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aplastic anemia

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.

AAMDSIF Virtual Film Festival

Over the past few years, several documentaries and dramas about people living with aplastic anemia have been created by independent filmmakers and by patients themselves. These depict the everyday lives of patients coping with a diagnosis, the challenges presented by treatment and the hardship caused by inadequate medical insurance coverage.

Whether fictional movies, or stories about actual patients and families, these portrayals bring you into the world of bone marrow failure disease in an uncompromising and straightforward manner.

Pregnancy in Bone Marrow Failure Disease


What is the impact of bone marrow failure disease and its treatment on pregnancy?

Bone marrow failure diseases frequently occur in women who are young and of child bearing age. People with these diseases have legitimate concerns about whether a pregnancy will cause their infants to suffer from the disease or its treatment, or whether their own disease will relapse. But the goal of modern therapy and modern obstetrics is to minimize both maternal and fetal complications.

Experience from published reports suggests that in the past ten years, both maternal health and fetal outcomes have improved in women with aplastic anemia and PNH. However each bone marrow failure disease (aplastic anemia, MDS, PNH) has to be evaluated separately for pregnancy complications. The issues are different for each condition.

Fertility appears to be unchanged in people with these disorders compared to people without them. But in people who have had an allogeneic stem cell/bone marrow transplant, the immunosuppressive medications may affect the ability to become pregnant.

For PNH, has the use of eculizumab in pregnancy been studied?

There are cases of women who have been successfully treated with eculizumab. Recent information shows that with modern obstetric care, women with PNH can successfully give birth to children, but there is an increased incidence of complications compared to people without PNH. The major complication is premature birth. Other complications include the need for blood and platelet transfusions, anticoagulation with blood thinners, thromboses (blood clots) and hemorrhage. However, fetal outcomes are also improved with this drug.

Use of lenalidomide (Revlimid®) during pregnancy is known to be harmful because it can cause birth defects. Does this mean only other drug therapies can be used?

Lenalidomide is a derivative medication of the drug thalidomide. In the late 1950s and early 1960s, thalidomide was used as an anti-nausea medication during pregnancy. This caused babies to be born with abnormal body parts, and significant birth defects are associated with its use.

Lenalidomide is used in people with low-risk stages of MDS, and particularly in the 5q-MDS subtype, but it must be stopped if pregnancy is even being considered. This applies to both men and women! Other medications or transfusions can then be used to treat the anemia.

The company that manufactures lenalidomide maintains a risk evaluation and mitigation strategy program (REMS) which requires that in a series of interviews, patients taking lenalidomide are carefully screened and strongly encouraged to prevent pregnancies.  In addition, pharmacists and doctors are all asked to assess their patients for careful use of this medication.

What is most important for patients to know and remember about fertility and pregnancy in bone marrow failure?

Much progress has been made, and modern obstetrics is able to support both mother and fetus through high-risk pregnancies. However, there are still significant issues in people with bone marrow failure diseases that can affect successful pregnancies. The mother is still considered to be in a high-risk pregnancy even though the majority of these pregnancies are able to be successfully managed with current techniques.

Problem areas that remain are in high-risk MDS and fertility in people who have received an allogeneic stem cell transplant. There is a risk of relapse of aplastic anemia during pregnancy, although the response rate to treatment for relapse has been good. Eculizumab can successfully be used during pregnancy to control PNH.

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.

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.

Moderate, Severe, and Very Severe Aplastic Anemia: How are treatment decisions made?

Dr.Townsley is a staff 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. Her research interests include the pathophysiology


Are treatments for each category aplastic anemia (moderate, severe, and very severe) also category-specific or are they decided more on a case-by-case basis?

That’s correct—an aplastic anemia diagnosis is categorized in one of these three groups. The severe and very severe categories always require treatment. Usually the type of treatment is dependent on age, but once the cytopenias (low blood counts) are severe or very severe, some kind of treatment must occur. Moderate aplastic anemia means the blood count criteria do not qualify as severe and treatment is not always required – there can be a ‘watch and wait’ approach. Treatment is usually indicated based on the need for transfusions.  So if patients who have moderate aplastic anemia need transfusions, some sort of treatment is usually recommended. The type of treatment is not standard and could vary, depending on the patient. There are different treatment options that usually involve some sort of immunosuppression, as basic as cyclosporine alone, but also eltrombopag is being tested at the NIH for moderate aplastic anemia.

Does the advent of the newly approved drug eltrombopag (Promacta®) affect treatment decisions?

It does, but at this point it is only approved for patients with refractory aplastic anemia. This is when there is no response or success from earlier immunosuppressive treatment. It should be distinguished from recurrent or relapsed disease, where there is a response, but the aplastic anemia returns. In our trials here at NIH, roughly half of refractory patients responded to eltrombopag. Now we have an option for those who failed one or even several rounds of immunosuppression. But it also means we have a potential therapy that will be interesting to explore for upfront disease – people who are newly diagnosed, and even those with only moderate aplastic anemia. This is currently being investigated in clinical trials at the NIH.

Have you found it challenging to help patients understand that this is not “just anemia”?

Actually what is more challenging is making people understand that what they have is not leukemia. We find that many patients come to us thinking they have a leukemia-like cancer. This may be because they are referred from a doctor’s office where they’re in an environment with other cancer patients and even may have been told that what they have is something akin to a leukemic cancer. Many doctors have rarely seen aplastic anemia, and it is more common to see pancytopenia associated to leukemia. So often patients have been told they may have leukemia even before bone marrow biopsy results are in. So for patients with severe aplastic anemia, we want them to understand that, while not leukemia, it is a very serious disease, but is very treatable.

For patients with moderate aplastic anemia who may not be transfusion-dependent and may feel fine even though they have a low platelet count -- it can be more difficult to get them to understand there are risks and that they need monitoring and perhaps treatment.  This is most often the case with younger patients – adolescents or young adults. 

Have you found it challenging to help patients understand that this is not “just anemia”?

Actually what is more challenging is making people understand that what they have is not leukemia. We find that many patients come to us thinking they have a leukemia-like cancer. This may be because they are referred from a doctor’s office where they’re in an environment with other cancer patients and even may have been told that what they have is something akin to a leukemic cancer. Many doctors have rarely seen aplastic anemia, and it is more common to see pancytopenia associated to leukemia. So often patients have been told they may have leukemia even before bone marrow biopsy results are in. So for patients with severe aplastic anemia, we want them to understand that, while not leukemia, it is a very serious disease, but is very treatable.

For patients with moderate aplastic anemia who may not be transfusion-dependent and may feel fine even though they have a low platelet count -- it can be more difficult to get them to understand there are risks and that they need monitoring and perhaps treatment.  This is most often the case with younger patients – adolescents or young adults.
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Overlap Syndromes: When PNH Appears with Aplastic Anemia or MDS

Although even rarer than


How common is PNH appearing in patients with MDS or aplastic anemia?

The dual diagnosis of PNH and aplastic anemia is quite common. Perhaps half patients with PNH will have some sign of aplastic anemia, and a little less than half of aplastic anemia patients will develop the PNH clone. There are patients who fall more on one side of the spectrum or the other. Some will require treatment for PNH, some for aplastic anemia, some for both, and some for neither.

PNH can present with MDS, but that is a much rarer occurrence. There are some features of PNH that can be confused with MDS, such as the fact that patients with PNH often also have a hypercellular marrow, and 25% of patients with PNH can have a chromosomal abnormality. So by just looking at these features, one can see how PNH and MDS could be confused with each other.

However, the PNH/MDS category should be limited only to those who have significant increase in blasts (leukemia cells), a complex cytogenetic (chromosomal) abnormality or those with monosomy-7 if they are not responding to immunosuppression.  Those would be the three types of patients that I would think have PNH/MDS, and I have seen patients like this only rarely.

There are two other overlap syndromes to mention: one is PNH/AML, which is even rarer than PNH-MDS. This would be a patient who probably had PNH/MDS, where the MDS transformed to acute myelogenous leukemia. Then there’s the very rare PNH/MPN category, only seen in a handful of patients, where the MPN stands for ‘myeloproliferative neoplasm’. In my view, this only applies to patients who have myelofibrosis (scarring in the marrow), a chronically high white blood cell or platelet count, especially if they have the JAK2 mutation.

Does PNH appear concurrently with the other diseases or does it manifest after the other diagnosis has been made?

It can be either way. With aplastic anemia/PNH, PNH can occur before, at the same time, or after the aplastic anemia is detected. With MDS/PNH, usually it’s PNH occurring beforehand, or maybe at the same time. PNH does not generally develop after an MDS diagnosis, if they didn’t already have PNH to begin with.

Are there any areas where the boundaries or definition of one disease appears to overlap with another?

With aplastic anemia/PNH, both of those can be associated with anemia, although this happens for different reasons. In classic PNH, there is breakdown of red cells and the reticulocyte count is high, but with aplastic anemia, there is low production of red cells and the reticulocyte count is low. Sometimes what happens in aplastic anemia/PNH is the reticulocyte count will be elevated, but not to the level it should be. With PNH/MDS, even though hemolysis is a primary symptom of PNH, hemolysis can occur in rare patients with MDS for other reasons. This could be due to a few things – the acquired hemoglobin-H syndrome, or acquired pyruvate kinase deficiency for example.

Is PNH treated any differently when it appears in a dual diagnosis?

Patients with either overlap syndrome would be treated differently from a patient with only PNH. Patients having classic PNH may need eculizumab (Soliris®) or anticoagulants to prevent blood clots. Aplastic anemia patients need immunosuppression, generally being horse ATG followed by cyclosporine.

But patients with PNH/aplastic anemia overlap maybe not respond as well to eculizumab if they have a low reticulocyte count. They may need immunosuppression first, and may not be not be able to receive anticoagulants if their platelet count is low.

Conversely, for a PNH/aplastic anemia patient, there can be problems with ATG treatment. The reaction patients get with ATG can trigger hemolysis.  In patients a with large PNH red cell population who need aplastic anemia treatment, one thing to do is give them enough red cell transfusions, in order to dilute their PNH red cells so there are very few of them still there that can hemolyze when they receive ATG.  This might be two units of red cells a week every week for three weeks, for example. This could be enough to prepare someone with many PNH red cells to get ATG.

In the PNH/MDS overlap syndrome, at least in the very narrow definition I use, those patients should generally be treated with a stem cell transplant, if they have a donor. To prepare them for the transplant, it may be necessary with to treat them first with methyltransferase inhibitors to normalize their marrow, before going into a transplantation.

Are there possible complications from these treatments?

One thing to keep in mind is that patients with aplastic anemia typically get iron overload, sometimes requiring treatment for this, but patients with PNH often become iron deficient, and patients with aplastic anemia/PNH can have either situation, depending upon where they are on the spectrum.

Another way that the overlap syndrome can be important has to do with kidney function. Patients with aplastic anemia who require cyclosporine can experience an effect of the drug on their kidneys, and rare patients with PNH will develop a serious loss of kidney function as well. I suspect that the use of cyclosporine in a patient with a large PNH clone will be more likely to have an effect on the kidney function-- unless they are also on eculizumab.

Another consequence of the overlap syndrome is the effect of the combination of eculizumab and cyclosporine. In practical terms, if a patient is on either drug, they must go immediately to the hospital if they develop a fever. For cyclosporine, this is to make sure that they do not have one of many possible infections. For patients on eculizumab, in general this would be to make sure that they do not have meningococcal infections. For patients on eculizumab who are also on cyclosporine, there is always a theoretical concern that they might not be able to make antibodies in response to a vaccination because of the effects of the cyclosporine, and that they would be doubly immunosuppressed. However, if one uses this type of caution, patients who need both can be on both.

There are rare cases where patients have a triple diagnosis – PNH, aplastic anemia, MDS. Is there anything different about these?

These are exceedingly rare, at least when the narrower definitions and criteria for overlap syndromes are applied. In the case of PNH/aplastic anemia/MDS overlap syndrome, when the criteria for MDS is excess blasts, complex cytogenetic abnormalities, or monosomy7 with lack of response to immunotherapy, these cases should be considered for a stem cell transplant. But this only applies if this criteria is used. If you have a patient with PNH/aplastic anemia, and trisomy 8, this does not give a triple diagnosis according to the strict criteria that I would use. Trisomy-8 can be seen in PNH or aplastic anemia, but it doesn’t secure a diagnosis of MDS.

Should patients with an aplastic anemia or MDS diagnosis be concerned about the possibility of also having PNH?

All aplastic anemia patients should be tested for PNH at diagnosis and then maybe every year. Their LDH level should be periodically checked, as that can be an early sign that PNH is emerging. Early stage MDS patients should be tested for PNH at diagnosis, and if the result is negative, they don’t need to be tested further.

Then conversely, patients with PNH should be monitored for MDS, which would require a different treatment. The way to do this is to monitor blood counts. If patient with PNH has stable blood counts or is responding well to immunosuppression, then they’re presumed not to have MDS.  However, if they have falling blood counts, or if they’re responding initially to aplastic anemia treatment and their counts are coming back down, then those patients should have a repeat bone marrow biopsy because the reasons for the low blood counts could be MDS.

A falling blood count in a patient with PNH should also prompt a workup for an enlarged spleen as that can be a consequence of blood clots in the spleen or liver. A falling blood count in PNH doesn’t always mean aplastic anemia or MDS – it could be a blood clot causing an enlarged spleen. So a patient with PNH who is doing well, whose platelet counts have fallen, should have a bone marrow biopsy and a sonogram of the abdomen to check the spleen and blood flow in the abdomen.

Aplastic Anemia and MDS Overlap Syndrome

Significant attention has been paid to


How common is one of these diseases coexisting with the other?

This is a complicated topic because the bone marrow failure overlap syndromes are in fluid motion in the diagnostic pathway. Classically, MDS has a hypercellular marrow – too many cells. In contrast, aplastic anemia has a hypocellular marrow, showing a very low number of cells. But there is a subset of MDS called hypocellular MDS. This means there’s a low number cells, but it is still more like MDS than aplastic anemia – and the two diseases are closely linked. What is most often thought of as the defining difference between hypocellular MDS and aplastic anemia would be the presence of chromosomal abnormalities observed when the karyotype of the bone marrow is examined, with MDS being far more likely to have these chromosomal abnormalities. Aplastic anemia has these more rarely.

Are there overlapping symptoms of these two disease that would initially be cause for confusion or misdiagnosis?

Despite the difference I mentioned, the symptoms of both are very similar. Patients with either disease often have low red cells, low white cells, and low platelets. Thus, the confusion could lie in the similar blood counts, but the reason for these low blood counts is different. In aplastic anemiam there are no cells to make new blood, but in MDS,  there are too many bad cells that are not effective in making blood,crowding out the good ones. 

Are cases as a dual diagnosis such as these counted along with the individually diagnosed cases or are they regarded as a separate category?

This is an area of a lot of scientific debate. Usually, they’re more often as classified as MDS if they have the chromosomal abnormality I have mentioned. Aplastic anemia, with a normal karyotype and an empty marrow, is really the only condition that is categorized this way.  Once there has been an evolution – a changing of the chromosomes, this moves away from aplastic anemia to MDS, some call that the overlap syndrome but they are usually treated more as an MDS patient. Hypocellular MDS is often treated initially like aplastic anemia,  with immunosuppressive therapy.

Is treatment each disease any different than when they appear separately?

The first line treatment for an older adult with pure aplastic anemia is immunosuppressive  therapy. In older adults with hypocellular MDS, immunosuppressive therapy could be considered, but would never be considered in MDS where the standard of care should be hypomethylating agents, azacitidine (Vidaza®) and decitabine (Dacogen®), which of course are not used in aplastic anemia.

Should patients who have been diagnosed for one of these diseases be tested for the other?

The testing is same for both. A bone marrow biopsy is performed and chromosomal abnormalities are looked for in both. The observation of dysplasia would be checked for in both diseases.  Measurements of the earliest progenitor cells (or blasts) that are CD34 positive can be helpful to distinguish as well.
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