BACKGROUND. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (T_N) cause more severe GVHD than memory T cells (T_M). We hypothesized that selective depletion of T_N from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and T_M to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively.

METHODS. In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with T_N-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of T_M purged of CD45RA⁺ T_N. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution.

RESULTS. All recipients of T_N-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell–replete grafts. T_M in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years.

CONCLUSION. Depletion of T_N from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory.

TRIAL REGISTRATION. ClinicalTrials.gov (NCT 00914940).

FUNDING. NIH, Burroughs Wellcome Fund, Leukemia and Lymphoma Society, Damon Runyon Cancer Research Foundation, and Richard Lumsden Foundation.