Peripheral Blood Stem Cell Allotransplantation For Hematological Malignancies Using Ex Vivo CD34 Selection - a Platform For Adoptive Cellular Therapies
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 CliniMACS[registered] CD34+
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 cellular immunotherapy. Adoptive cell transfer is the passive transfer
of immune cells, into a new recipient host with the goal of transferring the immunologic
functionality and characteristics into the new host.
This protocol is designed to evaluate the safety and efficacy of the Miltenyi
CliniMACS[registered] CD 34 selection system in HLA-matched sibling allogeneic peripheral
blood stem cell transplant. The manipulation of the graft is the primary research
intervention, subject to IDE# 13058, and all other aspects of clinical management on this
protocol are standard care. The target CD34+ dose range will be > 3 x 10(6)/kg and the
target CD3+ dose range will be 5 x 10(4)/kg to 1 x 10(6)/kg. Once we demonstrate adequacy of
this platform for engraftment and absence of significant GVHD in ten consecutive recipients,
we will seek IRB permission to proceed with planned adoptive cellular therapies.
The protocol will accrue up to 96 transplant recipients 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 myeloproliferative syndromes.
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 selected for CD34+
progenitors using the Miltenyi CliniMACS[registered] system. 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 +200. Stopping criteria for safety will monitor non-relapse mortality at day +200 and
late disease free survival at 2 years. 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 outcome of this protocol is to determine the rate of overall survival at 200 day using the Miltenyi CliniMACS CD34 selection system.
Minocher M Battiwalla, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
United States: Federal Government
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