T-Cell Depletion in Unrelated Donor Marrow Transplantation
Condition: Bone Marrow Transplantation; Graft vs Host Disease; Immunologic Diseases; Leukemia; Myelodysplastic Syndromes
MeSH terms: Myelodysplastic Syndromes; Graft vs Host Disease; Immune System Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine if a reduction in morbidity and mortality from acute and chronic graft versus
      host disease (GvHD) can be achieved through use of T-cell depletion techniques without a
      counterbalancing increase in relapse of leukemia in patients receiving an unrelated donor
      marrow transplant.
    

Detailed description: 
      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.
    

Intervention name(s): lymphocyte depletion
Intervention type(s): Procedure
Allocation: Randomized
Primary purpose: Treatment