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aplastic anemia treatments

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.

Eltrombopag Added to IST Yields Encouraging Results


“Our current work demonstrates that stimulating remaining stem cells with a drug that mimics the actions of a natural growth substance for marrow stem cells while suppressing the immune system improves the likelihood, quality and speed of recovery in seriously ill severe aplastic anemia patients.” – Danielle Townsley, MD

How was eltrombopag originally considered to be tried in aplastic anemia?

At first, we had only hoped eltrombopag would improve the platelet transfusion frequency in patients who had not adequately responded to immunosuppressive therapy (IST). These refractory patients were continuing to require weekly transfusions for platelets and we hoped to improve their transfusion burden by giving them a drug known to be a growth factor for platelets. To our surprise, we observed not only an improvement in platelet counts but also noticed recovering red and white blood cells numbers. Although the magnitude of the response was somewhat unexpected, it made biological sense because the target of eltrombopag, the MPL receptor, can also be found on blood stem cells.

This new eltrombopag study is for all untreated severe aplastic anemia patients. Did this study evolve from earlier work or was it a freestanding, new point of inquiry?

Very often, new drugs are first tested in scenarios where patients have failed to respond to all other available treatments. So when we see some promise in that setting, the next step is to investigate its activity when added to an established standard therapy, and that is what was done here.

How was the criteria of the three study cohorts determined?

This study was first envisioned with just one cohort – a group of newly diagnosed
severe aplastic anemia patients who received eltrombopag in combination with conventional IST (horse ATG and cyclosporine).  Eltrombopag was started two weeks after receiving ATG and starting cyclosporine to allow time to recover from the side effects of ATG. When we saw improvement in the complete overall response rate at six months, we used this observation to inform the treatment schedule for the subsequent cohort of patients. For the second cohort, we wondered if less eltrombopag could achieve the same result and stopped administering eltrombopag at three months. However, responses in the second cohort were lower and we determined that a longer treatment period of eltrombopag was needed and perhaps administered without delay. In the third cohort, participants started all three medications immediately and continued the eltrombopag for the entire six months. In each cohort we adjusted the timing of adding eltrombopag to ATG and cyclosporine based on the results of the prior cohort. We call this an adaptive study design – it wasn’t all envisioned at the start.

Were there any other general aims as the study got started?

The general aim of the study was to see if adding eltrombopag to standard immunosuppression would be efficacious and safe. We aimed to see if the addition of eltrombopag would improve the complete response rate at six months, i.e. increase the proportion of patients at six months with near normal blood counts. Historically, only around 10-15% of patients achieve this after IST. With this combination therapy, we observed a complete response rate of 39%. Furthermore, we noted that overall 87% of patients responded (94% in the third cohort that received eltrombopag for the maximal duration). These rates are about 20% higher than the response rates in our patients treated historically with ATG and cyclosporine alone.

We also searched for any signals prior to treatment that could predict which patients were more or less likely to respond. One factor was age, which we knew about from previous NIH studies – younger patients responded at higher rates than older patients, and we found that to be the case in this study also. When we explored the data further, we also noticed that telomere length – they are the bits at the end of the chromosomes – also indicated whether patients would respond to the treatment. Telomeres get shorter with cell divisions and may represent how exhausted the bone marrow is prior to treatment. Patients who had shorter telomeres at the start of therapy and therefore more exhausted bone marrow were less likely to respond. 

This study was described as a “phase 1-2 study”. Does this mean phases 1 and 2 run concurrently, or run sequentially?

Phase 1 studies investigate dosage and toxicity information about a drug. Based on these results, subsequent phase 2 trials examine whether -- and to what extent -- the drug is effective for treating the disease while still extending the knowledge about side effects. Phase 3 studies aim to measure more precisely how efficacious a drug is and more precisely identify the safety profile for a drug. Increasing this precision requires hundreds to thousands of patient volunteers.

NIH is one of the few institutions where you might see a study classified as “phase 1 / 2”, since many of our studies involve rare diseases where we need to answer questions about safety and efficacy using a small number of volunteers as these diseases are so infrequent. For this study, we combined both approaches to happen at once, so it was a concurrent effort.  We weren’t sure if eltrombopag would be helpful and we didn’t know if it would be safe to give in combination with IST. So in this case, we really had to examine both efficacy and toxicity at once.

What toxicities/side effects were observed?

There were some side effects related to eltrombopag when we gave the combination therapy, but it was generally well tolerated across all patients in the study. The most serious side effect was severe skin rashes in two patients which required discontinuation of eltrombopag, but they completely resolved.

What were the most important and most surprising findings?

For over 30 years, NIH has been trying to improve the response rates to conventional IST. Nothing we tried was successful. Immunosuppressive therapies have been successful in blocking the immune system that destroys bone marrow stem cells in aplastic anemia patients.  The current work demonstrates that stimulating remaining stem cells with a drug mimicking the actions of a natural growth substance for marrow stem cells while suppressing the immune system improves the likelihood, quality and speed of recovery in seriously ill patients.

Could this have an impact on how and when stem cell transplants are used in aplastic anemia treatment?

There’s a study going on right now in Europe called RACE (NCT02099747). It’s the same combination therapy as we were doing, but some patients are randomly assigned to receive a sugar pill/placebo instead of eltrombopag – whereas in our study all patients received eltrombopag, ATG and cyclosporine. We will be observing this study for confirmation of our results.

Additionally, we need to observe patients treated with the combination longer to determine how the addition of eltrombopag may impact the risk of clonal evolution to MDS. A small portion (10-20%) of patients with aplastic anemia can develop MDS over the course of 10 years. We need to see how patients fare over many years following this therapy, paying particular attention to survival, relapse and rate of clonal evolution. Thus far, the findings are encouraging, but the patients in our study have only been followed for a couple of years. Once we have that longer follow-up data, we can compare it to the same data following transplant.

How important are the stated secondary outcomes: overall survival, overall response, relapse, and clonal evolution?

The primary outcome, improvement in complete response rate, is a good signal that the therapy is promising, but we also want to know about overall survival and survival free of any blood problem. This is why it is so important that patients volunteer to participate in studies and we at NIH are particularly appreciative of patients returning to NIH to be seen for many years after their treatment. This allows us to report how patients do long term.  

We compared the results from the combination therapy with that of our historic results with IST alone, and the rate of clonal evolution and survival are similar. At least at this point in follow up, we’re encouraged but we can’t say for sure until there’s a longer follow up term – at least a few more years, and further confirmation from the European RACE study.

How much of a role did the data on self-reported health outcomes play in evaluating a trial like this?

With improved blood counts and lessened need for transfusions, it’s intuitive to think that patients will feel better when their blood counts improve. Still, we wanted to survey patients and more accurately confirm that their quality of life was better. We do this with well-validated surveys in medical research and included these surveys in this study. Not many studies of aplastic anemia have included this component. So we wanted it to be part of this study, and we were glad to see that patients’ perception of their quality of life improved right along with their clinical outcomes.

What are they key points for newly diagnosed and longer term severe aplastic anemia patients to remember about this study?

Based on our study and the one that preceded it, eltrombopag is now becoming a very promising therapy for patients with severe aplastic anemia who do not have a stem cell transplantation option or for whom transplantation is too risky. It may eventually be a viable therapy by itself or in combination with cyclosporine alone – something we will be testing here at NIH in our next study. We believe it will be useful in locations where ATG is unavailable, with patients who can’t tolerate ATG, and for patients who are more likely to respond to combination therapy that includes eltrombopag.

However, in newly diagnosed severe aplastic anemia it’s not yet clear whether eltrombopag will be something that all patients should receive. Whether it becomes a label indication that patients can receive from their own doctors has a lot do to with what happens when this study comes up for FDA review. But we believe the results are encouraging.

Are other studies in progress at NIH for aplastic anemia?

One new study is already underway – a protocol to try to prevent relapse in patients who remain on cyclosporine and are at risk of relapse when they stop. Long term, the effects of cyclosporine on the kidneys can be harmful. Approximately one-third of patients relapse when cyclosporine is discontinued.

Because of this, we are investigating whether brief treatment with another oral immunosuppressant drug, called sirolimus (also known as rapamycin), can prevent relapse from occurring. This is a study for patients who had improvement of their blood counts following IST but remain on cyclosporine. In our study, we randomly assign participants to stop cyclosporine and receive sirolimus for 3 months, versus just stopping cyclosporine.  We hope sirolimus will re-train the immune system to be more tolerant of the bone marrow stem cells and not attack them, as occurs in relapse.

Eltrombopag is under study in other NIH protocols and at academic institutions to treat additional types of bone marrow failure. At NIH, we are currently planning a study that investigates the use of eltrombopag in Fanconi anemia, an inherited bone marrow failure syndrome that mostly affects children and young adults. Eltrombopag may also benefit patients in developing countries where aplastic anemia is more common and bone marrow transplantation and other intensive therapies for marrow failure are unavailable.

Hematopoietic Stem Cell Transplantation in Aplastic Anemia


How do you currently think about the role of stem cell transplantation in aplastic anemia?

This is an exciting time for advances in stem cell transplantation, with marked improvements in outcomes for unrelated donor transplants. When considering treatments for newly diagnosed aplastic anemia, we explain to patients the short- term and long-term risks and benefits of the different treatment alternatives. For young patients, the risks of matched sibling donor transplantation are low and outcomes are excellent. Stem cell transplant is the only curative therapy for aplastic anemia, so if there is a matched sibling donor, that is the treatment of choice for young patients. This has low upfront and long-term risks for young people, so the pediatric and young adult populations are the best candidates.  

For young patients lacking an HLA-matched sibling donor, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine has been considered the first-line therapy. Up to 80% of patients become transfusion-independent and attain adequate neutrophil counts, and a smaller number of patients attain normal blood counts. Limitations of IST have included refractory disease, relapse and long-term risk of developing myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).  Many patients treated with immunosuppressive therapy do not need transfusions, but continue to have low blood counts that impair their quality of life.

Recently, the outcomes of unrelated donor transplantation have markedly improved. Previously, there was a high risk of adverse outcomes with unrelated donor transplants. The preference was to use immunosuppressive therapy (IST) because the upfront risks were low. In the past, when unrelated donor transplantation was much riskier, it was only resorted to as a third-line therapy, depending on the status of the patient.

Now we have retrospective data from Europe, and from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), a non-randomized prospective study in patients failing immune suppression undergoing unrelated donor bone marrow transplantation (BMT). This shows equivalent survival rates in young patients with unrelated donor transplant compared to matched sibling transplants. There appeared to be a long-term benefit when comparing unrelated donor transplant to immunosuppressive therapy. However, it is important to keep in mind that these studies were non-randomized, small and with a limited duration of follow-up. An important aspect of these studies was that in addition to excellent survival, the risk of events such as relapse, refractory disease, or clonal progression that we see with IST, was not seen after transplantation.

For the pediatric population, where we expect many years of life post-treatment, these long term issues are critical to consider. Although we do not have long-term data specific to transplantation for aplastic anemia on these regimens, these agents have been used for transplants at these types of dosages for many years with lots of long-term data. Overall, in discussion with my transplant colleagues, concerns of long-term effects are low, but still need to be studied carefully.

Should IST be tried first?

It could be asked what the potential downside is for trying IST first before going to transplant and resorting to unrelated donor transplant only if there is failure, relapse, or poor response to IST. After all, unrelated donor transplants are still associated with risks such as engraftment failure and graft versus host disease (GVHD).

However, potential transplant risks may increase with delayed time to transplant, which is especially true with refractory disease. With prolonged neutropenia, the risk of infection, particularly fungal infections, increases transplant risk. With multiple transfusions, the risk of failure of engraftment may increase when a stem cell transplant is finally performed. Iron overload from frequent red cell transfusions over a long term can increase transplant risk. We have observed that the rate of iron overload can be surprisingly rapid in some aplastic anemia patients with refractory disease.

Also, remember that if aplastic anemia develops into MDS or AML, then outcomes aren’t as good. The survival is lower due to increased treatment-related toxicities as these conditions have to be treated more aggressively – especially for AML. Even for MDS, you can’t use the standard conditioning regimen that would be used for aplastic anemia. You now have to give more intensive therapy to eliminate pre-malignant clones, which is associated with higher toxicity. With MDS and AML, you now have to also deal with the risk of relapse of the malignant cells. Relapsed MDS or AML is much more challenging to cure. It all just becomes more complicated.

We currently need more data to inform the role of unrelated donor transplant as upfront therapy for young patients lacking a matched sibling donor. Based on this, the North American Pediatric Aplastic Anemia Consortium (NAPAAC) in collaboration with the Pediatric Blood and Marrow Transplant Consortium (PBMTC) has begun a randomized, prospective analysis of IST versus matched unrelated donor transplants in pediatric aplastic anemia for patients lacking a matched sibling donor.

How does the diagnosis of a genetic bone marrow failure disease affect treatment?

A small subset of patients with aplastic anemia have a genetic cause of their disease.  The identification of a genetic cause affects decisions about the course of treatment. Patients with genetic bone marrow failure disorders generally have poor, partial, or transient responses to IST, so a transplant is the preferred treatment. However, these patients often have increased sensitivity to the standard chemotherapy and radiation regimens that are routinely used for an unrelated donor transplant. This calls for an individually tailored therapy, depending on the underlying disorder, to avoid excessive toxicity.

Does the use of eltrombopag in treating aplastic anemia affect the decision to proceed to stem cell transplantation?

Eltrombopag has been one of the most exciting recent advances in non-transplant treatment for refractory aplastic anemia. Results of the NIH trial of upfront treatment with eltrombopag plus IST are eagerly awaited. What is not known is if eltrombopag affects the risk of secondary events such as relapse and clonal progression, especially in the pediatric population. These are concerns that still need to be studied and fully evaluated because at this stage we don’t know.

Are there any other factors to mention?

For unrelated donor transplants, it takes time to identify the donor and harvest the bone marrow, so there is a delay in starting treatment. IST can be started right away.  However, responses to IST are typically not seen until 3 to 6 months of treatment, while recovery of blood counts after transplant is typically much sooner, typically within 3 to 4 weeks of initiating transplant. Whether eltrombopag might change response rates to IST remains to be determined. An important consideration when deciding between IST versus transplant is how quickly an HLA-matched donor can be found and cleared for collection. Donor availability will inform the decision as to which patients could consider an unrelated donor transplant.

So although recent data with unrelated donor transplants for young patients with aplastic anemia are very encouraging, more studies are needed to determine whether outcomes are superior to those with IST and to identify the factors that guide treatment decisions for each patient.

Dr. Kasiani Myers: Acquired and Inheirited Bone Marrow Failure


What is the difference between acquired and inherited bone marrow failure disease?

Hereditary bone marrow failure results from a genetic predisposition that makes marrow failure more likely to occur. There’s a wide variety of inherited bone marrow failure diseases that are caused by mutations in a wide range of pathways. Some involve DNA repair issues, some involve ribosome issues, (which are the enzymes that help translate the protein in our bodies) and others involve telomere diseases (the ends of our chromosomes that protect our DNA).

The mutations that lead to these diseases are in the DNA right from birth. The problems with these pathways lead to bone marrow failure. These often involve the accumulation of damage to the function of fast-dividing cells, such as in bone marrow.

Acquired aplastic anemia is thought to be primarily an autoimmune, or immune-mediated disorder. So a trigger of some kind sets off the immune system to destroy bone marrow stem cells. Usually acquired aplastic anemia patients don’t have other issues associated with it, but inherited aplastic anemia patients may have issues outside of the bone marrow, including other organ toxicities or functional issues that go along with the disease.

Even though the origins of bone marrow failure can be different, are the treatments the same?

Knowing how aplastic anemia originated is important because it helps determine the proper course of treatment. Some treatments are the same, but some are not. The common treatment they share is bone marrow/stem cell transplantation. This provides a new immune system to replace the one that no longer works, and has been functionally destroyed.

We do use chemotherapy for both categories of aplastic anemia, but the type and strength of this chemotherapy is often very different. The majority of inherited marrow failures are very sensitive to specific types of and doses of chemotherapy and the patient could be harmed if the wrong type of chemotherapy was chosen.

In acquired aplastic anemia, there’s an opportunity to reset or ‘reboot’ the abnormal immune system. In some patients who don’t have a matched sibling donor, instead of going to transplant we can try to reset the misbehaving immune system to retrain it to work properly and get rid of the cells that are attacking and destroying stem cells -- thus allowing the stem cells to repopulate the bone marrow. That’s not an option in inherited aplastic anemia—most patients have no response or if they do, it’s very short-lived if this is tried.

Why is that inherited aplastic anemia sometimes has other very rare disorders that also occur with it?

Inherited aplastic anemia is a systemic disease, so the entire body has a particular genetic predisposition toward it. This is generally a problem with a particular pathway that tries to prevent accumulation of DNA damage over time or helps fast dividing cells like stem cells. Because the bone marrow is such an active part of the body, it often runs into trouble in these diseases because it is busy all the time creating blood.

Conditions such as Fanconi anemia, Shwachman-Diamond syndrome and a few others are really the pathways to inherited aplastic anemia—different pathways, but the end result is the same. And because the pathways are somewhat different, the treatments are somewhat different.

These processes may have been going for years without anyone knowing it. But once patients start having symptoms of aplastic anemia, then they have medical examinations that trace back the cause and that’s when the discovery of inherited aplastic anemia and a family history is made.

Even though MDS has far less of a link to a hereditary component, there are still very rare instances where multiple members of a family, (including parents, children and grandparents) have MDS. What is at work here?

That’s an area of current, active research. Many of the inherited marrow failures also have a predisposition to MDS. So if you have multiple family members with MDS you should think about inherited marrow failure syndromes. There are many more diseases that are just beginning to be discovered, such as GATA-2. This a recent example showing that people who may not be predisposed to aplastic anemia may have a high risk of MDS. There are particular pathways at work that lead to the development of MDS, and research is ongoing to understand just why this happens.

How important is it for patients and families to be concerned about the origin of the disease if the real focus is be on treating it?

It’s critical, especially in pediatrics. 20 to 30% of pediatric aplastic anemia is thought to be inherited. So that’s a quarter of this pediatric population whose treatment could be dramatically different!  Here, you could really cause harm by choosing the wrong therapy, and that would also be a reason to make sure other family members aren’t at risk. Another reason why it is important to know about inherited aplastic anemia is because a potential sibling donor could also have it, even if they are asymptomatic, and then the transplant wouldn’t be successful.

Immunosuppression and Stem Cell Transplantation – How Are These Treatments Chosen?

Immunosuppressive therapy and stem cell transplantation are both used in treating


Aplastic Anemia

For around 80% of aplastic anemia patients, the underlying cause of the disease is immunologic – it’s an autoimmune disease. As with other autoimmune diseases like multiple sclerosis, lupus, or even rheumatoid arthritis, the body has misdirected its immune response. In the case of aplastic anemia, the immune system targets the bone marrow stem cells, which causes bone marrow failure. So an immunologically-based therapy has the potential to alleviate this immunologic defect. 

With patients for whom stem cell transplantation is not feasible – and there are different reasons for this -- immunosuppressive therapy is used, most often anti-thymocyte globulin (ATG), cyclosporine, or tacrolimus, and sometimes high dose cyclophosphamide.  These aren’t cures, and we don’t anticipate in an autoimmune disease that that immunosuppressive therapy will be curative. But it palliates the disease, and most patients still require long-term treatment with these immunosuppressive agents as the disease can easily recur, especially with events like pregnancy.

In 20 to 40% of aplastic anemia patients, there is significant stem cell loss, and immunosuppression does not offer much in the way of potential improvement.  In this situation, we will try to use stem cell transplantation if we have the option, as it is curative. Here, the treatment is giving a higher dose of immunosuppressive therapy, and then supply stem cells from a donor. Graft rejection can occur but it is uncommon with the intensive immunosuppression provided by the transplant conditioning regimen as well as the post-transplant immunosuppression.

A relatively new option for patients who have failed immunosuppressive therapy and are not eligible for a stem cell transplant is eltrombopag (Promacta®). Thus far, it has been shown to work in about 40% of this group. This is a marrow stimulant, that at least in the small number patients who have been studied, has been useful in stimulating blood cell production. Eltrombopag is a growth factor, which was originally developed to treat immune thrombocytopenic purpura (ITP). It mimics the effects of thrombpoeitin, which is a natural hormone that stimulates platelet production. There are some concerns about its use of because some patients develop mutated blood cells. But again, there are also concerns with ongoing immunosuppressive therapy -- patients developing PNH or MDS. So because of these scenarios, we prefer to do stem cell transplantation if possible.


For MDS, we typically try and do stem cell transplantation instead of immunosuppression. This is because MDS can sometimes progress to acute myeloid leukemia (AML) or on to progressive bone marrow failure. There’s really only one subset of MDS that responds well to immunosuppressive therapy – hypoplastic MDS – where’s there’s a nearly empty marrow, but the cells that remain are dysplastic cells.  So immunosuppressive therapy in this case does ameliorate cytopenias (low blood cell counts) and is not curative, but can be useful for older patients or those for whom transplantation is not an option.


PNH is more complicated because there are several manifestations of it – hemolysis, thrombosis, and bone marrow failure. Bone marrow failure in PNH is less responsive to immunosuppression. Here we use eculizumab (Soliris®) to reduce the risk of thrombosis (blood clots) and reduce hemolysis. This treatment is not curative and is often given for an extended term. Marrow transplantation is typically used in the setting of bone marrow failure, and there are scenarios where aplastic anemia enters the picture and complicates matters.  So immunosuppressive therapy is really only used in PNH when aplastic anemia also develops.

These are complex diseases with complex therapies which can have substantial risks. Stem cell transplantation can be curative, and the other therapies are not. But stem cell transplantation can’t and should not be used in every patient even though it is a potential cure. The other approaches can provide long term control of the disease, lessened the need for transfusion or even complete transfusion independent, and lessen the risk of complications from bone marrow failure.

Interviews with the Experts Pioneering Quality of Life Research for MDS Patients


Dr. Gregory Abel received his MD and MPH from Columbia University in 2000. He completed his postgraduate training in internal medicine at Massachusetts General Hospital and his hematology/oncology fellowship at the Dana-Farber Cancer Institute. In 2007, he joined Dana-Farber as a member of the Hematologic Oncology program, as well as a researcher in the Division of Population Sciences.

Dr. Abel is a 2010-2012 AA&MDSIF grant recipient for his research project, “Developing a Disease-Specifi c Measure for Quality of Life in Patients with Myelodysplastic Syndromes (MDS).” In this interview, he speaks about the origin, process, outcomes, and possible future applications from what was learned in his research.

How did your interest in quality of life issues for MDS patients begin?

It began by taking care of patients. As a fellow, I was lucky to be mentored by physicians such as Richard Stone and Daniel DeAngelo who have large practices of MDS patients. Most of these patients had the issues and concerns you would expect–for example, wondering how long they would live–but I noticed they also had many quality of life concerns.  For example, in addition to fatigue, they often experienced uncertainty and anxiety, changes in their day-to-day functioning, inability to care
for others, and financial issues, to name a few. In discussing these issues with my clinical mentors, we thought it would be important to measure MDS-related quality of life in a rigorous way..

How was your general interest in this area refined to the specific subject for your AA&MDSIF-funded project?

I’m a health services researcher, which means I focus on how blood cancers affect populations at large. While I was learning how to take care of patients with MDS, I also was learning how to perform research under the mentorship of the late Jane Weeks, who was a pioneer in this area for cancer. I wanted to focus on quality of life for a defined group patients. Developing a quality of life measure for MDS seemed liked a good match, since I wanted to devote my clinical time to taking care of patients with MDS.

Most of the measures that already existed only focused on general quality of life, or quality of life for patients with cancer, and while MDS has similarities to cancer, it’s not the same as other cancers like pancreatic or breast cancer. We felt that a new MDS-specific quality of life measure was needed. It was a good match because I had also learned about the program that AA&MDSIF has to help young researchers. So I applied for funding, was delighted to be awarded the grant, and that’s how I was able to develop this new instrument.

What specific activities were part of the research project?

The part that AA&MDSIF funded was the development of the tool. We first held a series of focus groups. One included patients with MDS and their partners and families. Another group included MDS physicians, and a third group contained nurses, physician assistants, social workers, and a representative from the A&MDSIF. Our mission was the same for each group: to elicit the most important ways in which MDS affects the quality of life of affected patients.

We categorized the information that we gathered from these three groups into broad domains and more specific question topics. We then refined those questions topics into actual questions and created our draft instrument, known as the Quality of Life in Myelodysplasia Scale or QUALMS-1. We next piloted it on another set of 20 MDS patients, which we interviewed one-on-one, adjusting the measure after each interview. We went through the instrument with each patient in detail, asking if the questions made sense to them and were relevant to them. We also asked if any of the questions were seen as offensive or intrusive. When we were done, we felt confident that our instrument captured many of the main concerns of patients with MDS.

The next step is to take our instrument and compare it to other ones that are not MDS-focused, but are concerned with quality of life, using a new multi-institutional group of patients (Canada, US, and Europe) to assess its performance. This is our current validation project which is being funded by the Canadian Cancer Society. This project is observational in that we are gathering information about patient’s quality of life but not intervening on the disease. We also have an interventional validation in the works which is going to be undertaken with the Clinical Trials Network that is funded by the AA&MDSIF Clinical Research Consortium.

What were the general findings, and were any of them surprising to you?

The primary observation was that around 40% of patients on the NIH trial who were refractory to immunosuppression did have a response to eltrombopag, whether platelets, white or red blood cells or any combination. Some actually were tri-lineage, meaning responses in all three cell types, some had two cell lines improve, and others were just one of the three. But 40% had a response of some kind that was clinically meaningful, for instance being able to discontinue red cell or platelet transfusions.

What are the next steps for building on the results of your research?

We’re in the process of validating the measure and figuring out the best way to score it. My hope is that once we have a validated measure, and once we understand the psychometric properties of our measure, we will see it incorporated into clinical trials. That’s one thing we will be doing through the AA&MDSIF Clinical Research Consortium. Another idea is that this measure can eventually be included in routine patient care. Some of my future work will focus on how we collect this information in the “real world” of patient care outside of clinical trials. Additionally, it might inform doctors about how patients are doing with treatments, or even if they are ready to have treatment because their quality of life is adversely affected by MDS.

What would you most like MDS patients and caregivers to know about your quality-of-life findings? Is there anything they can currently apply to their daily lives and long-term outlook?

Through the process of developing this measure and the validation study, I have been privileged to interact with many of the MDS thought leaders in the country. I am pleased to say they really understand what we are trying to do. They care about patients’ quality of life, and they understand that this is an important outcome in addition to helping patients live longer. There is a real enthusiasm about this measure and understanding of its importance for this disease.

So patients should feel comfortable talking to their doctors about their quality of life – for example, if they feel tired, anxious, or uninformed. These are some of the things that came out in our measure. Doctors who take care of MDS patients really do want to know about these things. So until the QUALMS-1 is ready for use in the clinic (and even after), I encourage patients can talk to their doctors about these issues. They will be surprised that the doctors are receptive to discussing issues like this in addition to disease and treatment-related topics.

Eltrombopag: Recent Discoveries on Potential New Applications for Aplastic Anemia


Dr. Townsley is a staff physician and clinical investigator in the Hematology Branch of the National Heart, Lung, and Blood Institute (NHLBI) at the Clinical Center of the National Institutes of Health (NIH) in Bethesda, Maryland. She conducts her clinical and laboratory research in the department of Dr. Neal Young, Chief of the Hematology Branch of NHLBI. Dr. Townsley is currently the principal investigator for multiple trials investigating new approaches to the treatment of bone marrow failure, primarily severe aplastic anemia. Her research interests include the pathophysiology of marrow failure syndromes and the use of eltrombopag, a blood growth factor to treat aplastic anemia. She receives research funding support from Glaxo SmithKline, the manufacturer of eltrombopag (Promacta®).

What is eltrombopag and how does it work when applied to aplastic anemia ?

This is a drug that is already FDA-approved to treat another blood disorder called Immune Thrombocytopenia Purpura (ITP) – a blood condition that occurs when the body makes antibodies against platelets and destroys them very quickly, resulting in low platelet counts. Eltrombopag (Promacta®) was originally developed to treat this condition, and has been available for about six years for that clinical indication. It is a medication that can be taken by mouth that mimics the action of the hormone thrombopoietin, a substance made by the body that is know to be very important to stimulate production of platelets, and thus it is termed a “thrombopoietin mimetic.” Since then, we designed a pilot trial to test its use in patients with severe aplastic anemia (SAA) who had failed other treatments, which were most often multiple rounds of immunosuppressive therapy. This is known as refractory SAA. When tested in this setting, it was found to not only improve platelet counts in some patients, but also improve white and red blood cell counts. This was a surprising finding, as the drug was really designed to improve platelet counts.

Based on that, when we looked closely at the biology of the way the drug works, we knew that it could potentially be stimulating the stem cells – these are the cells in the bone marrow that give rise to all blood cells.

What were the circumstances that led to its being tested in clinical trials for aplastic anemia?

Originally we weren't that hopeful that eltrombopag would be useful in aplastic anemia, because the drug is only used as a growth factor for platelet growth. We knew that other growth factor types of drugs were tried in aplastic anemia and they had not been successful. So we weren’t hopeful, but since eltrombopag is a pill and is easy to administer, the NIH decided to embark on a trial to prove or disprove its efficacy because there are few therapies available to patients with refractory aplastic anemia.  Additionally, we thought it would be likely that physicians would be using it even without data. We wanted some data to show whether or not it would be useful, but also it was a low-risk intervention that happened to have unexpectedly good results.

What is meant by the “breakthrough therapy” designation given to eltrombopag for use in severe aplastic anemia?

The FDA recently granted eltrombopag a ‘breakthrough therapy’ designation. This is part of a new FDA program that is aimed at accelerating development and review time of drugs needed for serious, or life threatening conditions.  In this case, it was not for newly diagnosed SAA, but specifically for patients with SAA whose disease was refractory to immunosuppression. The important thing to understand is that the designation does not mean the FDA has already approved its use, rather the designation only shortens the usual review time and approval process. Even if it is eventually approved, this approval at least initially will only apply to patients with refractory SAA -- not other patients with aplastic anemia.

What were the primary discoveries in these research studies on eltrombopag when used for treating aplastic anemia?

The primary observation was that around 40% of patients on the NIH trial who were refractory to immunosuppression did have a response to eltrombopag, whether platelets, white or red blood cells or any combination. Some actually were tri-lineage, meaning responses in all three cell types, some had two cell lines improve, and others were just one of the three. But 40% had a response of some kind that was clinically meaningful, for instance being able to discontinue red cell or platelet transfusions.

What general new insights into aplastic anemia gained through these studies?

This was a big insight – we didn’t think that additional growth factors for this disease would be helpful. Many researchers had totally abandoned the idea. If you measure the level of growth factors involved in stimulating blood cell production from the bone marrow, including thrombopoietin, in the bloodstream of patients with aplastic anemia, they are already quite high in comparison to healthy people.  The hypothesis that driving already high levels even higher with a drug didn’t make sense to us – we just did not think additional growth factors would be helpful, particularly outside the platelet lineage.  So the result we obtained was very surprising to us.

Is use of eltrombopag suited for all classifications of aplastic anemia (moderate, severe, very severe)?

Right now we’d say the use of eltrombopag is not suited to any of those classifications, unless it’s part of a clinical trial.  That’s what’s important about the FDA designation. It’s not saying that it’s approved. We are hopeful but have to remain cautious about the use of this drug until the ongoing trials are completed. We want to discourage physicians from treating patients with this drug, unless it is part of a clinical trial.

How does eltrombopag fit in with existing treatments for aplastic anemia? For example, is it used in conjunction with ATG and cyclosporine?

We have a clinical trial going on now where we are trying eltrombopag in patients with newly diagnosed severe aplastic anemia, as a combination therapy -- this is in conjunction with horse ATG and cyclosporine which is the standard immunosuppressive treatment.  Our current trial is asking whether eltrombopag is effective if given at the beginning of the disease alongside with the usual therapy, for instance whether it will speed the pace of recovery, or increase the percentage of patients that respond. There should be some results from this trial that will be published by the end of the year. Whether or not we will be able to definitely say if it will be useful by the end of the year is not known, but we can at least give initial findings from the current clinical trial.

Is eltrombopag something patients should bring to the attention of their hematologist?

We think this is something patients should make known to their hematologist, in the sense that it is a newer therapy that is only available as part of a clinical trial. We strongly encourage hematologists to refer patients for clinical trials -- especially for aplastic anemia patients, as it is rare disease and we need more patients to capture enough data.

Also although we are excited and hopeful, and although we have had encouraging results, we have to be cautious. This is why the very close monitoring of patients that is part of a clinical trial is so important. We’re seeing patients not in a clinical trial being put on the drug, but at the wrong dose and for the wrong time period.  This is important because we are giving eltrombopag at very different doses than what is given for the FDA approved use for ITP. We are finding that some physicians are prescribing it, even though it is not yet approved. Without the clinical trials completed, physicians won’t know how to effectively and safely administer the drug. 

Where can patients go for more information about eltrombopag and its use in treating severe aplastic anemia?

Of course www.clinicaltrials.gov is a good place for patients to see what trials are available in their area, or at the NIH and it lists the eligibility requirements for each one. But patients who are further interested can read the original primary paper that appeared in the NEJM in 2012 (Olnes MJ, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. NEJM 2012 Jul 5]. This paper documents the trial for patients with refractory SAA where a response of 44% was obtained. There’s a more recent publication that was about a follow-up trial with an expanded group of patients and the result here was the 40% that I mentioned earlier. This was in in Blood, (Desmond, Townsley, and Dunbar), published December 2013.

Platelet drug shows clinical benefits for severe, unresponsive aplastic anemia


What is Eltrombopag?

Eltrombopag is a chemical designed to bind to and activate the receptor for thrombopoietin, a cytokine produced by the body essential for production of platelets and it now appears also hematopoietic stem cells. Eltrombopag can be given orally and has been approved by the FDA for treating chronic immune thrombocytopenia (ITP)

How does it work?

It appears to stimulate hematopoietic stem cells to multiply, as well as stimulate increased production of platelets from platelet precursor cells.

How is it given and for how long?

It is given orally as a pill once or twice a day. Some patients with ITP have been treated with the drug for years. In our aplastic anemia trial several patients have been on the drug for over two years.

Is Eltrombopag being used for both children and adults?

In ITP, trials have been carried out in children, but it is not yet FDA-approved for children. The aplastic anemia trial reported in New England Journal of Medicine included only adults. However, we are designing a new trial for patients with refractory aplastic anemia that includes children. We also currently have a trial open for patients with new onset aplastic anemia combining eltrombopag with standard ATG and cyclosporin treatment, and this trial enrolls children.

How long before patients see response?

Most patients did not begin to respond until after 12 weeks of treatment, and did not reach their maximum response for a year or more.

What if there is no response? Are patients still able to try other therapies?

As far as we know there are no reasons that patients would not be able to try other therapies. Some patients that failed eltrombopag treatment on our trial went on successfully to have allogeneic stem cell transplantation.

Are there any side effects?

Very few. At very high doses some patients can become jaundiced and in some patients there is liver inflammation that necessitates lowering the dosage.

Are you still enrolling patients for any trials with Eltrombopag?

Yes, we are carrying out several trials at present. We have one for previously untreated moderate aplastic anemia in adults, another for refractory aplastic anemia in adults (an extension of the published study), and a trial for combining eltrombopag with ATG and cyclosporine in children and adults with previously-untreated aplastic anemia.

One of the trials is also for patients with low- or intermediate-risk MDS.

Do you have a timeline for the Phase 3 clinical trial period and how soon Eltrombopag could be possibly be approved for treatment of aplastic anemia?

It is difficult to predict. We hope that given the long-term safety data from the ITP trials, and the rarity of aplastic anemia, approval may be hastened.

The complete citation for the article is:
Eltrombopag and Improved Hematopoiesis in Refractory Aplastic Anemia

Matthew J. Olnes, M.D., Ph.D., Phillip Scheinberg, M.D., Katherine R. Calvo, M.D., Ronan Desmond, M.D., Yong Tang, M.D., Ph.D., Bogdan Dumitriu, M.D., Ankur R. Parikh, M.D., Susan Soto, B.S.N., Angelique Biancotto, Ph.D., Xingmin Feng, M.D., Ph.D., Jay Lozier, M.D., Ph.D., Colin O. Wu, Ph.D., Neal S. Young, M.D., and Cynthia E. Dunbar, M.D.

N Engl J Med 2012; 367:11-19 July 5, 2012

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