Bone marrow or peripheral blood stem cell transplant for chronic myeloid leukemia

The usual doses of chemotherapy drugs can cause serious side effects to quickly dividing tissues such as the bone marrow. Even though higher doses of these drugs might be more effective, they are not given because the severe damage to bone marrow cells would cause lethal shortages of blood cells and damage to vital organs.

A stem cell transplant (SCT) allows doctors to use higher doses of chemotherapy and, sometimes, radiation therapy. For the transplant, high doses of chemotherapy are given to kill the leukemia cells. Sometimes the whole body also is given a low dose of radiation. This treatment kills the leukemia cells, but also damages the normal bone marrow cells. Then after chemotherapy (and possibly radiation), the patient will receive a transplant of blood-forming stem cells to restore the bone marrow.

Blood-forming stem cells used for a transplant are obtained either from the blood (for a peripheral blood stem cell transplant, or PBSCT) or from the bone marrow (for a bone marrow transplant, or BMT). Bone marrow transplant was more common in the past, but it has largely been replaced by PBSCT.

There are 2 main types of stem cell transplants. They differ in the source of the blood-forming stem cells. The 2 types are:

• Allogeneic stem cell transplant
• Autologous stem cell transplant

Allogeneic stem cell transplant

In this type of transplant, the stem cells come from someone else. Usually the donor is a relative whose tissue type is almost identical to the patient's. Tissue type is based on certain substances present on the surface of cells in the body. These substances can cause the immune system to react against the cells. Therefore, the closer a tissue "match" is between the donor and the recipient, the better the chance the transplanted cells will "take" and begin making new blood cells.

Most often the donor is a brother, a sister, or another close relative. Less often, the donor is someone with the same tissue type, but who is not related by blood -- a matched unrelated donor (MUD). The stem cells from an unrelated donor can come from volunteers whose tissue type has been stored in a central list (registry) and matched with that of the patient. Sometimes umbilical cord stem cells are used. These stem cells come from blood drained from the umbilical cord and placenta after a baby is born and the umbilical cord is cut.

Allogeneic stem cell transplants (ASCT) are the main type of transplant done for patients with chronic myeloid leukemia (CML). They are the only known cure for this disease. The best candidate for this type of transplant is a young patient who has no other health problems and has a donor who is a good tissue type match. Younger patients tend to tolerate this procedure better than older ones, but age may not be as important as the overall health and fitness of the patient. Still, older patients may become very ill from this procedure and have a high chance of dying from it. However, non-myeloablative SCT can be used in some older patients.

Non-myeloablative transplant: Many older patients can't tolerate a standard allogeneic transplant that uses high doses of chemotherapy. Some may be able to have a non-myeloablative transplant (also known as a mini-transplant or reduced-intensity transplant). This is a type of allogeneic SCT that uses lower doses of chemotherapy and radiation that do not completely destroy the cells in their bone marrow. After the chemotherapy/radiation, the patient receives the allogeneic (donor) stem cells. These cells enter the body and establish a new immune system. The new immune cells see the leukemia cells as foreign and attack them. This is called a graft-versus-leukemia effect.

Doctors have learned that if they use small doses of certain chemotherapy drugs and low doses of total body radiation, an allogeneic transplant can still work with much less toxicity. In fact, a patient can receive a non-myeloablative transplant as an outpatient. The major complication is graft-versus-host disease.

This type of transplant isn't a standard treatment for CML, and studies are under way to determine how useful it may be against this disease.

Autologous stem cell transplant

In an autologous stem cell transplant, a patient's own stem cells are removed from his or her bone marrow or peripheral blood. They are stored while the person gets treatment (high-dose chemotherapy and/or radiation) and then are given back to the patient.

Autologous SCT is not used often to treat CML because some leukemia cells might be collected along with the stem cells and be given back to the patient after treatment. A process called purging can be used to try to remove the leukemia cells from the collected stem cells. Because you are given back your own cells in this type of transplant, you won't get the benefit of the graft-versus-leukemia reaction.

The transplant procedure

Blood-forming stem cells from the bone marrow or peripheral blood are collected from the donor, frozen, and stored. The patient receives high-dose chemotherapy and sometimes also radiation treatment to the entire body. (Radiation shields are used to protect the lungs, heart, and kidneys from damage during radiation therapy.)

The chemotherapy and radiation treatments are meant to destroy any remaining cancer cells. They also kill the normal cells of the bone marrow and the immune system. This prevents the stem cell transplant (graft) from being rejected. Several days after these treatments, the frozen stem cells are thawed and given as an intravenous infusion. The stem cells settle into the patient's bone marrow over the next several days and start to grow and make new blood cells.

In allogeneic SCTs, the person getting the transplant is given drugs like prednisone, methotrexate, and cyclosporine to suppress the immune system and help prevent graft-versus-host disease (see Long-term side effects). For the next few weeks the patient gets regular blood tests and supportive therapies as needed, which might include antibiotics, red blood cell or platelet transfusions, other medicines, and help with nutrition.

Usually within a couple of weeks after the stem cells have been infused, they begin making new white blood cells. This is followed by new platelet production and, several weeks later, new red blood cell production.

Patients usually stay in the hospital in protective isolation (guarding against exposure to germs) until their white blood cell count rises above 500. They may be able to leave the hospital when their white blood cell count is near 1,000. Because platelet counts take longer to return to a safe level, patients may receive platelet transfusions as an outpatient procedure.

Side effects

Side effects from SCT are generally divided into early and long-term effects.

Early side effects: The early complications and side effects are basically the same as those caused by any other type of high-dose chemotherapy (see the section called "Chemotherapy for chronic myeloid leukemia" in this document), and are caused by damage to the bone marrow and other quickly dividing tissues of the body. They can include low blood cell counts (with increased risk of infection and bleeding), nausea, vomiting, loss of appetite, mouth sores, and hair loss. Mouth and throat sores, called mucositis, can be severe and make it hard to eat.

One of the most common and serious short-term effects is the increased risk of infection from bacteria, viruses, or fungi. Antibiotics are often given for a time, even before there are any signs of infection, to try to keep this from happening. The risk of infection is high because the white blood cell count becomes very low for a few weeks during the transplant. During this time, patients are watched closely for fever or other signs of infection.

Other side effects, like low red blood cell and platelet counts, may require blood product transfusions or other treatments.

Long-term side effects: Some complications and side effects can last for a long time or may not happen until months or years after the transplant. These include:

• Graft-versus-host disease (GVHD), which can occur in allogeneic (donor) transplants. This happens when the donor immune system cells attack tissues of the patient's skin, liver, and digestive tract. Symptoms can include weakness, fatigue, dry mouth, rashes, nausea, diarrhea, yellowing of the skin and eyes (jaundice), and muscle aches. In severe cases, GVHD can be fatal. GVHD is often described as either acute or chronic, based on how soon after the transplant it begins. Drugs that weaken the immune system are often given to try to keep GVHD under control.
• Radiation damage to the lungs, causing shortness of breath
• Damage to the ovaries in women, causing infertility and loss of menstrual periods
• Damage to the thyroid gland that causes problems with metabolism
• Cataracts (damage to the lens of the eye that can affect vision)
• Bone damage called aseptic necrosis (the bone dies because of poor blood supply); if damage is severe, the patient will need to have part of the bone and the joint replaced.

Practical points

Before modern targeted therapy drugs like imatinib (Gleevec), SCT was commonly used to treat CML. That is because the drugs that were available then did not work very well. Before drugs like imatinib were available, less than half of patients survived more than 5 years after diagnosis. Now, drugs like imatinib are the standard treatment, and transplants are being used less often. Still, allogeneic SCT offers the only proven chance to cure CML, so doctors may still recommend a transplant for younger patients, particularly children. It is more likely to be considered for those with an available matched donor, like a well-matched brother or sister. Transplant may also be recommended if the CML is not responding well to tyrosine kinase inhibitors.

Bone marrow or peripheral blood SCT is a complex treatment. If the doctors think a patient may benefit from a transplant, it should be done at a hospital where the staff has experience with the procedure and with managing the recovery phase. Some bone marrow transplant programs may not be experienced in doing certain types of transplants, especially transplants from unrelated donors.

SCT is very expensive (more than $100,000) and often requires a lengthy hospital stay. Most insurance companies will cover the cost of a standard allogeneic SCT for CML, but some view other types of SCT as experimental when they are used to treat CML and so may not pay for them. Before deciding on a transplant, it's a good idea to find out what your insurer will cover and what you might have to pay.

For more information on stem cell transplants, see our document, Stem Cell Transplant (Peripheral Blood, Bone Marrow, and Cord Blood Transplants).