Bone marrow is the soft, sponge-like material found inside bones. It contains immature cells known as hematopoietic (or blood-forming) stem cells. Hematopoietic stem cells divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: White blood cells, which fight infection; red blood cells, which carry oxygen; and platelets, which help the blood to clot. Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants.
2. What are bone marrow transplantation and peripheral blood stem cell transplantation? almokbelra
Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:
In autologous transplants, patients receive their own stem cells.
In allogeneic transplants, patients receive stem cells from their brother, sister, or parent. A person who is not related to the patient (an unrelated donor) also may be used.
Non-myeloablative transplant — A non-myeloablative transplant, sometimes referred to as a “mini” or reduced intensity transplant, allows you to have less intensive chemotherapy before transplantation with allogeneic hematopoietic stem cells. This approach may be recommended if you cannot undergo standard bone marrow transplantation because of your age or other illnesses.
3. Why are BMT and PBSCT used in cancer treatment? almokbelra
One reason BMT and PBSCT are used in cancer treatment is to make it possible for patients to receive very high doses of chemotherapy and/or radiation therapy. To understand more about why BMT and PBSCT are used, it is helpful to understand how chemotherapy and radiation therapy work.
Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to treat cancer because cancer cells divide more often than most healthy cells. However, because bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT and PBSCT replace stem cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s ability to produce the blood cells the patient needs.
In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial to the effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cells that remain in the patient’s body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them. (A potential complication of allogeneic transplants called graft-versus-host disease is discussed in Questions 5 and 14.)
4. What types of cancer are treated with BMT and PBSCT? almokbelra
BMT and PBSCT are most commonly used in the treatment of leukemia and lymphoma. They are most effective when the leukemia or lymphoma is in remission (the signs and symptoms of cancer have disappeared). BMT and PBSCT are also used to treat other cancers such as neuroblastoma (cancer that arises in immature nerve cells and affects mostly infants and children) and multiple myeloma. Researchers are evaluating BMT and PBSCT in clinical trials (research studies) for the treatment of various types of cancer.
5. How are the donor’s stem cells matched to the patient’s stem cells in allogeneic transplantation? almokbelra
To minimize potential side effects, doctors most often use transplanted stem cells that match the patient’s own stem cells as closely as possible. People have different sets of proteins, called human leukocyte-associated (HLA) antigens, on the surface of their cells. The set of proteins, called the HLA type, is identified by a special blood test.
In most cases, the success of allogeneic transplantation depends in part on how well the HLA antigens of the donor’s stem cells match those of the recipient’s stem cells. 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. GVHD is further described in Question 14.
Close relatives, especially brothers and sisters, are more likely than unrelated people to be HLA-matched. However, only 25 to 35 percent of patients have an HLA-matched sibling. The chances of obtaining HLA-matched stem cells from an unrelated donor are slightly better, approximately 50 percent. Among unrelated donors, HLA-matching is greatly improved when the donor and recipient have the same ethnic and racial background. Although the number of donors is increasing overall, individuals from certain ethnic and racial groups still have a lower chance of finding a matching donor.
6. How is bone marrow obtained for transplantation? almokbelra
The stem cells used in BMT come from the liquid center of the bone, called the marrow. In general, the procedure for obtaining bone marrow, which is called “harvesting,” is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted through the skin over the pelvic (hip) bone or, in rare cases, the sternum (breastbone), and into the bone marrow to draw the marrow out of the bone. Harvesting the marrow takes about an hour.
The harvested bone marrow is then processed to remove blood and bone fragments. Harvested bone marrow can be combined with a preservative and frozen to keep the stem cells alive until they are needed. This technique is known as cryopreservation. Stem cells can be cryopreserved for many years.
7. How are PBSCs obtained for transplantation? almokbelra
The stem cells used in PBSCT come from the bloodstream. A process called apheresis or leukapheresis is used to obtain PBSCs for transplantation. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area). The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes 4 to 6 hours. The stem cells are then frozen until they are given to the recipient.
8. How are umbilical cord stem cells obtained for transplantation? almokbelra
Stem cells also may be retrieved from umbilical cord blood. For this to occur, the mother must contact a cord blood bank before the baby’s birth. The cord blood bank may request that she complete a questionnaire and give a small blood sample.
Cord blood banks may be public or commercial. Public cord blood banks accept donations of cord blood and may provide the donated stem cells to another matched individual in their network. In contrast, commercial cord blood banks will store the cord blood for the family, in case it is needed later for the child or another family member.
After the baby is born and the umbilical cord has been cut, blood is retrieved from the umbilical cord and placenta. This process poses minimal health risk to the mother or the child. If the mother agrees, the umbilical cord blood is processed and frozen for storage by the cord blood bank. Only a small amount of blood can be retrieved from the umbilical cord and placenta, so the collected stem cells are typically used for children or small adults.
9. Are any risks associated with donating bone marrow? almokbelra
Because only a small amount of bone marrow is removed, donating usually does not pose any significant problems for the donor. The most serious risk associated with donating bone marrow involves the use of anesthesia during the procedure.
The area where the bone marrow was taken out may feel stiff or sore for a few days, and the donor may feel tired. Within a few weeks, the donor’s body replaces the donated marrow; however, the time required for a donor to recover varies. Some people are back to their usual routine within 2 or 3 days, while others may take up to 3 to 4 weeks to fully recover their strength.
10. Are any risks associated with donating PBSCs? almokbelra
Apheresis usually causes minimal discomfort. During apheresis, the person may feel lightheadedness, chills, numbness around the lips, and cramping in the hands. Unlike bone marrow donation, PBSC donation does not require anesthesia. The medication that is given to stimulate the release of stem cells from the marrow into the bloodstream may cause bone and muscle aches, headaches, fatigue, nausea, vomiting, and/or difficulty sleeping. These side effects generally stop within 2 to 3 days of the last dose of the medication.
11. How does the patient receive the stem cells during the transplant? almokbelra
After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells through an intravenous (IV) line just like a blood transfusion. This part of the transplant takes 1 to 5 hours.
12. Are any special measures taken when the cancer patient is also the donor (autologous transplant)? almokbelra
The stem cells used for autologous transplantation must be relatively free of cancer cells. The harvested cells can sometimes be treated before transplantation in a process known as “purging” to get rid of cancer cells. This process can remove some cancer cells from the harvested cells and minimize the chance that cancer will come back. Because purging may damage some healthy stem cells, more cells are obtained from the patient before the transplant so that enough healthy stem cells will remain after purging.
13. What happens after the stem cells have been transplanted to the patient? almokbelra
After entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as “engraftment.” Engraftment usually occurs within about 2 to 4 weeks after transplantation. Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer, however—up to several months for autologous transplant recipients and 1 to 2 years for patients receiving allogeneic or syngeneic transplants. Doctors evaluate the results of various blood tests to confirm that new blood cells are being produced and that the cancer has not returned. Bone marrow aspiration (the removal of a small sample of bone marrow through a needle for examination under a microscope) can also help doctors determine how well the new marrow is working.
14. What are the possible side effects of BMT and PBSCT? almokbelra
The major risk of both treatments is an increased susceptibility to infection and bleeding as a result of the high-dose cancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give the patient transfusions of platelets to prevent bleeding and red blood cells to treat anemia. Patients who undergo BMT and PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions.
Potential long-term risks include complications of the pretransplant chemotherapy and radiation therapy, such as infertility (the inability to produce children); cataracts (clouding of the lens of the eye, which causes loss of vision); secondary (new) cancers; and damage to the liver, kidneys, lungs, and/or heart.
With allogeneic transplants, a complication known as graft-versus-host disease (GVHD) sometimes develops. GVHD occurs when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver, and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronic GVHD). To prevent this complication, the patient may receive medications that suppress the immune system. Additionally, the donated stem cells can be treated to remove the white blood cells that cause GVHD in a process called “T-cell depletion.” If GVHD develops, it can be very serious and is treated with steroids or other immunosuppressive agents. GVHD can be difficult to treat, but some studies suggest that patients with leukemia who develop GVHD are less likely to have the cancer come back. Clinical trials are being conducted to find ways to prevent and treat GVHD.
The likelihood and severity of complications are specific to the patient’s treatment and should be discussed with the patient’s doctor.
15. What is a “mini-transplant”? almokbelra
A “mini-transplant” (also called a non-myeloablative or reduced-intensity transplant) is a type of allogeneic transplant. This approach is being studied in clinical trials for the treatment of several types of cancer, including leukemia, lymphoma, multiple myeloma, and other cancers of the blood.
A mini-transplant uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for an allogeneic transplant. The use of lower doses of anticancer drugs and radiation eliminates some, but not all, of the patient’s bone marrow. It also reduces the number of cancer cells and suppresses the patient’s immune system to prevent rejection of the transplant.
Unlike traditional BMT or PBSCT, cells from both the donor and the patient may exist in the patient’s body for some time after a mini-transplant. 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 anticancer drugs and/or radiation. To boost the GVT effect, the patient may be given an injection of the donor’s white blood cells. This procedure is called a “donor lymphocyte infusion.”
16. What is a “tandem transplant”? almokbelra
A “tandem transplant” is a type of autologous transplant. This method is being studied in clinical trials for the treatment of several types of cancer, including multiple myeloma and germ cell cancer. During a tandem transplant, a patient receives two sequential courses of high-dose chemotherapy with stem cell transplant. Typically, the two courses are given several weeks to several months apart. Researchers hope that this method can prevent the cancer from recurring (coming back) at a later time.
17. How do patients cover the cost of BMT or PBSCT? almokbelra
Advances in treatment methods, including the use of PBSCT, have reduced the amount of time many patients must spend in the hospital by speeding recovery. This shorter recovery time has brought about a reduction in cost. However, because BMT and PBSCT are complicated technical procedures, they are very expensive. Many health insurance companies cover some of the costs of transplantation for certain types of cancer. Insurers may also cover a portion of the costs if special care is required when the patient returns home.
There are options for relieving the financial burden associated with BMT and PBSCT. A hospital social worker is a valuable resource in planning for these financial needs. Federal Government programs and local service organizations may also be able to help.
18. What is the role of the donor? almokbelra
Another important aspect of bone marrow transplantation is finding a suitable donor. The donor in allogeneic bone marrow transplant is an important person, and great care is taken to identify a suitable donor.
Donors are educated so they understand what will happen when marrow is harvested.
Donors must undergo several tests and procedures to ensure that they are physically able to safely donate marrow.
Immediate family members are tissue or DNA typed first to see if a matched donor can be found within the family. A matched donor in the recipient’s family is the best donor to have. Many of the donor’s and recipient’s genes are similar, and there are potentially fewer side effects from treatment.
If not one in the recipient’s family is a match, then the transplant coordinator will begin a search for a donor. There are three additional sources for donors in stem cell transplantation:
Unrelated Marrow Donors
Unrelated Cord Blood Donors – the cord blood is obtained from the umbilical cord at birth and is rich in stem cells.
Haploidentical Donors Parents – are half-matched to their children and may be a suitable donor.
Matched donor — to help minimize the problems that can be caused by the expected immune response, a donor who has similar genetic makeup to you is preferred. Your cells will seem “less foreign” to the transplanted donor cells. Siblings (ie, brothers and sisters who share the same parents as you) are typically the only members of your family that are tested for being a donor because they have a one in four chance of sharing genetic characteristics with you; these characteristics are critical for your body to accept the graft. In general, parents, children, and relatives are not suitable donors since they do not share the same parents, and therefore do not have the same genetic material.
An exception is called a haploidentical transplant, which may be considered under certain circumstances. Matched unrelated donor — if no siblings are available, or if testing the blood of the siblings does not reveal a match, a matched unrelated donor may be used. The search for an appropriate donor can be accomplished using transplant registries throughout the world. Mismatched related or unrelated donor — some patients are offered treatment with cells from a partially matched family member (called mismatched related donor). The hematopoietic stem cell product may be specially prepared to minimize the immune response in the patient. Another alternative is to use umbilical cord blood, collected from a healthy newborn infant at the time of delivery; this blood is a rich source of hematopoietic stem cells.
19. What is cord blood transplantation? almokbelra
Cord blood transplantation is an exciting area of research and a major focus of study in both pediatric and adult settings. When a baby is born, the umbilical cord is cut, and the placenta is discarded. Recently, it has been discovered that the blood inside the umbilical cord is rich in stem cells. The stem cells can be removed from the cord and frozen to use in transplantation.
Collecting, storing, testing and transplanting cord blood requires the expertise of highly qualified physicians. In searching for a match, a tiny DNA sample from the blood cord is tested to verify a DNA match with the recipient. If the DNA matches, this is used as a source for transplantation.
20. What is Autologous transplant? almokbelra
Using the recipient’s own stem cells, this method is used for:
Blood-related cancers (lymphomas, Hodgkin’s disease, and leukemia),
Connective tissue cancers (sarcomas),
Nervous system cancers (neuroblastoma),
And certain solid tumor cancers (breast, testicular and ovarian cancer)
Stem cells are harvested or collected at a certain point in therapy, then frozen, stored and given after high dose chemotherapy to rescue patients from the toxic effects of chemotherapy on one’s bone marrow. Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC) from the patient and storage of the harvested cells in a freezer. The patient is then treated with high-dose chemotherapy with or without radiotherapy with the intention of eradicating the patient’s malignant cell population at the cost of partial or complete bone marrow ablation (destruction of patient’s bone marrow function to grow new blood cells). The patient’s own stored stem cells are then returned to his/her body, where they replace destroyed tissue and resume the patient’s normal blood cell production. Autologous transplants have the advantage of lower risk of infection during the immune-compromised portion of the treatment since the recovery of immune function is rapid. Also, the incidence of patients experiencing rejection (graft-versus-host disease) is very rare due to the donor and recipient being the same individual. These advantages have established autologous HSCT as one of the standard second-line treatments for such diseases as lymphoma. However, for others such as Acute Myeloid Leukemia, the reduced mortality of the autogenous relative to allogeneic HSCT may be outweighed by an increased likelihood of cancer relapse and related mortality, and therefore the allogeneic treatment may be preferred for those conditions. Researchers have conducted small studies using non-myeloablative hematopoietic stem cell transplantation as a possible treatment for type I (insulin dependent) diabetes in children and adults. Results have been promising; however, at the time of this writing, it is premature to speculate as to whether these experiments will lead to effective treatments for diabetes.
21. What is Allogeneic transplant? almokbelra
Using stem cells from a donor, this method is used most often for:
Blood-related cancers (leukemia and lymphomas),
Bone marrow disorders (myelodysplastic syndrome and aplastic anemia),
Immune system disorders (reduce body’s ability to fight disease),
Metabolic disease (disrupt body’s ability to produce materials needed for life),
And other inherited (genetic) diseases.
If stem cells are taken from the bone marrow, the procedure is done under either general anesthesia, which puts the person to sleep, or local anesthesia, which causes loss of feeling. Only the bone marrow is collected or harvested from the hips. The bones are not removed or opened during the procedure. The amount of marrow needed is based on the weight of the transplant recipient, but it is usually one to two pints.
About 10 percent of the donor’s total bone marrow is harvested. Within a short time, the bone marrow will replenish itself. Side effects from the bone marrow harvest may be sore hips and mild anemia. Overall, there are few side effects. The surgery can be done as an outpatient procedure.
Stem cells taken from the bloodstream (peripheral blood stem cell transplant) is a less invasive option than bone marrow transplantation. The parent (or progenitor) cells are harvested via a collection catheter from the circulating blood instead of from the bone marrow. This procedure, called apheresis, is completed as an outpatient. The stem cells are collected, frozen, and stored for later use.
Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient. Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching is performed on the basis of variability at three or more loci of the (HLA) gene, and a perfect match at these loci is preferred. Even if there is a good match at these critical alleles, the recipient will require immunosuppressive medications to mitigate graft-versus-host disease. Allogeneic transplant donors may be related (usually a closely HLA matched sibling), syngeneic (a monozygotic or ‘identical’ twin of the patient – necessarily extremely rare since few patients have an identical twin, but offering a source of perfectly HLA matched stem cells) or unrelated (donor who is not related and found to have very close degree of HLA matching). A “savior sibling” may be intentionally selected by preimplantation genetic diagnosis in order to match a child both regarding HLA type and being free of any obvious inheritable disorder. Allogeneic transplants are also performed using umbilical cord blood as the source of stem cells. In general, by transplanting healthy stem cells to the recipient’s immune system, allogeneic HCSTs appear to improve chances for cure or long-term remission once the immediate transplant-related complications are resolved.
A compatible donor is found by doing additional HLA-testing from the blood of potential donors. The HLA genes fall in two categories (Type I and Type II). In general, mismatches of the Type-I genes (i.e. HLA-A, HLA-B, or HLA-C) increase the risk of graft rejection. A mismatch of an HLA Type II gene (i.e. HLA-DR, or HLA-DQB1) increases the risk of graft-versus-host disease. In addition a genetic mismatch as small as a single DNA base pair is significant so perfect matches require knowledge of the exact DNA sequence of these genes for both donor and recipient. Leading transplant centers currently perform testing for all five of these HLA genes before declaring that a donor and recipient are HLA-identical.