A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients

We conducted a phase I-II clinical trial to test the hypothesis that remova l of CD4 cells from an HLA-mismatched unrelated marrow graft would substant ially reduce the risk of grades III-IV graft-versus-host disease (GVHD) and that retention of a specified number of CD8 cells in the graft would be su fficient to prevent rejection. Patients were eligible for this study when a n HLA-A, -B, or -DRB1-matched unrelated donor could not be identified. HLA matching of the donor and recipient was based on typing of HLA-A and -B ant igens by serologic methods and by typing of HLA-DRB1 alleles by molecular m ethods, and donors were selected when disparity was limited to a single HLA -DRB1 allele or a single HLA-A or -B antigen. Twenty-seven patients with he matologic malignancy or aplastic anemia were prepared to receive a transpla nt with conventional regimens of cyclophosphamide and fractionated total bo dy irradiation, and a standard regimen of methotrexate and cyclosporine was given for GVHD prophylaxis. CD4 cells were removed from the donor marrow, and the numbers of CD8 cells were adjusted systematically in graded steps f or successive patients, depending on the occurrence of grades Ill-IV GVHD o r graft failure in previously enrolled patients. Removal of CD4 cells did n ot cause graft rejection or appreciably decrease the risk of grades III-IV GVHD. Depletion of CD8 cells was associated with an increased risk of rejec tion with either HLA-DRB1 disparity or with HLA-A or -B disparity. With eit her type of disparity, the risk of grades Ill-IV GVHD is likely to be highe r than 15% at any dose of CD8 cells associated with less than 5% risk of gr aft failure, The absence of graft failure associated with CD4 depletion sup ports the hypothesis that donor CD4 cells are not essential for preventing marrow graft rejection in humans. The correlation between graft failure and the number of CD8 cells in the donor marrow supports the hypothesis that d onor CD8 cells help to prevent marrow graft rejection. (C) 1999 by The Amer ican Society of Hematology.