Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Peri-transplant Encyclopedic on Chimerism
Bone marrow stem cell transplant studies carried out by the National Heart Lung & Blood
Institute (NHLBI) Bone Marrow Transplantation (BMT) Unit have focused on approaches to
optimize the stem cell and lymphocyte dose in order to improve transplant survival and
increase the graft-versus-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 reduced 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. We use the "Nexell Isolex 300i" system to
obtain high CD34+ doses depleted of lymphocytes to a fixed CD3+ T cell dose of 2 x 104/kg.
The use of the cell separator and the monoclonal antibodies is covered by an Investigational
Device Exemption. A persisting problem with these T cell depleted transplants has been the
slow acquisition of full donor T cell engraftment (T cell chimerism). Two previous protocols
have failed to increase the speed of donor T cell chimerism. 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
remains an important therapeutic goal. In this study we will test whether cyclosporine
given between day -6 and +21 after transplant can significantly improve day 30 T cell
chimerism (the principle end-point). The study also will measure the incidence of acute and
chronic GVHD, day 100 transplant related mortality, cytomegalovirus reactivation, relapse,
and disease-free survival with appropriate safety stopping rules.
This protocol follows closely previous studies in this series. Three additional
modifications will be made however: 1) The first T cell add-back will be delayed until day
60 (instead of day 45) so as to continue to allow a 45 day period without cyclosporine
immunosuppression. 2) No day 100 T cell add-back will be given. (In previous studies many
patients have, for protocol-defined reasons, not received the second transfusion and there
is no evidence that it is required). 3) Patients with high-risk leukemias with a high
relapse probability will receive an additional chemotherapy agent prior to transplant using
etoposide (VP16) 60mg/kg to improve the chance of remaining in remission.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The Proportion of Patients Who Develop Full Donor T Cell Chimerism at Day 30
The proportion of patients who develop full donor CD3+ lymphocyte chimerism by day 30. Full chimerism is defined as >95% donor alleles by molecular profiling (Short Tandem Repeat analysis).
A. John Barrett, MD
NIH National Heart, Lung and Blood Institute
United States: Food and Drug Administration
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