Stem cell transplantation

What is a bone marrow transplant?

Bone marrow transplantation (BMT) is a special therapy for patients with certain cancers or other diseases. A bone marrow transplant involves taking cells that are normally found in the bone marrow (stem cells), filtering those cells, and giving them back either to the patient they were taken from or to another person. The goal of BMT is to transfuse healthy bone marrow cells into a person after his or her own unhealthy bone marrow has been eliminated.

What is bone marrow?

The bone marrow is a soft, spongy tissue found inside the bones. The bone marrow in the hips, breast bone, spine, ribs, and skull contains cells that produce the body's blood cells. The bone marrow is responsible for the development and storage of most of the body's blood cells. The three main types of blood cells produced in the bone marrow include:

• Red blood cells (erythrocytes). These cells carry oxygen to the tissues in the body.
• White blood cells (leukocytes). These cells help fight infections and aid in the immune system.
• Platelets. These help with blood clotting.

Each of these cells carries a life-maintaining function. The bone marrow is a vital part of the human body.

What are stem cells?

Every type of blood cell in the bone marrow begins as a stem cell. Stem cells are immature cells that are able to produce other blood cells that mature and function as needed. Stem cells also may mature into lymphocytes, the source of a person’s immune system.

Stem cells are the most important cells needed in a bone marrow transplant. Stem cells, when transplanted, find their way to the recipient's marrow and lymphoid tissue and begin to differentiate (mature) and produce all types of blood cells that are needed by the body.

Why is a bone marrow transplant needed?

The goal of a bone marrow transplant is to cure many diseases and certain types of cancer. When a child's bone marrow has been damaged or destroyed due to a disease or intense treatments of radiation or chemotherapy for cancer, a bone marrow transplant may be needed.

A bone marrow transplant can be used to:

• Replace diseased, nonfunctioning bone marrow with healthy functioning bone marrow (for conditions such as leukemia, aplastic anemia, and sickle cell anemia)
• Replace the bone marrow and restore its normal function after high doses of chemotherapy or radiation are given to treat cancer. This process is often called rescue (for diseases such as lymphoma and neuroblastoma)
• Replace bone marrow with genetically healthy functioning bone marrow to prevent further damage from a genetic disease process (such as Hurler's syndrome and adrenoleukodystrophy disorder)

Bone marrow transplant has risks involved, some of which are life-threatening. The risks and benefits must be weighed in a thorough discussion with the bone marrow transplant team prior to the procedure.

Each child experiences diseases differently and a bone marrow transplant may not be appropriate for everyone who suffers from these diseases. Some of the diseases that have been treated with bone marrow transplant include the following:

• Leukemia
• Lymphomas
• Some solid tumors (for example, neuroblastoma, rhabdomyosarcoma, brain tumors)
• Aplastic anemia
• Immune deficiencies (severe combined immunodeficiency disorder, Wiskott-Aldrich syndrome)
• Sickle cell disease
• Thalassemia
• Diamond Blackfan anemia
• Metabolic/storage diseases (for example, Hurler's syndrome, adrenoleukodystrophy disorder)
• Cancer of the kidneys

What are the different types of stem cell transplants?

There are different types of stem cell transplants depending on the source of stem cells. The different types of transplant include the following:

• Autologous bone marrow transplant. The donor is the child himself or herself. Stem cells are taken from the child either by bone marrow harvest or apheresis (a process of collecting peripheral blood stem cells) and then given back to the child after intensive treatment. Sometimes the term rescue is used instead of transplant.
• Allogeneic bone marrow transplant. The donor shares the same (or similar) genetic type as the child. Stem cells are taken either by bone marrow harvest or apheresis from a genetically-matched donor, often a brother or sister. Other donors for allogeneic bone marrow transplants may include:
  • A parent. A haploid-identical match is when the donor is a parent and the genetic match is at least half identical to the recipient. Unfortunately, parents may not be a good enough match to be donors in many cases.
  • Unrelated bone marrow transplants (or MUD for matched unrelated donor). The genetically matched marrow or stem cells are from an unrelated donor. Unrelated donors are found through the national bone marrow registries.
• Umbilical cord blood transplant. Stem cells are taken from an umbilical cord immediately after delivery of an infant. These stem cells reproduce into mature, functioning blood cells quicker and more effectively than do stem cells taken from the bone marrow of another child or adult. The stem cells are tested, typed, counted, and frozen until they are needed for a transplant.
• Because the stem cells are "new," they are able to produce more blood cells from each stem cell. Another advantage cord blood has is that the T-lymphocytes (part of the immune system that causes a transplant-related problem called graft-versus-host disease) are not completely functional at birth. Recipients of cord blood transplants have a decreased risk for severe graft versus host disease.

The bone marrow transplant team

The group of specialists involved in the care of children who are undergoing a transplant procedure is often referred to as the transplant team. Each individual works together to provide the best chance for a successful transplant. The bone marrow transplant team consists of:

• Doctors. Doctors who specialize in oncology, hematology, immunology, and bone marrow transplantation and advanced care practitioners who support the doctors.
• Transplant coordinator. A professional who organizes all aspects of care provided to your child before and after the transplant. The coordinator will provide patient education and coordinate the diagnostic testing and follow-up care.
• Social workers. Professionals who will provide support to your family and help your family deal with many issues that may arise, including lodging and transportation, finances, and legal issues. They can also help coordinate alternative means for school, so that your child does not get behind.
• Dietitians. Professionals who will help your child meet his or her nutritional needs before and after the transplant. They will work closely with you and your family.
• Clinical pharmacists. Pharmacists provide patient care that optimizes medication therapy and promotes health, wellness, and disease prevention.
• Physical therapists. Professionals who will help your child become strong and independent with movement and endurance after the transplantation
• Pastoral care. Chaplains who provide spiritual care and support
• Other team members. Several other team members will evaluate your child before transplantation and will provide follow-up care, as needed. These include, but are not limited to, the following:
  • Physical therapists
  • Respiratory therapists
  • Lab technicians
  • Infectious disease specialists
  • Dermatologists
  • Gastroenterologists
  • Psychologists
  • Child life specialists

An extensive evaluation is completed by the bone marrow transplant team. The decision for your child to undergo a bone marrow transplant will be based on many factors including:

• Your child's age, overall health, and medical history
• Extent of the disease
• Availability of a donor
• Your child's tolerance for specific medications, procedures, or therapies
• Expectations for the course of the disease
• Expectations for the course of the transplant
• Your opinion or preference

Preparation for the recipient

For the child receiving the transplant, the following will occur in advance of the procedure:

• Prior to the transplant, an extensive evaluation is completed by the bone marrow transplant team. All other treatment options are discussed and evaluated for risk versus benefit.
• A complete medical history and physical examination are performed, including multiple tests to evaluate the child's blood and organ functions (for example, heart, kidney, liver, and lungs).
• A child will come into the transplant center in advance of the transplant for evaluation and other preparations. A peripherally inserted central catheter, also called PIC line, is surgically placed in a peripheral vein and threaded to a central location. Blood products and medications will be administered through the PIC line.
• A suitable (tissue typed and matched) donor must be available. Finding a matching donor can be a challenging and lengthy process. Voluntary marrow donors are registered in several national and international registries. A bone marrow search involves searching these registries for donors whose HLA system most closely resembles or matches the child needing the transplant.

Preparation for the donor

• Donor sources available include self, sibling, parent or relative, nonrelated person, or umbilical cord blood from a related or nonrelated person. There are national and international registries for nonrelated persons and cord blood. Family members may be tested for a match (typed) because of the desire to help. These relatives may or may not elect to have their type registered for use with other recipients.
• If the potential donor is notified that they may be a match for a child needing a transplant, they will undergo additional tests. Tests related to their health, exposure to viruses, and complete genetic analysis will be done to determine the extent of the match. The donor will be given instructions on how a bone marrow donation will be made.

How are a donor and recipient matched?

Matching involves typing human leukocyte antigen (HLA) tissue. The antigens on the surface of these special white blood cells determine the genetic make-up of a person's immune system. There are at least 100 HLA antigens, however, it is believed that there are a few major antigens that determine whether a donor and recipient match. The others are considered "minor" and their effect on a successful transplant is not as well defined. Because HLA markers are inherited, an identical twin is the best donor match.

Medical research is still investigating the role all antigens play in the process of a bone marrow transplant. The more antigens that match, the better the engraftment of donated marrow. Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin reproducing new blood cells.

How are the stem cells collected?

A bone marrow transplant is done by transferring stem cells from one person to another. Stem cells can either be collected from the circulating cells in the blood (the peripheral system) or from the bone marrow.

• Peripheral blood stem cells (PBSCs). PBSCs are collected by an apheresis, a process in which the donor is connected to a special cell separation machine via a needle inserted in the vein. Blood is taken from one vein and is circulated though the machine which removes the stem cells and returns the remaining blood and plasma back to the donor through another needle inserted into the opposite arm. Several sessions may be required to collect enough stem cells to assure a chance of successful engraftment in the recipient.

A medication may be given to the donor for about one week prior to apheresis that will stimulate the bone marrow to increase production of new stem cells. These new stem cells will be released from the marrow and into the circulating or peripheral blood system.

• Bone marrow harvest. Bone marrow harvesting involves collecting stem cells with a needle placed into the soft center of the bone, the marrow. The sites most commonly used for bone marrow harvesting is located in the hip bones.  The procedure takes place in the operating room. The donor will be anesthetized during the harvest and will not feel the needle. In recovery, the donor may experience some pain in the areas where the needle was inserted.
• If the donor is the child himself or herself, it is called an autologous bone marrow transplant. If an autologous transplant is planned, previously collected stem cells from either peripheral (apheresis) or harvest, are counted, screened, and ready to infuse.
• Umbilical cord blood. For umbilical cord blood transplants, blood has been collected at the time of a birth and stored. Cord blood is collected after delivery, when the placenta and umbilical cord are separated from the infant. The site of collection is cleaned to prevent bacteria from entering the collection process. The blood that is contained in the cord is collected in a sterile container. The blood is then tested for type and the presence of viruses or disease, and the stem cells are counted. The cord blood is then stored in special freezers and is registered in a national registry for potential recipient matches.

The bone marrow transplant procedure

The preparations for a bone marrow transplant vary depending on the type of transplant, the disease requiring transplant, and your child's tolerance for certain medications. Consider the following:

• Most often, high doses of chemotherapy and/or radiation are included in the preparations. This intense therapy is required to effectively treat the malignancy and make room in the bone marrow for the new cells to grow and to prevent rejection of donor cells by the patient. For patients with cancer, this therapy is often called ablative, or myeloablative, because of the effect on the bone marrow. The bone marrow produces most of the blood cells in our body. Ablative therapy prevents this process of cell production and the marrow becomes empty. An empty marrow is needed to make room for the new stem cells to grow and establish a new production system.
• After the chemotherapy and/or radiation is administered, the transplant, either from bone marrow, cord, or from peripherally collected stem cells, is given through the central venous catheter into the bloodstream. It is not a surgical procedure to place the marrow into the bone, but is similar to receiving a blood transfusion. The stem cells find their way into the bone marrow and begin reproducing and establishing new, healthy blood cells.
• Supportive care is given to prevent and treat infections, side effects of treatments, and complications. This includes frequent blood tests, close monitoring of vital signs, strict measurement of input and output, weighing your child daily (or twice daily), and providing a protected and clean environment.

The days before transplant are counted as minus days. The day of transplant is considered day 0. Engraftment and recovery following the transplant are counted as plus days. For example, a child may enter the hospital on day -8 for preparative regimen. Days +1, +2, etc., will follow the transplant. There are specific possible events, complications, and risks associated with each day before, during, and after transplant. The days are numbered to help the child and family understand where they are in terms of risks and discharge planning.

During actual infusion of the bone marrow, your child may experience any, or all, of the following symptoms:

• Pain
• Chills
• Fever
• Hives
• Chest pain

During the post transplant period, your child may:

• Spend several weeks in the hospital
• Be very susceptible to infection
• Be susceptible to bleeding
• Need blood transfusions
• Be confined to a very clean environment to minimize the chance of infection
• Take multiple antibiotics and other medications
• Be given medication to prevent graft-versus-host disease (if the transplant was allogeneic). The transplanted new cells (the graft) tend to attack the child's tissues (the host), even if the donor is a relative, such as a brother, sister, or parent.
• Undergo continual laboratory testing
• Experience nausea, vomiting, diarrhea, mouth sores, and extreme weakness
• Experience temporary emotional or psychological distress

Your child's physical and mental health are important in the success of a transplant. Every measure is taken to minimize complications and promote a healthy, happy, safe environment for your child.

When does engraftment occur?

Engraftment of the stem cells occurs when the donated cells make their way to the marrow and begin producing new blood cells. Depending on the type of transplant and the disease being treated, engraftment usually occurs between day +15 and +30. Blood counts will be performed frequently during the days following transplant to evaluate initiation and progress of engraftment. Platelets are generally the last blood cell to recover.

Engraftment can be delayed because of infection, medications, low donated stem cell count, or graft failure. Although the new bone marrow may begin making cells in the first 30 days following transplant, it may take months, even years, for the entire immune system to fully recover.

What complications and side effects may occur following BMT?

The following are complications that may occur with a bone marrow transplant. However, each child may experience symptoms differently. Complications may vary depending on the following:

• Type of marrow transplant
• Type of disease requiring transplant
• Preparative regimen
• Age and overall health of the recipient
• Variance of tissue matching between donor and recipient
• Presence of severe complications

Possible complications may include, but are not limited to, the following. These complications may also occur alone, or in combination:

• Infections. Infections are likely in the child with severe bone marrow suppression. Bacterial infections are the most common. Viral and fungal infections can be life threatening. Any infection can cause an extended hospital stay, prevent or delay engraftment, and/or cause permanent organ damage. Antibiotics, antifungal medications, and antiviral medications are often given to prevent serious infection in the immunosuppressed child.

Preventative measures for common sources of infection are also a part of transplant. This may include any or all of the following:

• Special air filtered rooms
• Diet restrictions
• Isolation requirements
• Restriction of visitors
• Strict hygiene regimen
• Frequent linen changes

Blood tests are performed to prevent, detect, and treat infections. Often, multiple antibiotics are started if an infection is suspected.

• Low platelets and low red blood cells. Thrombocytopenia (low platelets) and anemia (low red blood cells), as a result of a nonfunctioning bone marrow, can be dangerous and even life threatening. Most children will require multiple blood product transfusions. Low platelets can cause dangerous bleeding in the lungs, gastrointestinal (GI) tract, and brain.
• Pain. Pain related to mouth sores and gastrointestinal (GI) irritation is common. High doses of chemotherapy and radiation can cause severe mucositis (painful inflammation or ulceration of the mouth and GI tract). Without the normal immune system functioning, your child is unable to heal these irritations quickly. Often, pain medication is required. Mouth care is needed to prevent infection and injury when mucositis is suspected.
• Diarrhea, nausea, and vomiting. These may occur with chemotherapy, radiation, and/or GI irritation. Calories and proteins may be given through an intravenous (IV) line until your child is able to eat again and the diarrhea has resolved.
• Fluid overload. Fluid overload is a complication that can lead to respiratory disorders and high blood pressure. The primary reason for fluid overload is because the kidneys cannot compensate for fluid being given intravenously in the form of medications, nutrition, and blood products. The kidneys may also be damaged from disease, infection, chemotherapy, radiation, and/or antibiotics.

During transplant and recovery, your child will be assessed for signs and symptoms of fluid overload. He or she may be weighed at least daily, often twice or three times daily, and blood chemistries and input and output will be measured frequently. Medications that help kidney function and elimination of excess fluid may be given.

• Respiratory distress. Respiratory status is an important function that may be compromised during transplant. Infection, inflammation of the airway, fluid overload, graft-versus-host disease, and bleeding are all potential life-threatening complications that may occur in the lungs and pulmonary system. Supplemental oxygen may be needed to help your child breathe better until problems are corrected.

Close monitoring of your child's respiratory status may include:

• Chest X-rays. A diagnostic test that uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs on film
• Pulse oximetry. An oximeter is a small machine that measures the amount of oxygen in the blood. To obtain this measurement, a small sensor that looks like a Band-Aid is taped onto a finger or toe. When the machine is on, a small red light can be seen in the sensor. The sensor is painless and the red light does not get hot.
• Organ damage. The liver and heart are important organs that may be damaged during the transplant process. Temporary or permanent damage to the liver and heart may be caused by infection, graft-versus-host disease, high doses of chemotherapy and radiation, or fluid overload.

Close monitoring of your child's blood work and vital signs is important in minimizing and detecting any organ damage that has occurred.

• Graft failure. Failure of the graft (transplant) taking hold in the marrow is a potential complication. Graft failure may occur as a result of infection, recurrent disease, or if the stem cell count of the donated marrow was insufficient to cause engraftment. Graft failure may be treated with an additional marrow transplant if a source is available.
• Graft-versus-host disease. Graft-versus-host disease (GVHD) can be a serious and life-threatening complication of a bone marrow transplant. GVHD occurs when the donor's immune system reacts against the recipient's tissue. The new cells do not recognize the tissues and organs of the recipient's body. The most common sites for GVHD are the GI tract, liver, skin, and lungs.​ GVHD is graded from I to IV and can be acute (occurs early at the transplant) or chronic (occurs later; over 5 days post transplant). Your child will be monitored closely for signs and symptoms of GVHD. Diarrhea, fever, rash, skin changes, abdominal pain, respiratory complications, and decreased liver function may be present with GVHD. Medications will be given prior to transplant to reduce the risk of this complication.

When will my child be discharged?

When your child is discharged following a bone marrow transplant depends on many factors, including the following:

• Extent of engraftment
• Presence of complications
• Your child's overall health
• Distance from the facility. (This may be specified by your child's team of doctors. Occasionally, a bone marrow transplant patient will be required to stay within a certain distance or travel time from the facility to ensure safety if complications arise.)

Frequent visits to your child's transplant team will be required after discharge to determine effectiveness of treatment, detect complications, detect recurrent disease, and to manage the late effects associated with a bone marrow transplant. The frequency and duration of visits will be determined by your child's transplant team.

Long-term outlook for a bone marrow transplantation

Prognosis greatly depends on the following:

• Type of marrow transplant
• Type and extent of the disease being treated
• Disease response to treatment
• Genetics
• Age and overall health of the child
• Your child's tolerance of specific medications, procedures, or therapies
• Severity of complications

As with any procedure, such as bone marrow transplant, prognosis, and long-term survival can vary greatly from child to child. The number of transplants being done for an increased number of diseases and ongoing medical developments have greatly improved the outcome for bone marrow transplant in children and adults. Continuous follow-up care is essential for the child following a bone marrow transplant. New methods to improve treatment and decrease complications and side effects of a transplant are continually being discovered.