Allogeneic Transplant (Bone Marrow & Stem Cell)
What is bone marrow?
Bone marrow is a spongy material found inside our large bones, like the femur (thigh), hip, and ribs. Bone marrow is made up of cells called hematopoietic stem cells. Hematopoietic cells are given (transplanted) to you during a stem cell transplant. (NOTE: These stem cells are different than those used for research - those are embryonic stem cells).
Hematopoietic stem cells are "baby" cells that become white blood cells, red blood cells, or platelets. They can be called blood-forming stem cells. They grow and are stored in the bone marrow until they are needed. Each type of cell has a job:
- White blood cells (leukocytes): Cells that help fight infection.
- Red blood cells (erythrocytes): Carry oxygen from the lungs to the rest of the body and return carbon dioxide to the lungs as waste.
- Platelets (thrombocytes): Help the body form blood clots to control bleeding.
What does allogeneic mean?
Allogeneic means that the transplanted cells are coming from a donor – this may be a sibling, relative, or someone unrelated to the patient (these cells can even come from umbilical cord blood). If the cells come from your identical twin, the transplant is called syngeneic and is very much like an autologous transplant, because the cells are identical to yours.
The donated cells must be "matched" to you, which is done by human leukocyte antigen (HLA) testing or HLA typing. The HLA type is made up of either 8 or 10 HLA markers. Half are inherited from the mother and half are inherited from the father. There are 2 of each of the markers, called A, B, C, DRB1, and DQ (which is not always used).
Providers usually look first to a family member for a match. Siblings from the same parents have a 25% chance of being an identical match (all markers match, called an 8 out of 8 or 10 out of 10 match). If your sibling matches half of your HLA markers, it is called a haploidentical match (4 out of 8). If no siblings match, the patient's parents or children can be tested.
The match is "scored" based on the number of markers that match between the patient and donor’s typing. The higher the number of matching HLA antigens, the better the match and the greater the chance that the patient's body will accept the donor's stem cells. Patients are less likely to develop graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched.
About 70% of patients will not have a family member match and will need to enlist the help of the National Marrow Donor Program. They keep the HLA typing records from donors around the world and have access to millions of potential donors and numerous cord blood units.
In cord blood transplants, a well-matched donor seems to be less important. These cells are matched using 6 antigens (A, B, and DRB1), and a 4 out of 6 match is acceptable.
What diseases are treated with an allogeneic transplant?
Leukemias, lymphomas, multiple myeloma, severe aplastic anemia, and sickle cell disease, among others. (See the complete list from the National Marrow Donor Program)
How do we collect these cells?
When providers first started doing these transplants, the only way to get stem cells was directly from the bone marrow. This is where the term bone marrow transplant comes from. In the past, the cells would be collected in the operating room by inserting needles into the hip bones to remove the bone marrow. Stem cells were removed from the marrow and preserved in dimethyl sulfoxide (DMSO) and frozen until needed.
In recent years, providers found that giving a medication called granulocyte colony-stimulating factor, or GCSF, stimulates (revs up) your stem cells to be released from the bone marrow and into the bloodstream. Using a blood test, they can tell how many cells are in the bloodstream. Once the number is high enough, the donor will go to the pheresis department at the hospital to have the cells removed. This procedure is called "apheresis.” With apheresis, there is no longer a need to remove stem cells from bone marrow in the OR.
- The cells are removed using a catheter in the chest wall, or with 2 large intravenous (IV) catheters, one placed in each arm.
- Blood is taken out, run through the pheresis machine to remove the stem cells, and the rest of the blood is returned to the donor.
- The cells are frozen in the same DMSO preservative that is used for bone marrow. Preserving the cells on ice, called “cryopreservation,” is needed because the cells must be removed (“harvested”) months before the transplant.
- During the collection, the donor may have tingling or numbness around their lips. This is caused by a loss of calcium and often gets better by eating some calcium tablets.
- The donor may also have hand cramping which is caused by the blood-thinning agent used during collection. This will go away when the collection is done.
The whole collection takes 3-4 hours.
The donated cells can also be taken from umbilical cord blood. The umbilical cord is often thrown away after a baby is born. The blood in the cord is rich in hematopoietic stem cells that can be used in allogeneic transplants. One drawback to cord blood cells is that there are fewer cells than are often used in transplants. For this reason, cord blood is most often used in children and smaller-sized adults. Cord blood can take longer to engraft (see more on engraftment below) and may lead to an increased risk of infection. However, cord blood transplants appear to have lower rates of graft versus host disease.
What is the "preparative regimen"?
This is the chemotherapy, with or without radiation, that is given before the cells are transplanted into your body. This regimen is given to prepare your body to receive the donor’s cells. Chemotherapy is given for a few reasons:
- To destroy your marrow and immune system so that it does not attack the donor's cells.
- To destroy any cancer cells still in your body.
There are two types of preparative regimens: myeloablative (or standard intensity) and non-myeloablative regimens (low intensity or "mini" transplant). Standard intensity regimens use high doses of chemotherapy with or without radiation that completely destroys your bone marrow. Non-myeloablative regimens use lower doses of chemotherapy with or without radiation and are used if you cannot undergo the standard intensity transplant or, in some cases, if you are in remission. Your care team will determine which type is best for you.
Why do a transplant?
This depends on the disease being treated. If the disease affects the bone marrow (leukemias and aplastic anemia), then the hope is to cure the patient by replacing the diseased marrow with the healthy marrow of the donor. In some cases, higher doses of chemotherapy are used to treat the cancer, which also kills the patient's bone marrow. Giving the patient the donor's marrow after this marrow-killing (marrow-ablating) chemotherapy serves to "rescue" the patient with healthy bone marrow. With allogeneic transplants, providers look for the "graft versus tumor effect". This is the effect that the donor's immune system (which is part of the marrow that the donor donated) has on the recipient patient's cancer cells. The hope is that the healthy donor immune system can attack any stray cancer cells in the patient that survived the preparative regimen.
When does the bone marrow (or stem cells) get infused?
After the preparative regimen is complete, the patient is given a day or two to "rest". This rest gives the body time to clear the chemotherapy so it will not damage the donor cells. The cells are infused into a vein, like how a blood transfusion is given. The cells find their way back to the bone marrow space and get to work. Remember, when they arrive in the bone marrow, things are in bad shape – most of the blood cells have been killed by the chemo. The stem cells get right to work making new white and red blood cells and platelets. It can take 7 to 14 days for these stem cells to make new cells and for those cells to become mature enough to work the way they should.
What is engraftment?
Engraftment describes the point when the stem cells start doing their job and blood cell counts start to rise. The first number we look for is the neutrophil count, which is a type of white blood cell that is important in fighting bacterial infection. Often, once the neutrophil count remains above 500, the patient can stop preventive antibiotics. The time until engraftment varies from patient to patient and can be anywhere from 10-20 days. The red blood cell and platelet counts can take many weeks to get back to a normal range.
What are the potential complications of this treatment?
You may have side effects caused by the preparative regimen (chemotherapy and/or radiation), such as infertility, and damage to the liver, kidneys, lungs, and/or heart. Issues related to the transplant can vary depending on the medications used, but include mucositis (sores in the mouth and throat), diarrhea, nausea/vomiting, poor appetite, and fatigue. You can also have complications because of the destruction of your bone marrow leading to low blood counts. These include bleeding due to low platelet counts, infections due to low white blood cell counts, and fatigue due to low red blood cell counts.
There are a few side effects specific to allogeneic transplants. These are graft versus host disease, graft rejection or failure, pulmonary (lung) issues, and liver problems (veno-occlusive disease of the liver).
In graft versus host disease (GVHD), the "graft" refers to the transplanted (donor's) stem cells and the "host" refers to the patient. GVHD occurs when the donor's cells attack your body. GVHD can affect the skin (rash), intestinal tract (diarrhea) and liver (elevated liver blood tests and decreased liver function) in varying degrees, depending on how severe the GVHD is. It can occur any time after transplant and is grouped into acute GVHD (first 100 days after transplant) or chronic GVHD (starting 3-6 months after transplant). Almost all allogeneic transplant patients have GVHD, which can range from very mild to very severe.
GVHD is treated with medications that suppress your new immune system (the donor’s immune system), including steroids and cyclosporine. Antithymocyte globulin (Atgam) may also be used to remove the white blood cells that cause GVHD (called T-cells).
Graft versus tumor effect allows the donor cells to attack any remaining cancer cells. This is a good part of GVHD. We must be careful not to completely get rid of GVHD, or else we will lose the benefit of the graft versus tumor effect. Healthcare providers manage this carefully.
Graft rejection can happen if there are immune system cells left in the patient after the preparative regimen. These "native" cells then attack the donor's cells because they recognize them as foreign to the body. This can be prevented most of the time by making sure the preparative regimen is strong enough to kill any native immune cells.
Graft failure occurs when the donor's cells fail to start working (producing new blood cells). Healthcare providers usually consider a diagnosis of graft failure if engraftment has not happened by about 42 days after transplant. This is rare and the only treatment is to receive another transplant.
Lung issues, like pneumonia, can be very serious in these patients. Veno-occlusive disease (VOD) of the liver can cause jaundice (yellowing of the skin and eyes), enlarged liver, or swelling of the abdomen (belly) and can lead to liver failure. VOD can be very serious. You will be watched very closely for all of these concerns and will remain in the hospital for at least several weeks.
What happens when I am discharged?
Transplant centers vary in how they handle the time for discharge. Once an outpatient, you will need to visit the clinic often, maybe even daily. Most centers require you to stay near the hospital for the first 100 days after transplant. Even though the blood cells have started to work, it will be months to a year before you will have a "normal" immune system. You need to be very careful to avoid infection (avoiding crowds, washing hands frequently, wearing a mask in public places). Your energy level will not be like your "old self" for quite some time (some say years). Friends and family must understand that just because the transplant is over, it does not mean you are back to normal.
Transplant centers give detailed instructions to families who will be having the transplant patient stay at their home. These include help with chores, childcare, pet care, and other daily household errands. The National Marrow Donor Program has some great resources for preparing the home for a transplant recipient. This can be a lot of work, but it is a great way for friends and family to help out.
What is a mini-allo or reduced-intensity transplant?
A reduced-intensity transplant is an allogeneic transplant that uses a less intense preparative regimen before the donor cells are given. The use of lower doses of anticancer medications and radiation gets rid of some, but not all, of your bone marrow. Unlike a traditional transplant, cells from both the donor and you may exist in your body for some time after a mini-allo. When cells from both the donor and you are present, it is called "mixed chimerism.” Eventually, the cells will all be from the donor (called "full chimerism").
Once the cells from the donor begin to engraft, they can cause the graft-versus-tumor (GVT) effect that works to destroy the cancer cells that were not eliminated by the chemotherapy and/or radiation. This treatment is not appropriate for all cancers treated by an allogeneic transplant.
Read more about it at the National Marrow Donor Program.
Resources for more information
Abeloff M, Niederhuber JE, Armitage JO, Doroshow, JH, Kastan MB, Tepper, JE. Abeloff’s Clinical Oncology. 5th edition. Philadelphia: Churchill Livingstone; 2014.
Be the Match (Formerly The National Marrow Donor Program): www.bethematch.org
Blood Forming Stem Cell Transplants from the National Cancer Institute