PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

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Aplastic anemia and other forms of bone marrow failure have clinical and laboratory features consistent with a possible viral etiology followed by immunological pathophysiology. Aplastic anemia may follow on a viral infection, especially non-A non-B hepatitis. Patients have evidence of activation of cytotoxic lymphocytes, excessive lymphokine production, and decreased natural killer cells. We have recently established that aplastic anemia following hepatitis is non-C as well as non-A, non-B, and we have initiated chimpanzee inoculation studies and seroepidemiologic studies for hepatitis E. The immunophysiology of aplastic anemia has been investigated through gene amplification studies of RNA in bone marrow. We have found that the majority of patients presenting with aplastic anemia have detectable gamma-interferon mRNA in extracted bone marrow. Gamma-interferon mRNA is not found in normal individuals, in patients who have received multiple blood transfusions, or in patients with other forms of bone marrow failure. Gamma- interferon RNA predominates in the bone marrow of patients with aplastic anemia, not in this peripheral blood. In clinical studies, we have initiated a trial of intensive immunosupprccession consisting of combined anti-thymocyte globulin and cyclosporine. Preliminary response rates are approximately 70%, considerably higher than hematologic improvement rates observed with anti-thymocyte globulin treatment alone. For growth factors, we are continuing to treat patients with Diamond- Blackfan anemia with interleukin-3, after having observed significant durable and clinical remissions in 2/6 patients with congenital pure red cell aplasia. A trial of stem cell factor, a novel human interleukin, is scheduled to begin shortly in patients with severe refractory aplastic anemia. Finally, we have proposed a unifying model for post- aplastic anemia paroxysmal nocturnal hemoglobinuria and myelodysplasia based upon the diverse activities of cytotoxic lymphocytes.