Induction of a CD8+ T Cell Response to Tumor Antigens Is Associated with Improved Survival in Patients Transplanted for Acute Myeloid Leukemia

Disease relapse and graft-versus-host disease (GVHD) are the major causes of treatment failure after allogeneic stem cell transplantation (SCT). The DNA methyltransferase inhibitor azacitidine (AZA) possesses significant anti-tumor activity in myelodysplasia and acute myeloid leukemia (AML). Recently its administration post-transplant has been shown to both induce a CD8+ T cell response to a broad range of tumor antigens and augment reconstitution of T regulatory cells. We therefore prospectively studied the impact of post-transplant AZA on the outcome of patients allografted for AML. 37 patients were transplanted using an alemtuzumab based fludarabine/melphalan conditioning regimen. 36 mg/m² of AZA was administered for five consecutive days at four weekly intervals until 12 months post-transplant. AZA was commenced at a median of 54 days (range 40-194) post-transplant and was well tolerated. 31 patients completed three or more cycles. 16 patients relapsed at a median time of 8 months post-transplant. No patient developed chronic extensive GVHD. AZA induced a CD8+ T cell response to tumor-specific peptides in 16 of the 31 patients who received more than three treatment cycles. No such response was observed in matched controls who received no post-transplant AZA. Induction of a CD8+ T cell response was associated with an increased one year overall survival of 81% versus 41% in patients with no CD8+ T cell response (p= 0.02). An increased number of T regulatory cells was detected in 16 patients compared with matched controls. In conclusion administration of AZA post-transplant is associated with a low incidence of GVHD and induces a CD8+ T cell response to tumor antigens which correlates with a reduced risk of relapse. These data demonstrate the ability of AZA to improve the outcome of allogeneic SCT, potentially through epigenetic manipulation of the alloreactive response, and require validation in a randomised clinical trial.