Experimental Bone Marrow Transplant Protocol

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.

We have found that the outcome from transplant is improved by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose. 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 2 x 10(4)/kg. The use of the cell separator and the monoclonal antibodies was covered by IDE 8139. The study measured the incidence of acute GVHD and used chimerism assays to determine the percentage of donor and recipient cells circulating at different time-points after transplant. We found that in the first six weeks donor T cell chimerism varied widely reaching 100% only in 10/22 patients. Thus the goal or rapid donor immune recovery was achievable only in about half the patients. Patients with mixed donor-recipient T cell populations are known to be at higher risk for late graft rejection and leukemic relapse after transplant. Therefore the achievement of full donor chimerism is an important therapeutic goal.

To improve donor T cell chimerism we will test whether the addition of irradiated donor lymphocytes during the preparative regimen of the transplant can increase the chance of achieving 100% donor T cell chimerism within six weeks of transplant. It is known that irradiated lymphocytes do not cause GVHD and that they can suppress residual host immunity, thus promoting donor lymphocyte engraftment. The end point of the study will be the proportion of patients achieving full donor chimerism six weeks after transplant. Apart from this addition of irradiated lymphocytes and some minor modifications, this protocol will be identical to the predecessor protocol 02-H-0111. This involves the continued use of the Isolex 300i cell separator and the 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.