Current concepts in the pathophysiology and treatment of aplastic anemia

Abstract

Historically viewed in isolation as an odd, rare, and invariably fatal blood disease, aplastic anemia is now of substantial interest for its immune pathophysiology, its relationship to constitutional BM failure syndromes and leukemia, and the success of both stem cell transplantation and immunosuppressive therapies in dramatically improving survival of patients. Once relegated to a few presentations in the red cell and anemia sessions of the ASH, the Society now sponsors multiple simultaneous sessions and plenary and scientific committee presentations on these topics. This update emphasizes developments in our understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system.

Figure 1.

Somatic mutations in lymphocytes might drive an aberrant immune response. Tissue damage is a normal component of an inflammatory response and resolves with withdrawal of the stimulating antigen. Acquired mutations, altering proliferation, susceptibility to apoptosis, or a variety of signaling pathways in an effector population or in regulatory cells would lead to persistence of a clone, tissue destruction, exposure of new antigens, and further recruitment of immune cells.

Figure 2.

Survival after response to immunosuppression in severe aplastic anemia. A large cohort (N = 243) of NIH patients who responded to treatment with the standard regimen of horse ATG plus cyclosporine was analyzed. Shown are long-term outcomes including the negative impact of a complicating event. Events were defined as relapse (need for further immunosuppression after protocol treatment) and clonal evolution (myelodysplasia/acute myeloid leukemia; almost always accompanied by a new cytogenetic abnormality in the BM). Approximately half of the patients did not experience a clonal event and poor survival was largely a consequence of disease progression. Data were censored for transplantation.

Figure 3.

Stem cells as limiting in the response to immunosuppressive therapy. Combining immunosuppressive therapy with a factor that increases stem cell proliferation and/or self-renewal might overcome this limit.