Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants
Bone marrow stem cell transplants (otherwise called bone marrow transplants) from healthy donors are sometimes the only means of curing hematological malignant diseases such as acute and chronic leukemias, myelodysplastic syndrome, myeloproliferative diseases and lymphomas. Before transplant the patient receives chemotherapy and radiation treatment to reduce the malignancy to low levels and to prevent rejection of the transplant. The transplant restores the blood counts to normal and replaces the patients immunity with that of the donor. The donor's immune cells increase the effect of the transplant by attacking remaining malignant cells. Donor immune cells (especially those called T lymphocytes) also attack healthy non-cancerous cells and tissues of the recipient causing "graft-versus-host-disease" (GVHD). Strong GVHD reactions occurring within weeks after the transplant can be life-threatening . In this study we remove most of the T lymphocytes from the transplant to minimize the risk of GVHD. However to improve immunity against residual malignant cells and boost immunity to infections, donor T cells (stored frozen at time of transplant) are given back around 90 days after the transplant when they have a reduced risk of causing serious GVHD.
Any patient between 10 and 75 years of age with acute or chronic leukemia, myelodysplastic syndrome, myeloproliferative syndromes or lymphoma, who have a family member who is a suitable stem cell donor may be eligible for this study. Candidates are screened with a medical history and various tests and examinations.
Participants undergo apheresis to collect lymphocytes for research studies. This procedure involves collecting blood through a needle in the arm, extracting the lymphocytes through a cell separator machine and returning the rest of the blood through a needle in the other arm. Before treatment begins, patients have a central intravenous line (plastic tube) placed in a vein in the neck. This line remains in place during the transplant and recovery period for drawing and transfusing blood, giving medications, and infusing the donated cells.
To prepare patients for transplantation their immune system is suppressed by a combination of chemotherapy and radiation which will also help to fight remaining malignant cells. The chemotherapy consists of two anti-cancer drugs (fludarabin and cyclophosphamide) and will be infused over the central line starting eight days before the transplant. Patients will receive eight doses of total body irradiation, administered in two 30-minute sessions per day for 4 days. Patients above 55 years of age who tolerate transplants less well than younger individuals will receive a lower dose of radiation. One day after the preparative treatment is finished, patients receive the transplant of donors' stem cells as an infusion through the central line.
Patients receive cyclosporine, an immune-suppressing drug starting 6 days before the transplant until 21 days post-transplant. This helps prevent both transplant rejection and GVHD. The drug is stopped to allow the donor immunity to function and is restarted on day 89 to prevent GVHD from the infusion of T lymphocytes on day 90.
Patients are followed with various tests, treatments and examinations periodically for the first 3 years and then yearly thereafter.
Chronic Myelogenous Leukemia
Acute Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Acute Lymphoblastic Leukemia
Device: Miltenyi CliniMACS CD34 Reagent System
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using a Positive Stem Cell Selection Technique for T Cell Depletion, Followed by Delayed T Cell Add-Back|
- Increased rate of survival at day +200. Non-relapse mortality at day +200 will be monitored for safety. [ Time Frame: Day 200 ] [ Designated as safety issue: Yes ]
- Standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD and relapse of disease. [ Time Frame: 3 years maximum ] [ Designated as safety issue: Yes ]
|Study Start Date:||September 2006|
|Estimated Study Completion Date:||August 2014|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Device: Miltenyi CliniMACS CD34 Reagent System
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.
We have found 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 by postponed donor lymphocyte infusion (DLI). We found that T cell depleted transplants using the Nexell/Baxter Isolex 300i 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, when combined with a delayed T cell add-back (DLI). This protocol is designed to evaluate safety and efficacy of an improved T cell depletion procedure using the Miltenyi CliniMACs system (CD34 reagent system) with a delayed T cell add back in the HLA-matched peripheral blood stem cell transplant setting.
The protocol will accrue up to 68 subjects ages 10-75 with a hematological malignancy, in whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely indicated. 68 sibling donors will also be recruited. Diagnostic categories will include acute and chronic leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma and myeloproliferative syndromes.
Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection, and a delayed T-cell add back as donor lymphocyte infusion (DLI) at day 90. Older subjects will receive a lower dose of irradiation to reduce the regimen intensity.
Primary endpoint will be overall survival at day +200. Non-relapse mortality at day +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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00378534
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Minocher M Battiwalla, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|