Trial Information

BACKGROUND:

Allogeneic bone marrow transplantation is an accepted therapeutic option for many
hematologic, immunologic, and malignant diseases, including chronic myelocytic leukemia and
acute leukemia during or after first relapse (second remission). In order to maximize the
chance for a successful transplant, it is desirable that the donor and the recipient share
the same Human Leukocyte Antigen (HLA) histocompatibility antigens. Because of the
Mendelian inheritance of HLA antigens, the chances of finding a match are much greater among
relatives than in the general population. However, only about 30 percent of patients
needing a transplant have a matched sibling. Thus a transplant from an HLA-matched
unrelated donor may be an important alternative for these patients.

Graft versus host disease is a frequent and severe complication of marrow transplantation.
Acute GvHD typically occurs within three months after transplantation and is characterized
by skin rash, liver dysfunction, and diarrhea. Although the pathophysiology of this disease
is not fully defined in humans, data from animal studies suggest that it is mediated by
mature donor T cells that react against disparate recipient histocompatibility antigens.

One treatment modality that ameliorates or prevents GvHD following allogeneic marrow
transplantation is T cell-depletion of donor marrow before infusion into the recipient. T
cell-depletion can be divided into physical methods such as separation by elutriation or
sheep cell rosetting, and immunologic methods which use a T cell-specific antibody(ies) plus
complement or toxin to kill the cells. These different techniques may remove a
subpopulation of T cells, all T cells, or T cells plus other cell types such as B cells or
natural killer (NK) cells. The number of stem cells transferred may also be affected.

Unfortunately, in many of the published studies conducted in patients receiving transplants
from HLA-matched siblings, T cell-depletion used to prevent or treat GvHD increased the
chances of other complications, namely graft failure and leukemia relapse. This is not
surprising in light of studies of patients with both early and advanced leukemias that
demonstrated a decreased risk of relapse associated with acute and/or chronic GvHD. Because
the net effect of these opposing consequences of T cell-depletion on leukemia-free survival
in related donor transplants is generally unfavorable, T cell-depletion for related donor
marrow transplantation is controversial. The utility of T-cell depletion in unrelated-donor
transplants needs to be determined.

The initiative grew out of increasing concern on the part of Institute staff, the bone
marrow transplantation community, and members of Congress that graft versus host disease is
so frequent and severe a complication of unrelated donor transplants that it has become a
limiting factor in their outcome. The initiative was given concept clearance by the May
1992 National Heart, Lung, and Blood Advisory Council and released in January 1993.

DESIGN NARRATIVE:

The primary endpoint of this trial was disease free survival at three years post transplant.
Secondary endpoints included overall survival, incidence of GvHD, graft failure, infections
and other complications, and time to disease relapse. The covariates considered included
age of recipient, disease risk status, interval between diagnosis and transplant, disease
type, age and gender of donor, post-transplant chimerism, pre-transplant Karnofsky score,
and other measures of performance status. An economic analysis was performed.

Patients were randomly assigned to receive either a T-cell depleted or a non-depleted
transplant. Two methods of T-cell depletion were in use: an anti-CD3 monoclonal antibody,
T10B9, plus complement, or counterflow elutriation plus the Ceprate column. Each method of
T-depletion was part of a package that included a specific pre-transplant conditioning
regimen and additional GvHD prophylaxis. Patients randomized to the non-T-cell depleted arm
received a conditioning regimen containing cyclophosphamide and total body irradiation, and
a GvHD prophylaxis regimen of cyclosporin and methotrexate. A total of 410 patients were
enrolled. Enrollment ended October 31, 2000.

A total of 14 transplant centers participated in the study, Follow-up ended in April 2002.