Hematopoietic stem cell transplantation

The best stem cell donor for someone with PI is an HLA-matched sibling. The sibling must have the same mother and father as the recipient. Each full biological sibling of the recipient has a 25% chance of being a perfect match, so even recipients with many siblings may need to look elsewhere for a donor. Note that it is important that potential sibling donors are tested for PI before being used as donors.

If there are no sibling donors available, the search for stem cells will move to HLA- matched, unrelated donors. These are individuals who volunteer to provide their stem cells and have no family connection to the HSCT recipient.

People who are willing to donate their stem cells are placed on an anonymous list called a registry. There are several registries worldwide, and most of them cooperate with each other. Healthcare providers look through registries for donors that match the recipient's HLA types. If the donor stem cells match the recipient's HLA types, then those cells can be requested for transplant.

Another source of stem cells is umbilical cord blood. Umbilical cord blood is sometimes donated by a mother after she has a child. The blood comes from the umbilical cord of her child and contains hematopoietic stem cells. The blood is frozen and kept in cord blood banks. The cord blood, which typically comes from an unrelated individual, could be a match for an HSCT recipient.

Because HLA genes are inherited, recipients are most likely to find HLA-matched, unrelated donors among people from a similar ethnic background. Unfortunately, because of a lack of representation in registries and cord blood banks, this means some ethnic groups and those of multi-ethnic heritage may have more difficulty finding an HLA-matched, unrelated donor.

If there are no matched donors, a mismatched donor may be considered. If only one HLA type is different between the person with PI and the donor, that would be noted as a 7/8, 9/10, or 11/12 HLA match. However, having an HLA mismatch increases the risks of graft rejection and GVHD, and this must be considered when thinking about how the transplant doctor does the transplant.

When a sibling or unrelated HLA-matched donor cannot be found, then another option for stem cells is a haploidentical family match. Haploidentical means "half-matched." These donors are usually a parent of the recipient but can be a sibling or even an aunt, uncle, or cousin related by blood.

This type of transplant must be done in a special way because there is a higher risk of graft rejection or acute GVHD. Donor T cells must be removed from the graft or otherwise destroyed to decrease the risk of severe GVHD.

There are two major categories of conditioning medications; those that target stem cells in the bone marrow and those that target immune cells throughout the body. They have different goals. HSCT recipients may have one or both types of conditioning before treatment. Because these medications destroy cells, they are called chemotherapy, even when they are used in people that do not have cancer.

Conditioning targeting stem cells uses chemotherapy drugs to reduce the number of stem cells in the recipient's bone marrow (myelosuppression). The goal is to make space in the recipient's bone marrow for the donor stem cells. There are several intensities of myelosuppressive conditioning. They use the same drugs, such as busulfan or melphalan, but vary in the dose and number of drugs used. The three categories of myelosuppressive conditioning include:

• Myeloablative conditioning (MAC): This type of conditioning uses a higher dose of chemotherapy to completely get rid of the recipient’s stem cells. Successful MAC makes plenty of empty space in the recipient's bone marrow for new stem cells to land and grow. In general, MAC has the best chance to fully replace the recipient’s stem cells with donor stem cells to achieve a fully functioning immune system that can fight off infections. However, this approach does not always work in every patient and comes with the risk of more drug toxicity.
• Reduced-intensity conditioning (RIC): This type of conditioning uses lower doses of chemotherapy to achieve full replacement of the recipient's stem cells but with less toxicity. Successful RIC makes enough empty space for donor stem cells to land and grow. Use of RIC means less severe side effects and lower risk. But because RIC uses lower doses, there is a greater chance that replacement of the recipient's stem cells will be incomplete when compared with MAC. This means a higher risk that some of the recipient’s stem cells might remain post-transplant. For most conditions, this may still be enough to correct the underlying immune disorder.
• Low-dose conditioning: This type of conditioning uses very low doses of chemotherapy and is more commonly used in gene therapy.

Conditioning targeting immune cells uses medications to reduce the T and B cells in the recipient’s immune system. Doctors call this immunosuppression. The goal is to protect the donor stem cells from being attacked by the recipient’s immune cells. There are two categories of immunosuppressive medications:

• Antibody-based medications: Antibody-based medications, also called serotherapy, use antibodies to target and destroy the recipient’s immune cells with the goal of decreasing the risk of graft rejection. Examples include alemtuzumab and ATG (anti-thymocyte globulin).
• Chemotherapy medications: Some chemotherapy medications kill immune cells but not stem cells. Examples include cyclophosphamide and fludarabine.

Conditioning can have short-term side effects and long-term risks. Short-term side effects are temporary and usually go away when the new donor cells start growing. Long-term side effects may appear months or years after conditioning. On rare occasions, short-term side effects become chronic and last a long time.

Short-term side effects can be mild or severe. Some examples include:

• Inflammation of mucous membranes (mucositis) and nausea, vomiting, diarrhea: Chemotherapy can damage the lining of the mouth, throat, stomach, and intestines. The damage can be very mild or more problematic depending on the conditioning regimen. Recipients may have sores, drooling, nausea, pain, vomiting, diarrhea, and sometimes bleeding. These side effects can be treated with pain medications, anti-nausea medications, and nutrition and fluid support such as a feeding tube. They occur when the body’s defenses are very low, and start to heal once the new cells grow, usually within a few weeks to months after the transplant.
• Anemia, bleeding, and infection: Conditioning will reduce the number of all of the recipient’s blood cells, including immune cells, red blood cells, and platelets, for several weeks. During this time, the recipient is at an increased risk for infection, may have blood clotting problems, or may feel tired and weak because they have fewer red blood cells. It is likely that transfusion of blood and/or platelets, as well as antibiotics or other methods to minimize the risk of infections during the period of low white cells, will be needed during this time.
• Harm to vital organs, such as the brain, lungs, kidneys, and liver. These organs are all very closely monitored during the transplant period, particularly if their function was already affected prior to the transplant. Sometimes these complications can be treated with medication.

These long-term complications do not happen frequently, but recipients and their families or caregivers should know that they do sometimes occur [3]:

• Chronic problems from harm to vital organs, such as the brain, lungs, kidney, and liver. Sometimes these complications can be treated with medication.
• Reduced bone growth, which may result in shortened height as an adult.
• Endocrine abnormalities, such as growth hormone deficiency, underactive thyroid (hypothyroidism), and ovarian and testicular dysfunction.
• Reduced fertility.
• Increased risk of cancer.
• Developmental delay or problems with learning.
• Issues with the development and arrangement of teeth.