cyclosporine that, especially in children, is associated with an overall response rate of 75% to 80% and long-term survival of 90%. That’s really good, so I feel hesitant to recommend unrelated universally to all patients, not because the data are not good, just because of the complexity and the logistics of putting this all together and that patients actually might die waiting for an unrelated donor. So that’s not something that I think is too good.

I think it’s regardless of age. Having somebody wait 12 weeks or 3 months for an unrelated donor—I think that’s complicated. If you can do this in a month or 3, I think that’s OK, but you would have to be in a very select patient population. Some patient populations are just very heterogeneous. You look at some countries like Japan, which tends to be more homogenous, or in certain parts of Europe. But if you look in other places, the structure and the logistics and the ability to find this unrelated donor, depending even on your ethnicity, can have a huge impact on finding a donor in the registry. Patients who can wait, patients who don’t have complications of their disease, patients who can find a donor very quickly, who can then undergo all the pretransplantation evaluation and be admitted and have the transplantation done in a very timely fashion—I think you’re talking about a very small group of people. My concern is that you do have very effective therapy that you can offer.

For me, the more logical and rational approach, if you don’t have an unrelated donor, is to treat them, and in 3 months, you’ll know whether they responded to immunosuppressive therapy. By then you’ll know whether you have a donor. So you can kind of go to transplantation at that point if patients are not responding. But some centers can pull this off very quickly, and they tend to find unrelated donors also rather quickly. But again, it has to do with a lot of operational and logistical issues and genetic and ethnic backgrounds. I don’t think you can just make this into a broad statement. I think it has to be very center specific, country specific, state specific, in order to be confident to do that and try to recommend that.     

So the results for alternative donors or matched unrelated donors have improved over time, which is good given the fact that we’re better at supporting patients with blood banking, antimicrobials, better conditioning regimens, and better ways to diagnose infections and treat infections. The results have actually gotten better for the matched unrelated donors. Now, they have been preferentially used in patients who failed initial immunosuppressive therapy. So for those patients who don’t have a matched sibling donor, are younger, and do not respond to initial immunosuppressive therapy, that would be an option. But you have to start the donor search early because you can’t wait till the 6-month mark and say, “Oh, you didn’t respond, so let’s start looking for a donor.” That’s not good either. So you may want to start in these younger patients or somebody who you think you might offer an unrelated donor transplantation, to start looking as you start treating them with immunosuppressive therapy. Because by the time you research 3 and 6 months, you’ll absolutely know whether you have a donor, what kind of donor you have, and you can start making those decisions. This is a far more rational way of approaching this.
            
Now, the haploidentical is something relatively new. It’s being explored in several diseases, including in aplastic anemia. But if you look at the published literature with a more modern postcyclophosphamide day-3 or day-4 regimen, you only have 20 or 25 patients reported in the literature with limited follow-up. Conditioning regimens are a little bit different. So we don’t actually know how beneficial this treatment modality will be in rescuing patients with severe aplastic anemia. Clearly there is an activity. Patients do benefit, but there are only very few patients that have been reported, and we don’t have large prospective studies. So it is an option to consider. This should be done in the context of a research protocol or investigational protocol until we know better. But this is what shouldn’t happen in the setting of haploidentical, not because it doesn’t work or it doesn’t have activity; it’s just that we still have to understand more about it before we embark in this treatment modality for patients routinely, before we start recommending it.

Transcript Edited for Clarity 
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Transcript:

Phillip Scheinberg, MD: Age has a lot to do with transplantation eligibility because age and transplantation actually go hand in hand. We know that patients who are younger have better outcomes with stem cell transplantation. That’s true for both the matched related and the matched unrelated settings. So patients up to 20 do far better than those patients who are over 40. So if you look at a survival curve, matched sibling donor up to the age of 20 is about 80%. That number drops to about 60% and 65% between the ages of 20 and 40 and drops even more if you’re over the age of 40. You’re talking about a 50% overall survival. So you’re talking about survival of 80%, about 60%, 65%, to 50%. So this is a very linear, very correlative aspect between age and stem cell transplantation, both in the matched related and in the unrelated settings.

Although advances have been made in transplantation protocols in safety, the older patient is still a challenge. They’re still having a lot of complications from transplantation. Transplantation has also evolved, obviously, not only immunosuppressive therapy with the addition, for example, of eltrombopag. But there is still a drop of 10% or 20% of patients who actually either die from transplantation-related complications, complications of acute and chronic graft versus host disease, and infections. So it deceases with younger age. These tend to be more tolerated, but they can be very limiting in a nonmalignant disease like aplastic anemia.

Doing bone marrow transplantation or stem cell transplantation in patients with aplastic anemia is something that evolved historically, meaning that this was a modality that was developed in the early 1970s, when transplantation was starting to become more feasible. Aplastic anemia, interestingly, was one of the first diseases actually to benefit from stem cell transplantation because, remember, in order for a stem cell transplantation to be successful in aplastic anemia, you need to engraft and not die from the transplantation or not have complications from the transplantation. So you don’t have to have a graft versus tumor effect or graft versus leukemia or graft versus myeloma. You just have to engraft, and if they don’t have complications, you’re pretty much cured of the disease.

The issue is that the only trial that compared transplantation with something else with androgens was in the 1970s, and there’s been no trial comparing immunosuppressive therapy with transplantation frontline. So historically, the transplantation has been incorporated into treatment. So if you’re less than 20 and for sure have had a matched related donor, transplantation should be offered, given that the results long term are pretty good and the increased tolerability of this treatment modality in the up-front setting.

Now, this is also extended to patients between 20 and 40 years of age, given that although the risks are higher, they’re still acceptable. The issue becomes that of unrelated bone marrow transplantation in the up-front setting. Now, if you look at the data in the results, they look, especially in the very young patient population, very similar to those of the matched related donor. The problem is that it takes several months, actually, to find an unrelated donor, and this unrelated donor may not pan out. And now you’re going to have somebody 2, 3, 4 months out not getting any specific therapy, with complications of neutropenia and transfusions increasing their burden. And so that’s very problematic when you have very effective therapy, as in the horse ATG [antithymocyte globulin] cyclosporine that, especially in children, is associated with an overall response rate of 75% to 80% and long-term survival of 90%. That’s really good, so I feel hesitant to recommend unrelated universally to all patients, not because the data are not good, just because of the complexity and the logistics of putting this all together and that patients actually might die waiting for an unrelated donor. So that’s not something that I think is too good.

I think it’s regardless of age. Having somebody wait 12 weeks or 3 months for an unrelated donor—I think that’s complicated. If you can do this in a month or 3, I think that’s OK, but you would have to be in a very select patient population. Some patient populations are just very heterogeneous. You look at some countries like Japan, which tends to be more homogenous, or in certain parts of Europe. But if you look in other places, the structure and the logistics and the ability to find this unrelated donor, depending even on your ethnicity, can have a huge impact on finding a donor in the registry. Patients who can wait, patients who don’t have complications of their disease, patients who can find a donor very quickly, who can then undergo all the pretransplantation evaluation and be admitted and have the transplantation done in a very timely fashion—I think you’re talking about a very small group of people. My concern is that you do have very effective therapy that you can offer.

For me, the more logical and rational approach, if you don’t have an unrelated donor, is to treat them, and in 3 months, you’ll know whether they responded to immunosuppressive therapy. By then you’ll know whether you have a donor. So you can kind of go to transplantation at that point if patients are not responding. But some centers can pull this off very quickly, and they tend to find unrelated donors also rather quickly. But again, it has to do with a lot of operational and logistical issues and genetic and ethnic backgrounds. I don’t think you can just make this into a broad statement. I think it has to be very center specific, country specific, state specific, in order to be confident to do that and try to recommend that.     

So the results for alternative donors or matched unrelated donors have improved over time, which is good given the fact that we’re better at supporting patients with blood banking, antimicrobials, better conditioning regimens, and better ways to diagnose infections and treat infections. The results have actually gotten better for the matched unrelated donors. Now, they have been preferentially used in patients who failed initial immunosuppressive therapy. So for those patients who don’t have a matched sibling donor, are younger, and do not respond to initial immunosuppressive therapy, that would be an option. But you have to start the donor search early because you can’t wait till the 6-month mark and say, “Oh, you didn’t respond, so let’s start looking for a donor.” That’s not good either. So you may want to start in these younger patients or somebody who you think you might offer an unrelated donor transplantation, to start looking as you start treating them with immunosuppressive therapy. Because by the time you research 3 and 6 months, you’ll absolutely know whether you have a donor, what kind of donor you have, and you can start making those decisions. This is a far more rational way of approaching this.
            
Now, the haploidentical is something relatively new. It’s being explored in several diseases, including in aplastic anemia. But if you look at the published literature with a more modern postcyclophosphamide day-3 or day-4 regimen, you only have 20 or 25 patients reported in the literature with limited follow-up. Conditioning regimens are a little bit different. So we don’t actually know how beneficial this treatment modality will be in rescuing patients with severe aplastic anemia. Clearly there is an activity. Patients do benefit, but there are only very few patients that have been reported, and we don’t have large prospective studies. So it is an option to consider. This should be done in the context of a research protocol or investigational protocol until we know better. But this is what shouldn’t happen in the setting of haploidentical, not because it doesn’t work or it doesn’t have activity; it’s just that we still have to understand more about it before we embark in this treatment modality for patients routinely, before we start recommending it.

Transcript Edited for Clarity 
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