Pediatric Allogeneic Blood and Marrow Transplantation

Blood and marrow transplantation is a special therapy for patients with cancer or other diseases which affect the bone marrow.

Allogeneic transplantation is a procedure in which a person receives hematopoietic⁽¹⁾ (blood-forming) or blood stem cells, from a genetically similar, but not identical, donor. Blood stem cells are found in the bone marrow, peripheral blood, or umbilical cord blood⁽²⁾.

Treatments are available for:

• Aplastic anemia
• Fanconi anemia
• Immunodeficiencies
• Leukemia
• Metabolic syndromes
• Selected solid tumors
• Non-Hodgkin lymphoma
• Sickle cell disease
• Thalassemia

Allogeneic BMT is considered for patients with:

• Myelodysplastic syndromes and juvenile myelomonocytic leukemia (JMML) as soon as a suitable donor is identified.
• High-risk acute lymphocytic leukemia or ALL (e.g. Philadelphia chromosome positive ALL and MLL gene-rearranged infant ALL and those failing induction therapy) in first remission⁽³⁾
• ALL who relapse⁽⁴⁾ within 36 months of remission
• Acute myelogenous leukemia (AML) patients with matched related donors in first remission
• Secondary AML
• Elapsed AML
• Elapsed or refractory Hodgkin and non-Hodgkin lymphoma
• Adult-type chronic myelogenous leukemia (CML) who are refractory to tyrosine kinase inhibitors such as imatinib

Allogeneic transplantation is considered for patients with:

• Severe aplastic anemia (SAA) who have matched related donors and fail immune suppressive therapy
• Kostmann syndrome and Blackfan-Diamond anemia when matched sibling donors are available
• Fanconi anemia and other inherited bone marrow failure syndromes that have failed conventional therapies or show evidence of malignant transformation
• Infantile osteoporosis
• Severe symptomatic sickle cell disease
• Thalassemia

Allogeneic bone marrow transplantation is the only curative therapy available for patients with these conditions.

Children’s National is a nationally-recognized leader in treating children with primary immune deficiencies with allogeneic blood and marrow transplantation, such as:

• Severe combined immune deficiency (SCID).
• Hemophagocytic lymphohistiocytosis (HLH) (primary or inherited forms)
• Chédiak-Higashi syndrome
• Chronic granulomatous disease
• Leukocyte adhesion deficiency
• Reticular dysgenesis
• Wiskott-Aldrich syndrome
• Metabolic storage diseases

Children’s National's BMT team works closely with the Division of Genetics and Metabolism and the Division of Neurology to provide a comprehensive management program for children with these diseases undergoing allogeneic transplantation.

There are several metabolic or lysosomal storage diseases that benefit from allogeneic transplantation including:

• Globoid Cell leukodystrophy or Krabbe disease.
• Hurler syndrome 
• Metachromatic leukodystrophy 

There are two types of donors:

• Related donors are full siblings (or very rarely, other family members) of the patient who have the same tissue type as the patient. Tissue typing is usually determined by blood tests done on the patient and family members.
• Unrelated donors are individuals who have agreed to serve as volunteer donors if called upon whose tissue type very closely matches that of the patient.

When a patient is in need of allogeneic transplant, the first type of donor generally considered is an adequately-matched related donor. However, almost 75% of all patients who need a blood or marrow transplant (BMT) lack such a donor. In this case, unrelated donors are located through the National Marrow Donor Program (NMDP). The NMDP initiates and facilitates the search for unrelated donors, which allows Children’s National transplant physicians to access a world-wide registry of more than 10 million adult volunteer donors and public cord blood banks.

Once a donor has been identified as the best match for the patient, the donor has a pre-transplant evaluation, including a physical examination and multiple tests to evaluate the donor’s blood and organ functions. The donor will be evaluated with a physical examination and blood tests to make sure that he or she can serve as a bone marrow donor. Interviews with a social worker and where indicated, a psychologist, are also an important part of the process.

Stem cell collection from donors for blood and marrow transplantation happens in several ways:

• Peripheral blood stem cells (PBSC) are collected by apheresis, the process of extracting blood components from the peripheral blood with the help of a medical device that sorts blood into its separate factors. 
• Bone marrow harvest involves collecting stem cells with a needle placed into the soft center of the bone, the marrow. Most sites used for bone marrow harvesting are located in the hip bones and the sternum. The procedure takes place in the operating room and the donor is 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. 
• Umbilical cord blood is collected after delivery, when the placenta and umbilical cord are separated from the infant. The collection site is cleaned to prevent bacteria from entering the collection process. The blood contained in the cord is collected in a sterile container, tested for type and the presence of viruses⁽⁵⁾ or disease, and stored in special freezers.

• Medical history and physical evaluation: Up to 21 days before transplantation, the child comes to the hospital to receive a complete medical history and physician examination, including multiple tests to evaluate the child’s blood and organ functions.
• Preparative chemotherapy and radiation: Two to seven days before transplantation, the patient receives a high-dose of chemotherapy alone or with radiation, depending on the condition being treated, to destroy the patient’s bone marrow in order to create space for new marrow/stem cells to grow. In patients with cancer, this treatment also will help eradicate any residual cancer cells.

After chemotherapy, the patient receives blood-forming stem cells that were collected from the donor. The stem cells are given intravenously, just like a regular blood transfusion. The blood-forming stem cells automatically migrate and stick to the spots in the bone marrow within a few hours.

It takes two to three weeks for the stem cells to mature and begin to produce significant numbers of new blood cells, which is called engraftment. Although engraftment begins two to three weeks after transplantation, it can take months or years for the entire immune system to fully recover.

The first 100 days is a critical time in the transplant process. Children’s National transplant team monitors patients closely for infections and low blood counts, requiring patients to remain in the Washington, D.C. area for frequent follow-up visits. Depending on a child’s condition, he or she may need to stay in the hospital.

After a patient receives BMT and passes the high infection-risk period, he or she returns home to the care of his or her primary subspecialist for further treatment or follow-up visits. Children’s National's transplant doctors remain available to treat, or help a child’s subspecialist treat any transplant-related complications.

• Graft-versus-host disease (GVHD) occurs when the immune cells of the donor (graft) sense that cells of the patient (host) are different from them and attack them. This can be a serious complication of a transplant in up to 10% of patients who undergo transplantation from matched related donors. However, this attack also can contribute to the curative potential of BMT for patients with cancer. GVHD can be acute (occurring less than 100 days after the transplant) or chronic (occurring more than 100 days after transplant). It may damage the transplanted child’s skin, liver and/or the intestinal tract. Drugs are given to prevent or limit GVHD. Severe graft-versus-host disease that does not respond to treatment can lead to death in approximately 5% of patients who undergo matched sibling donor transplants.
• Graft failure/rejection⁽⁶⁾. There is a 5 to 10% risk (one in 20 to one in 10 chance) that the new bone marrow from a matched family member will be rejected by the patient. The chances for rejection may be higher if unrelated donors are used.
• Veno-occlusive disease⁽⁷⁾ (VOD). Blood vessels that lead into and pass through the liver are prone to damage after transplantation. This may result from chemotherapy and may lead to swelling and severe liver damage. The chances of severe VOD are less than 5%.
• Nutrition problems. The stomach and intestines are sensitive to chemotherapy. Nausea, vomiting, mouth sores, diarrhea, and loss of appetite may occur. Nutrition may be given intravenously or via nasogastric tube feedings until patients are able to eat. Pediatric nutritionists are part of the BMT team to help in managing these complications.
• Low blood counts. While waiting for new stem cells to make normal red blood cells⁽⁸⁾ and other blood cells, a patient usually needs transfusions of platelets⁽⁹⁾ and red blood cells, depending on the patient’s clinical condition.
• Social and emotional concerns. Transplantation is a challenge to both patient and family. They will encounter disruption of family relationships, absence from home, and isolation from school, friends and relatives. The family is the key to supporting the child through the transplant period. During this time, the Center for Cancer and Blood Disorder’s Patient and Family Support Program team is available to help families cope with these issues.
• Infertility. It is highly likely that transplant recipients will not be able to have children in the future due to side effects of chemotherapy drugs used during the preparative phase of the transplant. Sperm and egg collection and storage would be considered for all post-pubertal patients.