Mixed T-Cell Chimerism after Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen is Shaped by Persistence of Recipient CD8 T Cells

Prevention of graft versus host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat non-malignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide and alemtuzumab (‘Campath’) (FCC) regimen is associated with very low risk of GVHD and excellent clinical outcomes. We now report a single center study of 45 patients with longer follow up and investigation of lymphocyte recovery. Overall survival (OS) was 93% and event-free survival (EFS) 90.7%. Acute and chronic GVHD occurred in 6 (13.3%) patients, respectively, and only one case was severe. Mixed T-cell chimerism was frequent and persisted after cessation of post graft immunosuppression. T cells were extensively depleted comprising only 11.3% of lymphocytes at day 30 rising to 43.8% by one year, but still significantly below normal (67.2%, P=0.018) and deficiency persisted after immunosuppressive therapy withdrawal. Depletion of CD4 T cells was particularly profound causing inversion of the normal CD4 to CD8 T-cell ratio. T-cell subset composition was also abnormal, with memory and effector T cells predominate for at least six months after FCC HSCT. Analysis of T-cell subset chimerism showed CD4 T cells were predominantly donor-derived at one year whereas recipient-derived CD8 T cells shaped mixed chimerism with notable contribution of recipient effector CD8 T cells. Prolonged mixed T-cell chimerism after withdrawal of post graft immunosuppression and low incidence of GVHD indicates mutual tolerance is established, but incidence of viral disease was low suggesting that anti-viral immunity is maintained. The study showed that despite abnormality of the T-cell profile after allogeneic HSCT for SAA using the FCC regimen, it is conducive for excellent clinical outcome.