The current standard treatment for aplastic anemia (AA) is immunosuppressive therapy (IST), with only temporary symptom relief and high rates of paroxysmal nocturnal hemoglobinuria, clonal hematopoiesis, and myelodysplastic syndrome. When a matched donor is available, allogeneic hematopoietic cell transplant (allo-HCT) is the preferred treatment for severe aplastic anemia (SAA). But the survival rate for patients over 40 years of age is ~ 50%, mainly due to graft-versus-host disease (GvHD). There is an urgent need to find novel therapies for SAA patients who are refractory to IST and lack a matched donor.
Mixed chimerism (MC) is the co-existence of both host- and donor-derived cells in the recipient. Previous studies in SAA have shown that patients who develop stable MC after allo-HCT have improved clinical outcome. The Zeng lab at City of Hope has developed a novel regimen for induction of MC after HCT in mouse models. The regimen includes a non-myeloablative conditioning regimen (low dose of cyclophosphamide, pentostatin, anti-thymocyte globulin), and CD4+ T-depleted hematopoietic cell graft. Reasons for using CD4+ T-cell-depleted grafts are CD4+ T cells mediate GvHD that damages bone marrow and hampers donor stem cell engraftment and depletion of CD4+ T cells prevents GvHD in recipients with complete chimerism. Zeng lab studies demonstrate that induction of full MHC-mismatched or haplo-MHC-matched MC by this regimen in mouse models cures autoimmune diseases, without causing GvHD.
In a recent COH clinical trial using the same regimen in three patients with sickle cell disease, the therapy was shown to be safe, COH-MC-17 regimen safely induced haploidentical MC in two patients. In this clinical trial, we plan to extend this regimen to induce haploidentical MC in SAA. The goals of this study are to evaluate the safety and feasibility of COH-MC-17 regimen; and demonstrate the capacity to induce MC in SAA patients.