Thousands of hematopoietic stem cell transplants (HSCT) are performed in children and adolescents annually in the United States. HSCT is being used to treat a growing number of indications including malignancies, nonmalignant hematologic diseases, immunologic disorders, inborn errors of metabolism, and autoimmune disorders (Table 134-1). HSCT is not the first line of therapy for many of these diseases, but is reserved for patients for whom first-line therapy is not sufficient or is ineffective. While most pediatric transplants are performed at tertiary care centers, post-transplant patients receive a portion of their care in community hospitals and local oncologists’ offices. It is important for the pediatric hospitalist to have a general understanding of the medical issues facing HSCT patients who may present to their emergency departments or get admitted to inpatient units.

HSCT is the process of replacing diseased or dysfunctional bone marrow with stem cells capable of restoring normal hematopoietic function. The three main types of HSCT are autologous, allogeneic, and syngeneic. In autologous HSCT, stem cells are collected from the patient and stored until the time of infusion. Autologous transplant has the advantages of being readily available for current and future transplants if needed, eliminating the risk of graft-versus-host disease (GVHD), more rapid immune reconstitution, and lower short-term mortality rates.¹ High-dose chemotherapy followed by autologous stem cell infusion (often called rescue) is used to treat children with some high-stage or relapsed solid tumors, and is employed in gene therapy transplants.²

In allogeneic HSCT, stem cells are collected from another person and infused into the patient following conditioning with chemotherapy and/or radiation. A syngeneic HSCT is a transplant using the patient’s identical twin sibling as a donor. The benefits of allogeneic transplants are that there is no risk of residual tumor cells in the graft, the stem cells have not been potentially damaged by prior therapy, and the cells may exhibit a graft-versus-leukemia effect.³ Disadvantages include the risk of GVHD, less flexible timing of donation, the need for immunosuppression following engraftment, slower immune reconstitution with increased risk of infection, and greater overall morbidity and mortality.

Human leukocyte antigen (HLA) typing is performed to determine the suitability of potential allogeneic donors. HLAs are genetic markers found on the surface of white blood cells. The genetic composition of these antigens, located on the short arm of chromosome six, is determined from a blood test or buccal swab of the recipient and the potential donor.⁴ HLAs are inherited, making siblings more likely than unrelated donors or parents to have similar typing. There is an approximate 25% chance of two siblings having matching HLA typing.⁵ The closer the HLA match between the donor and the recipient, the lower the risk of GVHD and better overall survival.

Allogeneic donors may be related to the patient or found through an unrelated donor search. Related donors have the advantages of being more closely HLA-matched, are typically readily available for donation, and have lower risk of GVHD and higher survival rates. Unfortunately, only 30% of individuals needing an allogeneic HSCT have a suitably matched sibling.^5,6 Unrelated allogeneic donors may be less readily available than related donors, may be unavailable for potential future transplants, are less well matched, and are associated with an increased risk of GVHD.

The National Marrow Donation Program (NMDP) is a nonprofit organization in the United States that anonymously matches unrelated stem cell transplant recipients and donors.⁷ Using the NMDP and similar organizations, a suitable stem cell source can be found for approximately 80% of Caucasians with a transplantable disorder.⁸ However, African-Americans and Hispanics have a less than 30% chance of finding a well-matched, unrelated bone marrow or peripheral blood stem cell (PBSC) donor.⁸ Alternative donor sources, including umbilical cord blood and haploidentical transplants, are needed for many of these patients.

Sources of stem cells include bone marrow, peripheral blood, and umbilical cord blood (UCB). Bone marrow and umbilical cord blood are rich in stem cells and are the most commonly used stem cell sources for pediatric HSCT. Bone marrow is typically collected under anesthesia and requires no physical pre-donation preparation of the donor. Bone marrow donors undergo confirmatory HLA typing, health assessment, and infectious screening prior to being approved to donate. The process of identifying and clearing a bone marrow donor takes weeks to months.

UCB is removed via cannulation or drainage following delivery of the infant.⁹ The blood is stored frozen in public banks as an anonymous donation or in private banks for use by the family. The risk of GVHD is lower with UCB compared with bone marrow or PBSCs. UCB units that are matched at fewer HLA loci have equivalent GVHD risk compared to the other stem cell sources.¹⁰ This has increased the ability to find a suitable stem cell source for patients for whom fully matched unrelated bone marrow or PBSC donors are not found in international registries.¹¹ Another advantage is the rapid availability of the stem cell product. Clinical challenges with the use of UCB is that the stem cell yield is limited to what is collected at birth, a single unit may not be adequate for adults or large children, there may be lack of complete medical follow-up on the child who donated the UCB, and there is a slower immune reconstitution compared to other stem cell sources.⁵

Peripheral blood has a low concentration of circulating stem cells.¹² Chemotherapy or stimulating factors are used to mobilize stem cells from the bone marrow into the peripheral circulation. Chemotherapy with or without stimulating factors is commonly given to autologous donors prior to PBSC collection as part of treatment of their underlying disease. Granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) are given to allogeneic PBSC donors prior to collection.¹³ PBSCs are removed via apheresis through large peripheral intravenous access or central venous line. For young sibling donors, the need for large intravenous access can preclude the collection of PBSCs. Advantages of using PBSCs are more rapid neutrophil and immune recovery, potentially greater graft-versus-leukemia effect, and the collection procedure is less invasive on the donor. The primary disadvantage of using PBSC is the greater risk of GVHD. In pediatrics the use of PBSC is associated with greater GVHD and increased mortality, and no decrease in relapse rate.¹⁴ PBSC is not a favored stem cell source in pediatrics because of higher mortality rates without improvement in relapse rates.

Prior to receiving stem cells patients receive a conditioning regimen of chemotherapy or chemotherapy with radiation. Patients are admitted to the hospital for conditioning and typically remain hospitalized until neutrophil engraftment, though some centers allow discharge prior to engraftment following autologous stem cell infusion. The purposes of conditioning are to create marrow space for the transplanted cells, eliminate diseased marrow cells when applicable, and remove host lymphocytes capable of rejecting the transplanted cells. The specific conditioning protocol used depends on the disease being treated and the practices of the transplanting institution. Commonly used myeloablative conditioning regimens include one or more of the following: cyclophosphamide, total body irradiation, busulfan, treosulfan, carboplatin, melphalan, and carumustine. Toxicities common to many conditioning regimens are myelosuppression, nausea, emesis, mucositis (inflammation, irritation, and ulceration of gastrointestinal mucosal cells), alopecia, increased risk of infection, organ dysfunction, and infertility. A detailed discussion of specific conditioning agents and their toxicities is beyond the scope of this chapter.