Blood and Bone Marrow Tests | Aplastic Anemia and MDS International Foundation

Blood and Bone Marrow Tests

First-in Human Clinical Transplant Trial for Severe Aplastic Anemia

An interview with Richard Childs, MD.


How did the idea to study a particular type of stem cell transplant originate?

The idea for the study in question is an extension of a long line of prior research that was focused on ways to offer safe allogeneic stem cell transplants using alternative donors for patients who lack an HLA identical sibling or unrelated donors. This work that we began aimed at helping patients that did not have an HLA matched donor started about 12 years ago. This is when we tried to come up with a transplant regimen that would have a good chance of engrafting in patients who historically are at very high risk for graft rejection with mismatched transplant, while not causing GVHD even though a mismatched donor was used.

There was concurrent interest in using unrelated cord blood transplants and in using half-matched (haploidentical) donors for this objective. Each transplant approach has advantages and disadvantages. Cord blood has a very low probability of GVHD, but about half of aplastic anemia patients were rejecting cord blood transplants in initial trials. So aplastic anemia quickly defined itself as being very different in outcome than most patients receiving cord blood transplants, which were for hematological malignancies like various leukemias and lymphomas, all having a lower risk of graft rejection.

Aplastic anemia patients who are often heavily transfused leading up to a transplant (and thus sensitized to alloantigens because of the transfusions), are at increased risk of graft rejection. The lower T cell content and stem cell content in cord blood units likely accounted for why their rejection rate was so much higher.

Haploidentical transplants were just starting to be tested at that time and problems occurred with infections and graft rejection because the T cells that come with the transplant must be depleted, or you will encounter possibly lethal GVHD. Methods for T cell depletion included removing all the T cells from the transplant before it’s infused, something we call ex-vivo T cell depletion.

The other way to prevent GVHD is by performing the transplant with the T cells still present and then about 4 days later giving chemotherapy to kill these T cells. The approach we studied involved using a cord blood unit combined with haploidentical stem cells or CD 34+ positive cells that underwent ex-vivo T cell depletion.

This trial started in 2009 and was the first of its kind for aplastic anemia. It’s still open, has enrolled 29 patients and has an 84% long-term survival rate – with all surviving patients being cured of their aplastic anemia.

So that study got us started, showing that we could have a high engraftment rate with a low GVHD rate, and a surprisingly high survival rate for patients who did not have a matched donor.

What is the goal of your current study?

This more recent study could be thought of as the second-generation version of the cord blood transplant trial just described. The idea now is to dramatically increase the number of cells we transplant from the cord unit by expanding those stem cells outside of the body (ex-vivo) for 3 weeks to increase their number, and then refreeze the unit and thaw it when we are ready to do the transplant. The transplanted cord unit will have a substantially higher number of stem cells, and almost every study to date has shown the higher the cord blood stem cell number infused, the better the transplant outcome and the higher the survival. This expanded unit has the trade name of Cordin®.

Prior studies have also shown that the risk of graft rejection decreases dramatically if you have higher cord blood stem cell numbers. That alone may be sufficient to overcome the high incidence of graft rejection seen with cord blood transplants. We hope that by infusing a huge number of stem cells we will be able to prevent rejection, which will allow for faster engraftment than would occur with either a haplo or standard cord blood transplant.

The accumulated data suggests the best outcomes occur with patients having fully matched donors. Still, we’re very excited, actually amazed that our study with combining the mismatched expanded cord blood units and half matched donor stem cells had survival rates that are comparable with those from the fully matched, related donors.

The idea now is that if we can get much higher number of stem cells out of a single cord blood unit we should still have the advantage of the cord units not causing GVHD, but will overcome the disadvantages of the traditional cord transplant, namely high graft rejection rates. We hope to make graft rejection rates much lower and make engraftment occur much earlier than seen with a non-expanded cord unit or with a haplo transplant.

Why is cord blood mentioned less often when speaking of stem cell transplants?

You hear less about cord blood than you do about bone marrow or peripheral blood as source of stem cells because even though there’s a worldwide cord blood registry, there is just a limited number of frozen cord units available, usually around 700,000 units at any time.

Even though this number is limited, it still can potentially benefit many patients because with cord transplants you can do mismatched transplants. They can be mismatched for many different issue antigens. They rarely cause GVHD, in contrast to mismatched marrow or peripheral blood transplants where if one or more antigens are mismatched, there’s a significant increase in GVHD.

What’s remarkable is GVHD incidence with mismatched cord blood stem cells is lower than with fully matched related donor cells from marrow or peripheral blood.

How was it decided that this experimental stem cell transplant would be tried in aplastic anemia only after it was tried in other diseases?

Other diseases were tried before aplastic anemia for this kind of transplant we’re studying.  The technology that supports the expanded cord blood unit is very new -- only available in research settings for a few years. The concern was if cord blood transplants have a high rejection rate, this ex-vivo expansion could provide a higher stem cell number but still could hurt the other cells you need to facilitate engraftment, including T-cells.

The expanded cord units only have about one-third the number of viable T cells as a non-expanded one. One of the concerns we had with using an expanded cord unit with a lower T cell numbers was that it might compromise engraftment. But we are optimistic that the much higher stem cell numbers in these expanded units will offset any negative effect of a lower T cell number on engraftment.

We are still in uncharted territory at this point, and there is a concern that if this approach were not to work, the patient could reject the transplant and end up in worse condition than before the transplant.

That is why we decided for this study, the first cohort of patients would continue to receive added haplo ex-vivo selected CD-34+ positive cells as a safety net. This is so if the cord unit failed or was rejected, we would have still have the haplo transplant working independently, continuing to function. In our original study, we did see in three patients who had non-expanded cord units with haplo stem cells, where the cord unit was rejected but the haplo cells remained, and those alone were enough to cure the aplastic anemia.

If we see that the cord units are working as planned, the second cohort in the study will only receive the expanded cord units. Our hope is that we only need to use the cord unit, because we think this approach can have significant advantage over a half- matched transplant, including the lack of any need for chemotherapy after a haplo transplant. With those types of transplants, there is a need to use high doses of cyclophosphamide to kill GVHD-causing haplo T-cells which can make patients quite ill for a few days after the transplant. Further, treatment with cyclophosphamide after the transplant can also delay the time to engraftment because cyclophosphamide can suppress the transplanted stem cells.

With using only the expanded cord unit, this spares patients from the side effects of over-reactive allogeneic T-cells that cause “cytokine storms” and the need for chemotherapy after the transplant. There is also the real possibility that patients will engraft much quicker since we are transplanting a graft that has more stem cells than any other stem cell source, including a peripheral blood stem cell transplant.

Why is a particular male patient significant in this study?

In the case of the patient John V., we first told him about what we learned from the prior study, and the advantages we hoped to find in this new study using these enhanced cord units. He wanted to wait for this new trial to start rather than go in the older study that was currently open, and we felt it was safe for him to wait a few months for this happen.

We obtained the half-matched stem cells from his brother, and we found a good cord unit which after the expansion procedure had an extraordinarily high stem cell number. This transplant regimen uses a nearly identical conditioning regimen (chemotherapy, low dose radiation).as the earlier study. Normally there’s no engraftment seen with conventional transplants for at least 10 days – but in John’s case we could tell within just five days that his white cell count was starting to recover, and in seven days it had returned to a normal state.

We had hoped to see the cells come back quickly, but this was by no means a given. I have doing transplants for 23 years, but it was unprecedented in my experience with stem cell transplantation to see anyone with aplastic anemia recover their counts that quickly. There’s never been an aplastic anemia patient before John who has received one of these expanded cord units, nor an expanded cord unit after reduced intensity conditioning,  so he has made history in a few ways.

All the early engraftment studies show engrafting blood in his body has come from the cord blood stem cells, not the haplo cells. He is currently transfusion independent, has normal blood counts, and with the exception of reactivation of CMV virus, is doing absolutely great. We hope that after a few more transplants like this one we will be able to proceed without using the haplo stem cell backup as we move to the second cohort in this study.

What do you hope results from this current study?

At this point, things are happening as we had hoped. Our goal is to have expanded cord blood units available for aplastic anemia patients who need a transplant but don’t have a fully matched donor. The best case scenario is that these transplants will have high levels of engraftment, fast recovery of blood cells and a very low chance of complications such as GVHD.  

At NIH we work on “first in human” studies – these are pilot studies to establish proof of principle and proof of concept. If we are on to something that really looks promising, possibly even a new standard of care, then often further comparison studies are done outside NIH at multiple large academic centers. If results of this trial look good, that might be what happens next.