Research Retrospective for AA&MDSIF 30th Anniversary - Dr. Neal Young | Aplastic Anemia and MDS International Foundation

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.


Neal Young, MD, MACP

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Position / Title: 
Chief of the Intramural Research Hematology Branch
National Heart, Lung, and Blood Institute, National Institutes of Health

Dr. Young is the Chief of the Hematology Branch of the National Heart, Lung and Blood Institute and the Director of the Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation.  His professional career of over 30 years has been at the Bethesda campus of the National Institutes of Health.  Dr. Young’s research is in hematopoiesis, with an emphasis on the human and diseases of bone marrow failure, particularly aplastic anemia.  In his laboratory, there is a wide range of efforts in this area, from basic biology, as for example studies of human parvovirus B19 and stem cell mitochondrial DNA, to pure clinical research, including interventional trials in patients who are acutely ill with severe pancytopenia.  Dr. Young’s work work also includes epidemiology and has been highly collaborative, involving other NIH institutes as well as many academic investigators in the United States and other countries. He has have published over 350 original research articles, more than 150 book chapters and review articles, and is the editor or co-editor of ten monographs, including a textbook of hematology.  Many of his papers have been cited hundreds of times.  In his capacity as Hematology Branch Chief, Dr. Young supervises half a dozen Section Chiefs which include the current editor of Blood and the President of the American Society for Blood and Marrow Transplantation.  Dr. Young’s laboratory has trained several dozens of post-doctoral fellows, many of whom now occupy positions as professors and department chairman in Europe and Asia.  His clinic is noted to be the largest center nationwide for the study of bone marrow failure. The therapeutic advances developed there have changed the standard of care for patients with aplastic anemia, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, and have introduced many new approaches to the treatment of these serious blood diseases

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