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Neal S. Young, M.D.
Chief, Hematology Branch
National Institutes of Health
National Heart, Lung & Blood Institute
Aplastic Anemia Foundation of America NEWSLETTER, June, 1995
Members of the Aplastic Anemia Foundation of America will be pleased to learn that an International Meeting on Mechanisms of Bone Marrow Failure was held in Paris from April 3rd to April 6th. The conference was held under the auspices of several prestigious organizations: The National Institutes of Health; the European Haematology Association; the European School of Haematology; Inserm (the French National Institute of Health and Medical Research); and the Ministry of Research and Technologies of France.
The meeting was organized by Eliane Gluckman of the Hospital Saint-Louis in Paris, Joachim Deeg of the University of Washington in Seattle, and Neal Young of the National Institutes of Health. The meeting attracted experts in bone marrow failure, both clinical investigators and basic laboratory scientists. The congress was convened at the Maison de la Chimie. The individual speakers gave excellent presentations, and the informal discussions among participants during coffee sessions and lunch were extremely stimulating.
Although the major focus of the meeting was on the causes of aplastic anemia, there were ample discussions of treatment results. In this disease, much has been learned about blood cell production from the study of bone marrow failure and important inferences have been derived from clinical results. Conversely, conclusions of laboratory experiments have led to new therapies. Clinical results in four areas were described: conventional bone marrow transplantation, transplantation from unrelated HLA-matched donors, immunosuppression, and hematopoietic growth factors.
In the largest single center study by marrow transplantation from the University of Washington, 664 patients have been treated from 1970-1974. Overall survival is 61%. However, more than 90% of patients who more recently underwent transplant are alive. For the International Bone Marrow Transplant Registry, 1,305 patients have received sibling transplants. Survival has also increased over time, so that for the most recent interval (1988-1992), survival at five years is 66%.
Results with unrelated bone marrow transplants are not as good. At Seattle, only 33% of recipients are alive, and in the IMUST European study, survival among recipients of unrelated donors is considerably lower than that for concurrently treated transplants from matched siblings: about 40% at one year compared to 65% for conventional transplants. A major problem with unrelated transplantation is graft failure, which may be overcome by more aggressive conditioning regimens employing a wide range of more intensive cytotoxic chemotherapeutic drugs. The best results for unrelated transplants have been obtained in children, who better tolerate this arduous therapy. The results for a group of 83 such unrelated donors at four major American transplant centers were reviewed. In 15 patients, there was either failure of engraftment or late graft rejection; almost all these patients died. Moderate to severe acute graft-versus-host disease occurred in about half of the evaluable patients.
Overall disease-free survival was 40%, but about half the children survived compared with less than one-third of adults.
Concerning transplantation in general, the consensus was that matched sibling transplants were the treatment of choice in aplastic anemia, certainly for patients under 20 and for some transplanters for patients up to the age of 50. Unrelated transplants have been less successful, possibly because for logistical and psychological reasons patients are transplanted later, after alloimmunization from multiple transfusions and other complications of aplastic anemia have occurred. Unrelated transplants can be considered as secondary therapy in children for whom a donor is located in HLA registries.
As with marrow transplantation, results with immunosuppression have also improved over time. Using intensive immunosuppression, a combination of antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) plus cyclosporine and moderate does of corticosteroids, response rates in severe disease are now 70% or higher. In the most recent European Bone Marrow Transplant Group study, over 90% of treated patients were alive at two years. Similar excellent response rates have been obtained with an ATG plus cyclosporine regiment at the National Institutes of Health. All agreed that cyclosporine was an important addition to therapy.
There was some disagreement between European and American groups as to the value of cyclosporine alone: a European trial is now underway to directly compare ALG to cyclosporine by randomizing patients to either drugs. A potentially helpful role of growth factors was suggested by the routine use of G-CSF in the recent European study. Immunosuppressive treatment has several major problems. Relapse occurs in about one-third of patients, although most respond to a second course of immunosuppression and some will not relapse again. A more serious problem is the evolution of clonal hematologic disease. Most often, this clonal disease is paroxysmal nocturnal hemoglobinuria (PNH), which may not be clinically troubling to the patient. However, a significant proportion of patients may develop myelodysplasia or acute leukemia even many years after recovery of blood counts.
Both the European and American experience with hematopoietic growth factors was reviewed. These treatments are not recommended as first therapy for patients with aplastic anemia, and the now common practice of treating patients with colony stimulating factors or erythropoietin before referral for either transplantation or immunosuppression was deplored. In general, the results with growth factors as single therapy have been disappointing. Usually only granulocytes are supported, and growth factors tend to work best in those patients who already have a modest number of white cells. Platelets and red cells have not increased in most protocols using G-CSF, GM-CSF, or IL-3. Thrombopoietin, which increases platelet production in the test tube and in animals, may be helpful for patients with severe thrombocytopenia; however, thrombopoietin may also resemble erythropoietin in its lack of effect in patients without stem cells. As mentioned above, growth factors are helpful when used in the course of a bone marrow transplant and they may be also useful in immunosuppression to support neutropenic patients until the donor marrow or their own bone marrow begins to function to produce blood cells.
For pathophysiology, a number of points can be made more briefly. First, tissue culture assay now exist for a measurement of human stem cells. These have been applied by several groups to aplastic anemia and the results are uniform: almost all patients have severe depression in blood and bone marrow stem cell numbers. More surprising, even patients who have recovered bone marrow function and have stable blood counts for months or years also show marked reduction in stem cells. Apparently, relatively normal blood cell production can be sustained for some period of time by very limited numbers of stem cells, and stem cells may not be able to increase once they are depressed. The reduced numbers of stem cells in patients may be an important clue as to the origin of late clonal disease as well as the risk of relapse.
The immune basis for aplastic anemia was also discussed. Cytotoxic lymphocytes and their products, especially gamma-interferon, no only suppress hematopoiesis but actively kill marrow cells, including stem cells. The molecular pathways for these actions is now well understood and may offer the possibility of more novel therapy specifically directed at the immune system. In many respects, the mechanism of organ destruction in acquired aplastic anemia resembles other autoimmune diseases like multiple sclerosis, childhood diabetes mellitus, and psoriasis.
The recent discovery of two genes related to aplastic anemia was also the subject of several talks. The gene responsible for PNH has been cloned. Animal and tissue culture studies indicate that this defect does not confer an intrinsic advantage for PNH like cells to proliferate (in contrast to leukemia mutations). Apparently, PNH cells are selected in some environments, perhaps because they resist immune system attack. Finally, the gene for one type of an inherited aplastic anemia, called Fanconi's anemia Type C, has also been cloned. Although the structure of the gene is understood, its function remains unknown. Biological activity of the FA gene should provide important clues as to one mechanism of bone marrow failure and leukemia development.