Biologic parents are haplocompatible, or half-matched, with their children since every child inherits half of the total number of histocompatibility genes from their mother and half from their father. Siblings, on the other hand, have a 50 percent chance of being haplocompatible. The purpose of the Haplocompatible Donor Program at UCSF Benioff Children's Hospital is to study the effectiveness of using stem-cell enriched, T-cell depleted peripheral blood stem cells (PBSC) for transplantation into children with:
- Leukemia and pre-leukemia, such as myelodysplasia
- Marrow cell defects, such as aplastic anemia
- Cytopenias that result in the absence of red blood cell, platelet or white cell production
- Severe immunodeficiency diseases
The program evaluates the ability of this processed source of marrow stem cells, along with high dose chemotherapy and radiation therapy, to engraft and restore the functioning of the body's immune system.
T Cell Depletion
In order for a haplocompatible donor bone marrow transplant to work, the stem cells must be specially treated after they are collected from the donor and before they are transplanted into the patient. This treatment depletes the donor T lymphocytes, which are white cells important for fighting infection and cancer cells in the body. Donor T cells can cause a reaction called graft-versus-host disease (GvHD) when they attack certain tissues or organs of the transplant recipient. Donor T cells also are important in helping the donor stem cells to engraft in the patient.
The risk of GvHD increases the more mismatched or incompatible the donor is with the recipient. Parents and most siblings are usually only partially compatible with their children. Therefore this donated marrow or PBSC must be treated to remove the T cells that are responsible for GvHD.
There are advantages and disadvantages to T cell depletion. The technique that we use significantly reduces the risk of GvHD both in terms of its chances of occurring, as well as its severity if it does occur. However, because donor T cells are important for engraftment, there is an added risk that the marrow stem cells might not engraft. In order to improve the chances that they will engraft to greater than 95 percent, radiation treatment must be added to the conditioning regimen in most cases.
Also, there may be a delay in the recovery of the immune system, resulting in a higher risk of infections after transplant. T cell depleted marrow from a parent, sibling or first cousin may be considered for children who do not have a human leukocyte antigen (HLA) matched related or unrelated donor.
The UCSF Pediatric BMT Program is currently evaluating a novel approach to using haplocompatible donors in order to improve the safety and optimize success of this kind of transplant. Based on information acquired over the past 20 years of doing these transplants at UCSF, we have modified both the composition of the donor cells in the graft and the conditioning regimen. In addition, we have instituted highly sensitive techniques for monitoring engraftment and detecting early infections in order to optimize engraftment while minimizing the delay in immune reconstitution.
Haplocompatible Peripheral Blood Stem Cells
Bone marrow stem cells can be collected from the blood that circulates throughout the body. When healthy people are treated with a type of chemical normally made in small amounts in the body called granulocyte colony stimulating factor (G-CSF), increased numbers of stem cells leave the marrow and enter the blood stream. These cells, referred to as peripheral blood stem cells (PBSC) can be collected along with other white cells by a process called leukapheresis.
In the past 15 years, leukapheresis has been used routinely for patients with cancer to donate their own cells that will be transplanted after they have undergone therapy to remove the cancer. Because a PBSC collection can result in as many as 10 times the number of bone marrow stem cells that can be acquired from a standard bone marrow harvest, it is being used for collecting stem cells from healthy haplocompatible parents, siblings or first cousins for transplantation into children or adult recipients.
The UCSF Pediatric BMT Program is researching answers to the following questions regarding haplocompatible PBSC transplants:
- How often will the transplants engraft?
- How safe is the procedure?
- Will there be a sufficient number of healthy donor stem cells to restore marrow function?
- Will secondary or "booster" transplants be necessary after the initial transplant to accelerate the recovery of the immune system?
- Can small numbers of donor T cells be safely administered post transplant in order to accelerate immune recovery, treat viral infections and prevent relapse?
- Are there any complications associated with this particular source of bone marrow stem cell?
Children who might be eligible for the Haplocompatible Donor Program include those with the following diagnoses:
- Acute lymphoblastic leukemia (ALL) in second or third morphologic remission
- Myelodysplasia prior to transition to frank leukemia
- Chronic myelogenous leukemia (CML) in first or second chronic phase
- Juvenile myelomonocytic leukemia (JMML)
- Acute myelogenous leukemia (AML) in second or third remission, or in early relapse (less than 30 percent blasts in the marrow)
- Severe aplastic anemia in a child who has an absolute neutrophil count (ANC) less than 500, who is platelet and/or red cell transfusion dependent (not Fanconi's anemia) and who is unresponsive to immunosuppressive therapy
- Congenital marrow aplasias unresponsive to cytokines and transfusion dependent
- Inherited immunodeficiency diseases including Chediak-Higashi disease, Wiskott-Aldrich syndrome, combined immunodeficiency disease (Nezelof's), hyper IgM syndrome (CD40 ligand deficiency)
- Children with severe combine immunodeficiency disease (SCID) are eligible for a separate protocol using haplocompatible donors and no conditioning regimen
In addition, the child must not have a closely matched related or unrelated donor available in sufficient time to do the transplant. And, a haplocompatible relative including parent, sibling who is at least 12 years of age or first cousin must be available and willing to donate.
Patients who are in relapse and have more than 30 percent blasts in the marrow, who have active infections, significant heart, kidney, lung or liver abnormalities or who are less than 6 months of age will not be eligible for this research program.