Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using Ex Vivo CD3, CD19 Depletion and CD34 Selection
Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on
transplant techniques designed to decrease graft versus host disease (GVHD), increase the
graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.
Through incremental transplant clinical trials we have shown that by controlling the stem
cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose, severe GVHD can be reduced whilst
beneficial GVL effects can be preserved. We found that T cell depleted transplants using the
Nexell/Baxter Isolex 300i system and subsequently, the Miltenyi CD34+ CliniMACs system to
obtain high CD34+ doses depleted of lymphocytes were safe to administer and associated with
less severe acute GVHD and promising response rates and overall survival. Our previous
trials have helped us to create the transplant environment (significant lymphodepletion and
minimal post transplant immunosuppression) that make for an ideal platform for adoptive
This protocol is designed to evaluate the safety and efficacy of an improved ex vivo graft
manipulation procedure using the Miltenyi CliniMACs CD 34, 3 and 19 selection system in
HLA-matched sibling allogeneic peripheral blood stem cell transplant. The manipulation of
the graft is the primary research intervention and all other aspects of clinical management
on this protocol are the standard of care. The target CD34+ dose range will be 3 times
10(6)/kg to 10 times 10(6)/kg and the target CD3+ dose range will be 5 x 10(4)/kg to 1 times
10(6)/kg. The technique will preserve greater numbers of NK cells. Once we demonstrate
adequacy of engraftment in the first ten recipients, we plan an amendment to permit further
use of this protocol to serve as a platform for several planned adoptive cellular therapy
The protocol will accrue up to 20 subjects aged 10-75 with a hematological malignancy and
their HLA-matched sibling donors, in whom allogeneic stem cell transplantation from an
HLA-matched sibling would be routinely indicated. Diagnostic categories will include acute
and chronic leukemia, myelodysplastic syndromes, lymphomas, multiple myeloma and
Subjects will receive a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg
total), fludarabine (125 mg/m(2) total) and total body irradiation (1200 cGy with lung
shielding to 600 cGy), followed by an infusion of a stem cell product prepared using the
Miltenyi CliniMACS system for CD34, 3 & 19 selection. Older subjects will receive a lower
dose of irradiation (600 cGy) without lung shielding to reduce the regimen intensity.
The overall objective is to assess the feasibility of using this system as a platform for
cellular immunotherapy initiatives. The primary study endpoint will be overall survival at
day plus 200. Non-relapse mortality at day plus 200 will be monitored for safety. Secondary
endpoints will be standard transplant outcome variables such as non-hematologic toxicity,
incidence and severity of acute and chronic GVHD and relapse of disease.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary endpoint is all cause mortality at day 200, and the proportion of subjects who have survived at day 200 will be used to determine the sample size.
Minocher M Battiwalla, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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