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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2192-2199
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
Paul J. Martin,
Scott D. Rowley,
Claudio Anasetti,
Thomas R. Chauncey,
Ted Gooley,
Effie W. Petersdorf,
Jo-Anne van Burik,
Mary E.D. Flowers,
Rainer Storb,
Frederick R. Appelbaum, and
John A. Hansen
From the Division of Clinical Research, Fred Hutchinson Cancer
Research Center and Department of Medicine, University of Washington,
Seattle, WA.
We conducted a phase I-II clinical trial to test the hypothesis that
removal of CD4 cells from an HLA-mismatched unrelated marrow graft
would substantially 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 sufficient to prevent rejection. Patients were
eligible for this study when an 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 antigens by serologic methods and
by typing of HLA-DRB1 alleles by molecular methods, 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 hematologic
malignancy or aplastic anemia were prepared to receive a transplant
with conventional regimens of cyclophosphamide and fractionated total
body 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 for successive patients, depending on
the occurrence of grades III-IV GVHD or graft failure in previously
enrolled patients. Removal of CD4 cells did not cause graft rejection
or appreciably decrease the risk of grades III-IV GVHD. Depletion of
CD8 cells was associated with an increased risk of rejection with
either HLA-DRB1 disparity or with HLA-A or -B disparity. With either type of disparity, the risk of grades III-IV GVHD is likely to be
higher than 15% at any dose of CD8 cells associated with less than 5%
risk of graft failure. The absence of graft failure associated with CD4
depletion supports 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 donor CD8 cells help to
prevent marrow graft rejection.
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