Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Role of Preparative Regimen and T Cell Dose in Graft Rejection and GVHD
Bone marrow stem cell transplant studies carried out by the NHLBI BMT Unit have focused on
approaches to optimize the stem cell and lymphocyte dose in order to improve transplant
survival and increase the graft-vs.-leukemia effect. The aim is to create the transplant
conditions that permit rapid donor immune recovery without causing graft-versus-host disease
(GVHD) by using no post-transplant immunosuppression in conjunction with a transplant
depleted of T cells to a fixed low dose, below the threshold known to be associated with
GVHD. A primary objective of the protocol is therefore to test whether the low dose of T
cells chosen minimizes the risk and severity of GVHD.
We have found that the outcome from transplant is improved by using high stem cell doses,
and in successive protocols we have achieved progressive improvement in transplant-related
mortality from 35% in the first protocol in 1993 to 22% for the latest study. In the last
study, in this series, we used the Nexell Isolex 300i system to obtain high CD34+ doses
depleted of lymphocytes to a fixed CD3+ T cell dose of 5 x 10(4)/kg. The use of the cell
separator and the monoclonal antibodies is covered by IDE 8139. The study focused on the
role of cyclosporine in preventing GVHD after T cell depletion. We found that CSA appears
to protect against both GVHD and graft failure, with a higher incidence of both
complications occurring in patients not receiving CSA.
To address the results and shortcomings of the previous protocol, while continuing to avoid
immunosuppression post-transplant, we will now test two hypotheses: (1) GVHD incidence and
severity can be reduced by transfusing a T cell dose of 2 x 10(4)/CD3 cell/kg. (2) Graft
rejection can be prevented by increasing the immunosuppressive intensity of the
pre-transplant preparative regimen using fludarabine and cyclophosphamide and a reduced dose
of total body irradiation (12 Gy instead of 13.6 Gy). We will use the same in vitro cell
separation system namely the Isolex 300i and monoclonal antibodies provided by CTEP (anti CD
6, anti CD2, anti CD7). This is covered by a continuing IND for the selection of CD34+ and
CD3+ cells for T cell depleted peripheral blood stem cell transplantation.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The proportion of patients with clinically significant acute GHVD (Grade II or higher) following the T depleted PBPC transplant.
Before day 45.
A. John Barrett, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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