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.