Acquired severe aplastic anemia: progress and perplexity.

T HE PATHOPHYSIOLOGY and treatment of acquired severe aplastic anemia (ASAA) has been the subject of recent reviews.’2 Whether idiopathic or idiosyncratic, ASAA is a “likely-to-be-fatal” disease.3 However, it has long been recognized that some patients will recover spontaneously, and a few lucky ones may do so with surprisingly rapid restoration of hematopoiesis.35 The inherent unpredictability of the natural course of this disorder has made evaluation of therapeutic efforts most difficult. In particular, the commonly used agents-steroids and androgenshave never been shown to be of value in a prospective study, and their toxic side effects can contribute to the patient’s problems. Some insight into the pathogenesis of this disorder was acquired through studies of bone marrow transplantation. In Seattle, three patients with ASAA were infused with syngeneic bone marrow from a normal identical twin, without any preparative regimen. 8 All three patients recovered bone marrow function over the course of the subsequent few weeks. These observations indicated a rather simple pathogenetic mechanism, that is, that ASAA is due to something that damages or destroys the hemopoietic stem cells and that the disorder can be corrected by infusion of normal stem cells. Further, success in these patients indicated that ASAA is not due to a disorder of the microenvironment, lack of a humoral factor, persistence of a toxin, or to an autoimmune disorder. However, the plot began to thicken when it was recognized that some patients with ASAA did not recover following a simple infusion of syngeneic bone marrow.9 When conditioned with an immunosuppressive regimen (cyclophosphamide, 50 mg/kg on each of four days), most of these patients did recover following a second infusion of syngeneic marrow. The observations of these patients suggested that the ASAA might well be an autoimmune disorder that could be overcome by an intensive immunosuppressive regimen. Further, the more recent demonstration that marrow engraftment may include the grafting of macrophages,’#{176}osteoclasts,” and the cells that constitute the feeder layer in long-term marrow cultures in vitro’2 revived the possibility that marrow grafting might actually restore the microenvironment in vivo. Additional confounding clinical data began with the observation by Math#{233}et al that some patients with ASAA could recover following the administration of antilymphocyte globulin (ALG) ,13,14 Initially, there was skepticism about these observations, which might have been explained by the unpredictable natural history of the disease. However, Speck and colleagues produced convincing clinical data that ALG therapy may result in recovery of an appreciable fraction of patients with ASAA, with 1 2 of 29 patients showing sustained hematologic improvement.’5 A subsequent study in Seattle showed that the administration of Upjohn (Kalamazoo, Mich) antithymocyte globulin (ATG) results in long-term survival of some patients (six of 19 responders).’6 A randomized study was carried out at UCLA that demonstrated that 1 1 of 21 patients given Upjohn ATG responded as compared to 0 of 21 control patients during the three-month observation period.’7 A cooperative randomized study demonstrated an improved recovery rate following administration of Swiss ALG (76% survival at two years compared to 3 1% for the controls).’8 A recent uncon-