Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T-Cell Add-Back for Hematological Malignancies - Role of Cyclosporine
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. A CD34 stem cell dose of greater than
3 x 10(6)/kg was found to increase survival and reduce relapse, while a CD3+ lymphocyte dose
of less than 1 x 10(5)/kg was associated with a very low incidence of GVHD. Although
processing of 2 peripheral blood progenitor cell (PBPC) collections with the CellPro
immunoabsorption method (combined CD34-positive selection and CD2-negative selection)
provided an improvement over previous methods, the system did not always achieve these
optimal cell doses. A recent preclinical evaluation by the Department of Transfusion
Medicine of a new immunomagnetic cell selection system available from Nexell, Inc. has
demonstrated improved recovery of CD34+ cells and increased depletion of T lymphocytes,
compared to the CellPro method. Incorporation of the Nexell system (Isolex 300i) into this
clinical protocol will allow us to more consistently achieve CD34+ cell doses above the
threshold of 3 x 10(6)/kg and CD3+ lymphocyte dosing in the region of 0.5 x 10(5)/kg. This
will make it possible to test (1) the potential benefit of optimized transplant cell doses,
(2) elimination of post transplant immunosuppression to enhance immune recovery.
In this study, we will use the Nexell Isolex 300i system to obtain more data on the
relationship between CD34+ stem cell dose and outcome. In recipients who receive a T cell
dose less than 0.5 x 10(5) CD3+ cells/kg the effect of withdrawing cyclosporine on
development of GVHD will be evaluated in a cohort study: 20 patients will receive low dose
cyclosporine. If the incidence of grade II or worse GVHD is 10% or less, no post transplant
immunosuppression will be given to the next cohort and the incidence and severity of acute
GVHD again assessed. Stopping rules for unacceptable GVHD severity will be applied. Two
match groups HLA 6/6 and 5/6 donor-recipient pairs will be separately studied using this
In a second phase of the study we will continue to accumulate data on T lymphocyte add-back
given on day 45 and day 100 after transplant. For this phase, cyclosporine will be
reintroduced on day 44 and continued until day 120 to accelerate immune recovery.
Up to 70 patients aged between 10 and 55 years will be studied in each subset (HLA 6/6 and
5/6 matched cohorts). The major endpoint of the study is acute GVHD after transplant. We
will also measure engraftment, acute and chronic GVHD, leukemic relapse, transplant-related
and all causes of mortality, cytomegalovirus reactivation and leukemia-free survival.
Patients will be followed for a minimum of 5 years.
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 (and before D45 add-back).
A. John Barrett, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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