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aplastic anemia

Overlap Syndromes: When PNH Appears with Aplastic Anemia

Although even rarer than


How common is PNH appearing in patients with 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. With aplastic anemia-PNH, the PNH can occur before, at the same time, or after the aplastic anemia is detected. 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.

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.

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

Patients with the 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.

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 AA/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.

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.

The Pathologist’s Role in an MDS Diagnosis


Can you explain in general terms what pathologists do and what their specific roles are in an MDS diagnosis?

The pathologist is involved at every stage in the diagnosis and subsequent follow up of a patient being treated for MDS. Often, when the patient is detected to have low blood counts on a CBC, by evaluating a peripheral blood smear, the pathologist alerts the clinician that there may be underlying MDS and the patient should be investigated further in this direction. The pathologist is the one who examines the bone marrow specimen, confirms the diagnosis of MDS, and assesses for morphological features that are required to generate the prognostic score of high-risk or low-risk disease necessary for management decisions. Since the bone marrow sample is sent to the laboratory, often the pathologist is there to triage the specimen and see that it is sent to the cytogenetic lab, and for appropriate molecular testing to make sure all the necessary tests are conducted.

What should the two-way interaction be between an MDS patient’s treating physician and the pathologist?

Communication between the pathologist and clinician is very important in the diagnosis of MDS. A report by the pathologist of dyspoietic or abnormal morphological appearance of the blood cells on the peripheral blood smear of a patient with low blood counts may often initiate the further evaluation of MDS by the clinician However,  neither low counts nor dyspoiesis are specific only to MDS, and several other clinical conditions may mimic MDS morphologically.  Dyspoiesis in peripheral blood or bone marrow is not enough to make an MDS diagnosis. Talking to the clinician to find out the details of the patient history, results of other lab tests that may have been ordered, and other medical issues that may be affecting the patient are important for the correct interpretation of dyspoiesis, and to make a diagnosis of MDS. Sometimes the pathologist has to ask the clinician to order additional tests before a diagnosis can be rendered. An ongoing communication is needed to make this happen. There are situations when a definite categorization of MDS may not be possible, or there are co-morbid conditions confounding the interpretation. In these circumstances in particular, a discussion via a phone call or a meeting between the clinician and pathologist is necessary to resolve the concerns. In academic centers like ours, all newly diagnosed patients are discussed in a team setting at an MDS or leukemia meeting, attended by the treating physician, oncologist, hematopathologists, radiologists, and other specialty physicians as necessary,  so it is definitely a team-based approach.

From a pathologist’s perspective, what factors complicate an MDS diagnosis?

One of the complicating issues is simply not having the right tools, which include the appropriate specimen and the necessary clinical information about the patient. It may be that a CBC is not provided, or there is no concurrent peripheral blood smear with the bone marrow, or that the specimen is inadequate­­­­--and this can happen frequently. The technique of obtaining the bone marrow specimen is very important. Common problems are the biopsy being too small or fragmented or it includes cartilage and bone rather than marrow. Or else, the aspirated bone marrow material may be diluted with peripheral blood, or the smears not prepared properly even if the material is adequate resulting in crushing of the cells. Finally, a perfect specimen may be difficult or impossible to interpret if the staining is not optimal. These pre-analytic issues are the most important ones that can create a problem. Fortunately, these are problems that can be resolved by attention to detail and by training.

Of course then there are issues inherent to the disease. MDS is a diverse disease in terms of morphology with many reactive mimics. Although most often the bone marrow is hypercelluar, in about 5-10% of patients, it may be hypocellular when a distinction from aplastic anemia is very difficult. The dysplastic changes can be very subtle, and more often than not, in a hypocellular setting, when a diagnosis of MDS is dependent on cytogenetics, an adequate specimen for cytogenetic evaluation cannot be obtained. There are situations where the MDS may be associated with fibrosis, and distinction from myelofibrosis or a myeloproliferative/myelodysplastic overlap disease is very difficult. Similar to a hypocellular marrow, marrow aspirate material can often not be obtained from fibrotic marrows.

There are situations when there is an associated hemolysis, or the bone marrow is obtained after repeated transfusions, which can alter the morphology and confound the interpretation. And I must mention there are inherited bone marrow failure syndromes that may present for the first time at an older age. These bone marrow failure syndromes may not only mimic MDS, but they often predispose to MDS. The distinction is important for management and requires specific tools for diagnosis and involvement of geneticists and other specialty physicians.

How involved are pathologists in the diagnostic process in determining an MDS classification or subtype?

I would say very involved since the diagnosis is made and confirmed by the pathologist. The blast percentage important for prognosis is also determined by the pathologist, so the pathologist is very involved in the diagnosis, classification, and generation of the IPSS or other risk score necessary for outlining the treatment strategy for the particular patient.  The involvement does not end with a diagnosis. The pathologist is involved in the follow up – in assessing response to treatment or evolution of the disease.

Should patients be asking their doctor about what happens ‘behind the scenes’ in the pathology lab?

They should be curious to know what happens to the specimen obtained from their body. I think it is important for them to know the processes involved in arriving at a diagnosis. Patients should know about the procedure, ask what the tests are for; or should the specimen be submitted, if cytogenetics will be performed. They need to understand that many quality control measures are required to ensure the pathologist gets the right materials (we discussed the adequacy of the biopsy and the aspirate smears earlier, and the importance of the clinical history). MDS is often a difficult diagnosis, and many patients move from one institution to another before they find a doctor they are most comfortable with.  In most cases, a bone marrow procedure is performed at each institution. So there are several reports with different wording and interpretations, and since the disease may evolve with time, to get a complete picture, as a hematopathologist, I would like to evaluate all the previous materials. For continuity of care, it is important to have copies of all their reports. Generally, the patient does not directly contact the pathologist for questions regarding the report. The treating physician is the better person to answer their question and they should be the first contact, but the patient should know who the hematopathologist is, and if they can contact them if they wish to.

What is most important for patients to know and remember about the pathologist’s involvement in arriving at an MDS diagnosis?

Most patients do not know there is another physician involved in making the diagnosis, other than the one they see at appointments who reads out the report to them. They should understand that the diagnosis and management of MDS is a team approach. Also, if I were the patient, I would want to know if the physician reading their slides has a specialty certification.

How important is it for patients to have a pathologist who sees a significant number of cases of MDS, knows very specifically what to look for, and knows what to communicate to the treating physician?

It is essential. Hematopathology is a very specialized field. Just as a breast or prostate biopsy is best examined by a person who has special training in these fields, has seen many of these biopsies, and knows what to look for, a bone marrow biopsy is best examined by a pathologist with special training in the field, and preferably with many years of experience. Having worked in academic institutions that receive many consult cases, I have seen instances of both over-diagnosis and under-diagnosis of MDS. 
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Research Retrospective for AA&MDSIF 30th Anniversary - Dr. Neal Young


What do you think are the most impressive or significant advances in aplastic anemia research and treatment over the last five years since our 25th anniversary? If you extend this back 30 years, to 1983 (when AA&MDSIF was founded), what does the longer perspective indicate?

Of the advances in the clinic in the last five years, the most striking is the ability to extend transplants beyond just younger people, who have HLA matched siblings. Even though many individual studies have been relatively small, in general, the use of unrelated donors and transplant of older adults have been successful in many patients. The movement is even to more aggressive transplantation, for example, using half-matched family donors, and the good results obtained have been extraordinary and not entirely anticipated. In the non-transplant area, but also affecting transplant, our supportive care has improved. We are much better treating infections, especially fungal infections, excellent blood bank support means that platelets are readily available to most patients, changes in red blood cell transfusion methods have decreased the problem of alloimmunization, and removal of iron is easier with oral chelation. All these measures make transplant and immunosuppression much more likely to be successful and they impact on patients’ quality of life. .

Going back 30 years, there were almost no effective non-transplant treatments and transplants were restricted to limited numbers of patients. More broadly, our understanding of aplastic anemia is much better in the last decade or 15 years than it was in the 1980s. Understanding stem cell loss, the role of the immune system, less emphasis on the presumed chemical or drug that might have incited the disease –these are all positive developments.

At the same time, in the last five years, have there been setbacks or instances where you feel progress has not kept up with general expectations or predictions made five years ago?

There have been disappointments. In transplant, it appears that the use of bone marrow is really superior to peripheral blood as a source, and it seems the trend in transplant is moving away from harvesting bone marrow to the much easier (for the hematologist) collection of mobilized peripheral blood. While recognized scientifically. it is difficult for the community as a whole to revert to the more traditional harvesting of bone marrow even if that is more effective.

On the immunosuppression side, the issue is more intensive immuosuppresion using rabbit ATG or cyclophosphamide. I think those have yielded disappointing results. It is good that horse ATG works as well as it does, but the hope was that we could move beyond the standard regimen by intensifying, or making more specific the immunosuppression. Despite a very good basic conception of the underlying pathophysiology, we really don’t’ understand it in detail. So, empirically, horse ATG remains our best treatment.

Another thing the bone marrow failure community will have to contend with is the very real problem of antibiotic drug resistance. Aplastic anemia patients undergoing treatment are susceptible to infection, and it’s a sobering prospect to have to worry about bacteria that we cannot treat. General attentiveness in the medical community to appreciate use of antibiotics including the teams at hospitals doing surveillance, and general education of the population as a whole about the proper use of antibiotics—all this will have an impact on the bone marrow failure community and we should not lose sight of this.

With aplastic anemia, is there a consensus on overall direction research will take or needs to take --- or is this as diverse as the areas of interest that individual researchers or research teams have?

Here the answer is yes and yes. There is a consensus displayed in the interest in genomics, including high throughput technology that is very popular now in hematology and oncology and being applied successfully to bone marrow failure states. My own belief is that science works best when there is a balance between the community having general agreement on the important issues and some members of the same community who just don’t follow that lead and go with their own intuition and do something off the proscribed path.

In 2009, we asked a similar panel if generalist hematologists/oncologists were adequately informed about bone marrow failure disease, and what could be done to bridge any gap between the generalists and researchers/specialists. What are your thoughts in 2013?

This is difficult to answer. On one hand, there are internists or hematologists who aren’t specialized in bone marrow failure, but who feel confident --perhaps overly confident -- in their ability to evaluate and treat patients. In my opinion, that can be difficult because treating one patient per year with aplastic anemia doesn’t provide the experience they need to acquire.

A bigger issue is the future of hematology, and the bone marrow failure diseases are an excellent example of the desirability of a few highly specialized treatment centers that have vast experience in these rare diseases leading the way. By this, I mean having a patient’s treatment be directed from those centers and not by the community doctor who really has very little hands-on experience in rare diseases. I think that we would do better if patients were referred to major centers, to the largest extent possible, and that they enter into treatment research protocols so that we can amplify the rate at which we accumulate experience and data. Both referring physicians and patients need to support this approach. In my experience, patients want an answer to their specific situation but most of them have been treated by individual physician who has only seen a very few aplastic anemia patients. Patients and physicians often do not realize that treatments are established in clinical protocols. When I ask an audience of hundreds of patients how many are in a clinical trial, one or two raise a hand! So patients want the information, but they don’t understand where it really comes from--it’s not magic, and it’s not one very smart doctor. It comes from clinical research trials, replication of results, and associated basic lab work with patients’ blood and bone marrow samples. There’s going to need to be a ground shift in how we take care of patients with rare diseases like aplastic anemia.

So an important paradigm that comes from this thinking is that of coordinated care. Of course, patients are first seen by an internist, pediatrician, or hematologist somewhere close to home. But they come from all over the world to NIH to be evaluated, some to make a diagnosis, most to enter treatment protocols, and they all have their blood and marrow banked for future studies. Many can be treated in Bethesda, contribute to research and the good of other patients, and probably get the best support possible due to our huge experience in marrow failure--and then they’re sent home. Their care can be coordinated between experts at NIH and home treating physicians, who get very detailed instructions on how to manage neutropenic fever, how often to transfuse, and when iron chelation should be started. The patient returns to NIH periodically for landmark visits so we can collect data for our clinical research trials, but routine care is conveniently in the hands of the local hematologist. All groups – the patient, their local doctor, and the research community are well served by this arrangement. Most patients are able to travel to NIH relatively easily – we have people from all around the world coming here for the study, evaluation, and some treatment, and then the routine treatment is handed off to their local doctor. This is why coordinated care is a very desirable model to treat a rare disease such as aplastic anemia. But there is inconvenience and there is risk, and we as researchers, and patients with marrow failure in general should be very grateful to those who choose to enter research trials.

Education Topics: 


AAMDSIF hosts Patient & Family Conferences around the United States each year. Conferences are free to attend and include presentations by the leading medical experts in rare blood cancers and bone marrow failure diseases. It is also an incredible and important opportunity for patients to connect with one another and share support, answers and hope.

2020 dates and locations announced. Registration is now open! LEARN MORE