Myelodysplastic Syndromes Clinical Trial
Official title:
Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Irradiated Donor Lymphocytes on Chimerism
Bone marrow transplantation (BMT) is a risky procedure. If doctors could reduce the
complications, BMT would be safer to use for a wider range of conditions. The purposes of
this study are
- to prevent graft rejection by increasing the amount of immunosuppression and by giving
some lymphocytes from the donor before transplant;
- to prevent graft-versus-host disease (GVHD) by transplanting T-cell depleted stem cells;
- to improve the immune effect against residual leukemia by the add-back of donor
lymphocytes before transplant and six or more weeks after transplant.
Beyond the standard transplant protocol, study participants will undergo additional
procedures. First, along with total body irradiation, patients will receive two drugs (a high
dose of cyclophosphamide and fludarabine) to suppress immunity and prevent rejection of the
transplant. Second, four days before the transplant, patients will be given donor lymphocytes
that have been irradiated to make them incapable of causing GVHD. On the day of the
transplant, patients will receive an infusion of T-cell depleted bone marrow stem cells.
Finally, patients will receive two doses of add-back donor T-cells (45 and 100 days post
transplant) and the immunosuppressive drug cyclosporine starting on day 44 until about six
months after transplant.
Study participants must be between the ages of 10 and 56 and have a family member who is a
suitable stem cell donor match.
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.
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