|Carolyn Vachani RN, MSN, AOCN & Lara Bonner Millar, MD|
|The Abramson Cancer Center of the University of Pennsylvania|
| Last Modified: August 13, 2010
What is bone marrow?
Bone marrow is a spongy-like substance found inside our large bones, like the femur (leg), hip, and ribs. It is made up of cells called hematopoietic stem cells. It is these cells that are given (transplanted) to the patient during a transplant. These stem cells are different than those we hear about in the news - those are called embryonic stem cells and are obtained from a growing embryo, not an adult. Hematopoietic stem cells are "baby" cells that grow up to become white blood cells, red blood cells and platelets. The bone marrow acts as a greenhouse for these cells, growing them and storing them until they are needed. What do we need them for?
What does allogeneic mean?
Allogeneic means that the transplanted cells are coming from a donor – this may be a sibling, other relative, or someone unrelated to the patient (the cells can even come from umbilical cord blood). If the cells come from an identical twin of the patient, the transplant is called syngeneic and is essentially like an autologous transplant, because the cells are identical to the patients.
The cells must be "matched" to the patient, which is done by human leukocyte antigen (HLA) testing. The HLA type is made up of 6 antigens: 3 are inherited from the mother, and 3 are inherited from the father. Doctors usually look first to a family member for a match. Siblings from the same parents have a 25% chance of matching each other, but if no siblings match, that patient's parents or children can be tested. A donor may "match" the patient in 6 out of 6, 5 out of 6, or 4 out of 6 antigens. The higher the number of matching HLA antigens, the greater the chance that the patient's body will accept the donor's stem cells. In general, patients are less likely to develop a complication known as 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, which keeps the HLA typing records on over 8 million volunteer donors and 400,000 units of umbilical cord blood. The program can also access international programs, which have over 5 million donors.
How do we collect bone marrow cells?
When doctors first started doing these procedures, the only way to get stem cells was directly from the bone marrow. This is where the term bone marrow transplant originated. The donor is taken to the operating room and put to sleep lying on his or her stomach. The doctors put long needles into the hip bones and pull out the bone marrow in syringes in a procedure called bone marrow aspiration. This solution is then poured through a special column that is able to pull out the desired stem cells, allowing any other cells (mature red and white blood cells and platelets) to be reinfused into the donor. In order to get the number of cells needed, the needles need to be inserted many times, which is why the donor is put to sleep for the procedure. These cells are then frozen in a special preservative (called Dimethyl sulfoxide or DMSO) to protect them from "freezer burn" until they are used. The donor still has plenty of cells to produce blood cells for him/herself.
A second method of collecting stem cells, called apheresis, which is used for most autologous transplants, is currently being used in clinical trials for allogeneic transplants. This method involves giving the donor a medication called granulocyte colony stimulating factor, or GCSF, which causes the stem cells to be released from the bone marrow and into the blood stream. Using a blood test, doctors can tell how many cells are circulating in the blood stream. Once the number is high enough, the donor goes to the pheresis department at the hospital to have the cells removed. The cells can be removed using either a catheter in the chest wall or 2 large intravenous (IV) catheters, one placed in each arm. Blood is taken out of the donor, circulated through the pheresis machine to remove the stem cells, and then the rest of the blood is returned to the patient. The cells would be frozen in the same DMSO preservative mentioned earlier for the bone marrow. During the collection, the patient may experience tingling or numbness around the lips. This is caused by a loss of calcium and can usually be resolved by eating some calcium tablets.
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)
What is the "preparative regimen"?
You may hear doctors talk about the preparative regimen. This is the course of chemotherapy, with or without radiation that is given before the cells are transplanted into the patient. In traditional transplants, this regimen is given to wipe out the patient's own bone marrow to make room for the donor marrow and to prevent a complication known as "Graft Versus Host Disease" (GVHD). We'll talk more about that later. It is necessary to give this chemotherapy for a few reasons:
Why do a transplant?
This answer varies depending on the disease being treated. If the bone marrow is affected by the disease, as in 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, the hope is to administer much higher doses of chemotherapy to treat the cancer, which would also kill 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. One effect that doctors see as a very important part of all allogeneic transplants is called the "graft versus tumor effect". Basically, 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 may have 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". In reality, the doctors are waiting for the chemotherapy to be cleared from the patient's system so it will not damage the donor cells. The cells are infused into a vein, similar to the way in which a blood transfusion is given. The cells are quite smart, and they 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 producing new white and red blood cells and platelets. It can take anywhere from 7 to 14 days for these stem cells to produce new cells and for those cells to become mature enough to function properly.
What is engraftment?
Engraftment is a term the doctors use to describe the point when the stem cells start doing their job and blood cell counts start to come up. The first number we look for is the neutrophil count, which is a type of white blood cell that is especially important in fighting bacterial infection. Generally, once the neutrophil count gets above 500, the patient can stop protective, prophylactic 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 several weeks to get back to a normal range.
What are the potential complications of this treatment?
The patient can 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. Complications related to the transplant itself can vary depending on the medications used, but include mucositis (sores in the mouth and throat), diarrhea, nausea/vomiting, poor appetite, and fatigue. (Read more about specific medication side effects) The patient can also have complications because of the destruction of the 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.
In addition to these problems, there are a few complications that are specific to allogeneic transplants. These are graft versus host disease, graft rejection or failure, pulmonary (lung) complications, and liver problems (veno-occlusive disease of the liver).
In graft versus host disease (GVHD), the "graft" refers to the transplanted (donorâ€™s) hematopoietic stem cells and the "host" refers to the patient. GVHD occurs when the donor's cells attack the patient's 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 anytime after transplant and is grouped into acute GVHD (1-2 months after transplant) or chronic GVHD (starting at least 2-3 months after transplant). Almost all allogeneic transplant patients have some degree of this complication, which can range from very mild to very severe. It is treated with immunosuppressing medications, including steroids. Antithymocyte globulin (Atgam) may also be used to remove the white blood cells that cause GVHD in a process called T-cell depletion. We mentioned previously the value of the "graft versus tumor effect", which allows the donor cells to attack any remaining cancer cells. This is a good part of GVHD, so we must be careful not to completely eliminate GVHD, or else we will lose the benefit of the graft versus tumor effect. It is a fine line between the unwanted and the wanted effects, so doctors need to carefully manage this balance.
Graft rejection can occur 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 sufficiently strong to kill any native immune cells. Graft failure occurs when the donor's cells fail to start working (producing new blood cells). Doctors usually consider a diagnosis of graft failure if engraftment has not occurred by 42 days after transplant. This complication is rare, occurring in about 5% of patients, and the only treatment is to receive another transplant.
Pulmonary complications are generally caused by pneumonia and can be very serious in these patients. Veno-occlusive disease (VOD) of the liver is a complication that can present with jaundice, enlarged liver, or swelling of the abdomen and can lead to liver failure. VOD can be very serious, and can even be fatal.
What happens when the patient is discharged?
Transplant centers vary in how they handle the time for discharge. Once an outpatient, the patient will need to visit the clinic often, maybe even daily. Most centers require patients to stay near the hospital for the first 100 days after transplant. Even though the blood cells have started to perform, it will be months to a year before the patient will have a "normal" immune system. The patient needs to be very careful to not get an infection (avoiding crowds, washing hands frequently, wearing a mask in public places). The patient's energy level will not be like his or her "old self" for quite some time (some say years), so friends and family must understand that just because the transplant is over, the patient will not be back to normal. Transplant centers give detailed instructions to families who will be having the transplant patient staying at their home. These include help with domestic 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?
This is an allogeneic transplant that uses a less intense preparative regimen before the donor cells are infused. The use of lower doses of anticancer drugs and radiation eliminates some, but not all, of the patient's bone marrow. Unlike traditional transplant, cells from both the donor and the patient may exist in the patient's body for some time after a mini-allo. Once the cells from the donor begin to engraft, they may cause the graft-versus-tumor (GVT) effect and work to destroy the cancer cells that were not eliminated by the chemotherapy and/or radiation.
Read more about it at the National Marrow Donor Program.
This article is meant to give you a basic understanding of the allogeneic transplant process. Use the links on the left or the resources below to learn more.
Abeloff, M., Armitage, J., Niederhuber, J., Kastan, M. & McKenna, G. (Eds.): Clinical Oncology (2004). Elsevier, Philadelphia, PA.
The National Marrow Donor Program: www.marrow.org