During the past year, we have collaborated with Dr. John Barrett (NHLBI) in two retrospective clinical studies examining the relationship between donor cell engraftment and clinical course after allotransplantation. The first addressed the impact of T cell depletion of donor stem cell graft products on engraftment and clinical course in patients transplanted for hematologic malignancy. Consistent with the low level of T cells administered, the study documented delayed early T cell engraftment and prolonged mixed chimerism in standard risk recipients. This was associated clinically with a low rate of GVH. Despite initial concerns that slow engraftment and persistent mixed chimerism might favor tumor recurrence, this was not observed clinically. A somewhat different pattern was observed using the same regime to treat patients with higher risk tumors. Presumably because they had sustained greater marrow injury from extensive prior chemotherapy, these patients experienced rapid T cell engraftment (full chimerism is less than a month) despite the very low T cell content of the donor graft. This rapid engraftment was associated with more frequent and severe GVH, and paradoxically, despite the rapid engraftment of donor T cells, a higher rate of disease recurrence. The studies conclude that T cell-depleted grafts can be used safely in patients allotransplanted for hematologic malignancy to minimize GVH complications without compromising the graft antitumor effect needed to prevent recurrence. The second study addresses the impact of a novel protocol for selective depletion of alloreactive T cells from donor graft products on the clinical course in patients allotransplanted for hematologic malignancy. Selective depletion is achieved by stimulating donor lymphocytes with irradiated recipient leukocytes, and then adding immunotoxin-labeled anti-CD25 antibodies to selectively kill any responding alloreactive donor T cells. After treatment the remaining lymphocytes are mixed with purified stem cells for infusion into the patient. The goal of this approach is to reduce the incidence of early GVH without adversely affecting engraftment of donor stem cells or the graft versus tumor effect needed to prevent disease recurrence. Serial chimerism studies of T cells and myeloid cells post transplant demonstrated that treated stem cells still engraft successfully. Clinically GVH was mild but was not completely prevented using the selective depletion regimen. Based on retrospective comparison, there was no indication of increased disease recurrence using this regimen. We are actively involved with Dr. Barrett?s group in developing second-generation depletion procedures to further reduce graft versus host incidence after transplant.
