clinical trial | Aplastic Anemia and MDS International Foundation

clinical trial

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.

What MDS Patients Should Know About Clinical Trials

Dr. Sekeres is Professor of Medicine, Director of the Leukemia Program, and Vice Chair for Clinical Research at the Cleveland Clinic Taussig Cancer Institute.  He earned his medical degree and a


Do you find that some patients don’t understand what clinical trials are?

There’s a wide range of patient knowledge and opinions about clinical trials. I have some patients who ask me about them because they want to be part of the latest research and latest opportunities to try new drugs or drug combinations for MDS. I also have patients who want nothing to do with them, saying in effect, “I don’t want to be a guinea pig,” – not wanting to be part of any kind of experimental study. 

Do some patients feel when clinical trials are recommended that this is a ‘last resort’ treatment option?

There are a wide variety of clinical trials, and it also depends on what the patient’s philosophy is on engaging in them.  Some reserve clinical trials for when all other options are exhausted –when there’s nothing else available for them. This isn’t really a last resort, though – I consider this another option when available therapies either aren’t appropriate or haven’t worked, after which there’s nothing but blood and platelet transfusions to turn to.

At present we have only a limited number of FDA approved drugs available for people with MDS. These are lenalidomide (Revlimid®), azacitidine (Vidaza®), and decitabine (Dacogen®). We use a few other drugs off-label, such as erythropoiesis stimulating agents (ESAs) like erythropoietin or darbepoeitin, or immunosuppressants like anti-thymoctye globulin, (ATG).  My approach is that we’ll always have those three approved drugs to fall back on. But if we have a trial that is available and right for the patient, let’s try that first and if there’s no success we can always go back to those available therapies.

Can you describe some current areas of MDS clinical research?

Clinical research runs the spectrum of a person’s individual experience with MDS. I try to think about research from a patient’s perspective –how we can improve this person’s experience from the very moment he or she is diagnosed. In a way, clinical trials are designed to answer these intrinsic questions. How can we improve a person’s quality of life? For this, we engage in research about quality of life issues. How can we help patients minimize the number of blood or platelet transfusions they receive? Here, we conduct research that looks at supportive care issues. How can we improve treatments for a patient’s lower-risk or higher -risk MDS?  Should we look at developing drugs specifically for those conditions? How can we develop drugs for those who have been exposed to other therapies that didn’t’ work for them? We call this refractory MDS, where there was no improvement after 4 or 6 months, or recurrent/relapsed MDS, where there is initial improvement, but then MDS returns to its original state. Ideas for clinical trials are built around areas of inquiry like these.

Who are the primary sponsors of clinical trials?

Trials can be sponsored by a number of different sources. A trial can be born in the institution where the patient is receiving care. The primary investigator may be the patient’s doctor, or perhaps this doctor wrote the trial. It could be for a drug that was developed in the cancer center that is finally reaching MDS patients. The National Institutes of Health (NIH) can also be a sponsor. Here at Cleveland Clinic, we just  last year completed a randomized study called the North American Intergroup study where trial participants -- people with higher risk MDS -- received either azacitidine alone, azacitidine and lenalidomide, or azacitidine combined with vorinostat.  I wrote this study under the auspices of the Southwest Oncology Group, which is one of the National Cancer Institute’s (NCI) cooperative groups.  We participated in this trial along with the Eastern Cooperative Oncology Group, the Alliance Oncology Group (which are all sponsored by NCI), and the National Cancer Institute of Canada. So, in this case, four government-sponsored cooperative groups participated in one study funded by the NIH.

Another common source of sponsorship are the drug companies themselves. Many drugs are discovered or developed by these companies, and they will conduct trials to see if the drug is safe and effective enough to be approved by the FDA – the majority of drugs have this point of origin.

What can an MDS patient in a clinical trial expect to learn?

Every clinical trial that is conducted in the US is registered in the domain, so the results will be reported there. It may take years before a clinical trial is finished, but the final results are always reported and those results are intended to be publically available. So patients have a great resource to learn about many clinical trials – their purpose and their actual progress.

Why is it important for MDS patients to consider participating in a clinical trial?

There are different reasons. My patients tell me one reason they will participate is the strict, rigorous schedule that is adhered to. Everyone has access to the standard level of care, but some are receiving care far beyond current standards. They may have access to a drug that works for them years before it’s approved by the FDA and widely available. Some participate for completely altruistic reasons – they really do want to help the next generation of MDS patients. But all patients know that there’s a chance they can’t be included in the trial and that even if they are, they may not benefit from the drug regimen being tested.

It’s an exciting time for MDS research, but we need MDS patients for the many clinical trials that are being planned or are in process. That’s the only way new treatments can result from the progress being made in basic research.

Clinical Trials: What Are Phases, and What Happens in Each One?


Clinical Trials: What Are Phases, and What Happens in Each One?

Generally, clinical trials go through three phases.

A Phase 1 study may represent the first time a drug has ever been used in human beings, but for our purposes, it’s more common that it’s the first time a drug has been used in someone with MDS. Frequently the drugs we use in a Phase 1 setting are ones that have been used for other conditions, and we’re now trying to find out if they are safe or have any effect at all in MDS.

The goal of a Phase 1 study is basic – just to determine the best dosages, and/or the best schedule for taking the drug, and that the drug is safe to give. Most people who enter a clinical trial are most interested in whether a drug works, though, which is counter to the express purpose of these trials! Drug efficacy is actually a secondary aim in Phase 1 trials, though sometimes we are pleasantly surprised at how effective even a Phase I trial drug can be. Everyone in a Phase 1 trial gets the drug.

A Phase 2 trial is often similar to a Phase 1 trial in that everyone in the trial gets the drug. There is often no placebo arm of this trial. This is called a ‘single arm’ study. However some newer Phase 2 designs do have a control arm, whether it is a placebo or another therapy – and this is known as a two-arm study. By ‘control therapy’ we often mean a known, existing therapy in use that is being tested against the new drug being evaluated. The primary goal of a Phase 2 study is to see whether or not the drug works. In MDS, this could mean eliminating blood transfusions or improving blood counts.

A phase 3 study is always randomized and always has a control arm, whether a placebo or standard therapy. The primary goal of these studies is to see whether a new therapy or a new combination of therapies, works better than an established therapy, or a placebo. These trials are frequently used for registration purposes, meaning for a drug to be approved by the FDA.

From Bench to Bedside: Why Research is Important

The speed of science often feels extremely slow for patients and families looking for a cure to a rare disease. Many treatment options available today are a result of many years of painstaking scientific discovery. AA&MDSIF believes in the benefits of research for the patients that rely on us for answers, support, and hope. Research is an essential element of that hope.[TODO]

Clinical Trials and Children

If your child has a bone marrow failure disease and you are considering a clinical trial, there are important things you need to know. For example, clinical trials in children, by law, must provide the potential for at least a minimal benefit. This section provides information and guidelines to help you make an informed choice about clinical trial participation for your child.