A Multicenter, Prospective Trial to Evaluate the Role of NK Cell Kir Epitope Mismatch on Mortality and Disease Relapse in T-Cell Depleted Hematopoietic Stem Cell Transplantation from HLA-C Mismatched, Unrelated Donors for Myeloid Malignancies
This is a multi-center study coordinated by the National Marrow Donor Program (NMDP), the Center for International Blood and Marrow Transplant Research (CIBMTR) and the University of Minnesota.
You may be asked to be in this study if you have a myeloid leukemia (AML, CML) or myelodysplasia (MDS). We know that transplantation of normal blood forming cells from someone else can provide you with a chance of cure for your type of cancer. If a fully matched donor (family member or unrelated) has not been found for you, you may be eligible for this particular study.
This research study is being done to compare the treatment course of subjects who have received different types of donor Natural Killer (NK) cell matches in order to answer the following question: which donor match is the most effective and safest type to use in NK cell transplantation?
Natural Killer (NK) Cells in Donor Selection:
After transplant, NK cells develop from donor blood or marrow stem cells. NK cells are important cells in the immune system that help fight infection and can kill cancer cells under certain conditions. NK cells have proteins on their surface called receptors that bind to other cell proteins (ligands), and direct the activity of the NK cell to either ignore or kill the target cell. NK cell receptors called killer immunoglobulin-like receptors (KIRs) are thought to be very important for NK cell activity. This study will help to determine the importance of NK cells and KIRs in selecting donors for patients with myeloid leukemias and myelodysplasia.
Interestingly, the beneficial effects of NK cells have been seen in transplants where the donor and patient are histocompatibility antigens (HLA) mismatched. In general, stem cell transplants are safest when the donor is closely matched to the patient for tissue type proteins called histocompatibility antigens (HLA). Many patients with leukemia do not have a family member or unrelated donor that is HLA matched. GVHD is much more likely to occur when the donor cells (the graft) are not closely matched to the patient.
Previous studies have also suggested that the positive effects of NK cells for patients depend on the number of white blood cells (T cells) in the transplant being reduced or depleted. A drug called Thymoglobulin? (ATG) will be given with chemotherapy before the transplant to decrease the number of T cells in the transplant. Treatment with ATG has also been shown to decrease the risk of graft-versus-host disease (GVHD) in patients receiving transplants from unrelated donors. Also, T-Cells will be removed from the donor cell graft before it is transplanted.
Depending on the differences between donor and patient HLA type and NK cell receptor type (KIR type); some patients may receive transplants where the NK cells are more active than others. By studying groups of patients who receive the same chemotherapy and radiation before transplant, but different types of NK cells from their donors, we can determine the effects of the NK cells on transplant outcomes.
We are conducting this study because we do not know if selecting donors with certain types of NK cells is better than other treatments for myeloid leukemias or MDS.
NK Cells effect on cancer cells and GVHD:
Experiments done in animals suggest that under certain conditions NK cells can eliminate leukemia cells (graft-versus-leukemia, or GVL).
Some types of NK cells can also prevent graft-versus-host disease (GVHD). Graft-versus-host disease (GVHD) results when some donor cells react against the patient’s tissues causing damage particularly to the skin (severe rash), gut (diarrhea), or liver. GVHD is a serious complication of stem cell transplant.
Earlier studies done in patients with myeloid leukemias and MDS have found that the presence of certain types of NK cells in the transplant can lead to better outcomes for recipients—less GVHD and a lower risk of leukemia returning after the transplant. The goal of this study is to determine the effects, both good and bad, of NK cells in patients receiving stem cell transplants for myeloid leukemias and myelodysplasia (MDS).
In general, stem cell transplants are safest when the donor is closely matched to the patient for tissue type proteins called histocompatibility antigens (HLA). Many patients with leukemia do not have a family member or unrelated donor that is HLA matched. GVHD is much more likely to occur when the donor cells (the graft) are not closely matched to the patient.
About 15 patients will take part in the study at Washington University. There will be a total of 100 patients at all seven study sites combined.
