2008-12-09

When Dr. Neal S. Young graduated from Johns Hopkins School of Medicine in 1971, almost all patients who developed severe aplastic anemia (AA) died within just a few months. Today, nearly four decades later, their outlook is much improved. With modern immunosuppressive therapy and stem cell transplantation, more than 75 percent of patients diagnosed with AA survive at least five years. An important part of this progress has resulted from the ground-breaking laboratory work and clinical trial programs of Dr. Young and his colleagues in the Bone Marrow Failure Program at the Hematology Branch of the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute. Yesterday, Dr. Young — now the chief of the NIH Hematology Branch — discussed these exciting developments in biology and treatment of bone marrow failure when he presented the honorary E. Donnall Thomas Lecture.

One of the first obstacles that Dr. Young had to overcome to move toward a better understanding of the pathobiology of marrow failure was the widespread perception that AA is a difficult or even impossible disorder to study because of its heterogeneity, coupled with the paucity of cells in the marrow to examine. But epidemiological observations and other clues (e.g., the extreme hypocellular marrow seen in murine models of graft-versus-host disease, and AA’s concordance with other autoimmune disorders) suggested that AA was perhaps an autoimmune condition. Early successes with immunosuppressive therapies then prompted further mechanistic laboratory studies. As Dr. Young stated, “The pleasure in studying AA has really been the true bidirectional nature of translation between clinical observations and laboratory results.”

There are still many unanswered questions about AA etiology. For instance, the post-hepatitis forms of AA seem likely to be initiated by an aberrant response to a viral infection, yet markers of known hepatitis viruses are usually absent. A large NIH epidemiologic study in Thailand that Dr. Young mentioned in his presentation also indicated that a virus is likely to underlie many cases of AA. Likewise, interest in viral causes of AA stimulated the NIH Hematology Branch’s work on parvovirus B19.

Improved understanding of AA has yielded insights into other related marrow failure disorders, such as myelodysplastic syndromes (MDS) and paroxysmal nocturnal hemoglobinuria (PNH), which share several clinical features with AA and can also evolve from AA. For instance, a subset of patients with MDS will respond to AA-like treatments including anti-thymocyte globulin (ATG). Data from Dr. Young and his colleagues suggest that MDS patients with trisomy 8 obtain clinical benefit with ATG just as frequently as patients with deletion of chromosome 5q respond to lenalidomide. In addition, emerging AA-related pathobiological mechanisms such as excessive telomere shortening and alterations in stem cell/progenitor cell dynamics appear to have broad relevance in other fields, including neoplasia generally.

A recent high-profile event illustrates just how influential Dr. Young and the NIH Hematology Branch have become in AA research and treatment. As reported earlier this summer, when 58-year-old American Olympic swimming coach Michael Lohberg was diagnosed with AA just weeks before the Beijing Games, he immediately flew to Bethesda to consult with Dr. Young and begin ATG-based therapy. At last report, Coach Lohberg had experienced an encouraging response to this treatment and was able to begin watching swimmers in the pool again. Yesterday, ASH meeting attendees had a much shorter trek to benefit from Dr. Young’s expertise.

Dr. Steensma indicated no relevant conflicts of interest.

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