CHAPTER 76 Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) can cure some patients with primary immunodeficiency disease (Table 76-1). It is not available to all patients, however. Use of HSCT is limited to immunodeficiency diseases with T-cell defects, some metabolic storage diseases (see Chapters 55 and 56), malignancies (see Chapter 154), aplastic anemia (see Chapter 150), and a few other disorders. The principle of HSCT is to replace a patient’s defective bone marrow stem cells with normal stem cells.
TABLE 76-1 Immunodeficiency Diseases Curable by Stem Cell Transplantation
Hematopoietic stem cells reside in the bone marrow and can be obtained from peripheral blood or cord blood. Peripheral blood does not contain a significant proportion of stem cells unless the donor’s bone marrow is actively stimulated to generate stem cells. Cord blood is a good source of stem cells and is used for sibling and unrelated HSCT.
Major histocompatibility complex (MHC) compatibility is important in the choice of stem cell donor to avoid rejection of the donor cells by the host immune system and to prevent graft-versus-host disease (GVHD) from contaminating mature T cells. The donor stem cells give rise to T cells that develop in the host thymus and need to interact with donor and host antigen-presenting cells. Stem cells from a partially mismatched donor, such as a parent, can give rise to a functioning immune system because the patient shares at least half of the MHC molecules with the donor stem cells. Mature T cells need to be removed from the bone marrow, however, before transplantation. The reduction in risk of GVHD outweighs the disadvantage of a prolonged time of 90 to 120 days before T cells develop in patients with severe combined immunodeficiency (SCID). Patients with other immunodeficiency diseases are at risk for developing lymphoproliferative disease, especially associated with Epstein-Barr virus, with T-cell–depleted stem cell transplantation, probably because of the delay in T-cell engraftment. Hematopoietic stem cells can be obtained from MHC-identical siblings (25% chance of a matched sibling), matched unrelated cord blood or bone marrow, or, for patients with SCID, haploidentical bone marrow from a parent (preferred) or a sibling.
MHC molecules are highly polymorphic; typing is performed at the DNA level rather than by serology. Bone marrow and cord blood registries are available worldwide. Searching and identifying a donor can be a lengthy process, especially for some underrepresented ethnic backgrounds. Finding a suitable cord blood donor is faster because the cord blood already has been obtained and stored, whereas bone marrow donors have to be identified, located, and tested. A matched sibling, if available, is the preferred source of hematopoietic stem cells.
Patients with SCID are ideal candidates for HSCT, which is the only option for treatment of SCID at this time. Patients are unlikely to survive beyond 1 to 2 years of age without transplantation, and they have no T-cell function to reject donor cells. Patients with SCID may not need to undergo preconditioning with chemotherapy or irradiation before transplantation. The development of transplantation using T-cell–depleted, haploidentical bone marrow from a parent for SCID has provided almost every patient with SCID a potential donor. The mother is the preferred source for haploidentical bone marrow, if she is able to donate, because some transfer of maternal T cells can occur during pregnancy and these maternal T cells can reject cells obtained from the father. The survival rate after HSCT for SCID is 84% with MHC-identical and 61% with haploidentical bone marrow transplantation. The earlier the patient is transplanted, the better the outcome. Because the outcome of stem cell transplantation as soon after birth as possible is excellent, the risks of in utero transplantation and the inability to observe the fetus for signs of GVHD make it difficult to justify this type of transplantation. In addition, the development of newborn screening for SCID allows initiation of stem cell transplantation as early as possible, providing the best opportunity for a cure.
The decision to treat other patients with primary immunodeficiency diseases is more difficult because HSCT is not always successful. Patients with some, albeit decreased, T-cell function require preconditioning, with the risks that it entails. It is difficult to predict the prognosis of a particular patient because of the variability in clinical course of most primary immunodeficiency diseases, although there is only a small chance of reaching adulthood. The availability of a matched related sibling favors the decision to perform HSCT. Disorders of B cells have not been treated with HSCT because, in many cases, donor B cells do not engraft and patients usually do well with IVIG. If HSCT techniques improve to allow for better B-cell engraftment and the risks of GVHD and preconditioning are reduced, however, treatment of agammaglobulinemia and other immune system diseases with HSCT may be possible.
COMPLICATIONS
Rejection of the grafted cells is the first potential complication of HSCT and depends on the immunocompetence of the patient, the degree of MHC incompatibility, and the number of cells administered. Preconditioning with myeloablative drugs, such as busulfan and cyclophosphamide, can prevent graft rejection but may be complicated by pulmonary toxicity and by veno-occlusive disease of the liver, which results from damage to the hepatic vascular endothelium and can be fatal. Myeloablation results in anemia, leukopenia, and thrombocytopenia, making patients susceptible to infection and bleeding disorders. Neutropenic precautions should be maintained and patients supported with red blood cell and platelet transfusions until the red blood cell, platelet, and neutrophil lineages engraft. Reduced intensity preconditioning has been used recently to prevent graft rejection and decrease the adverse effects of myeloablation. Lymphoproliferative disease can develop after T-cell–depleted bone marrow transplantation.
HSCT, in contrast to solid organ transplantation, can be complicated by rejection of the host by mature T cells from the donor. GVHD can arise from an MHC-mismatched transplantation or from mismatch in minor histocompatibility antigens that are not tested for before transplantation. T-cell depletion of haploidentical bone marrow reduces the risk of GVHD. Patients with SCID transplanted with T-cell–depleted haploidentical bone marrow do not usually develop severe GVHD. Acute GVHD begins 6 or more days after transplantation and can result from transfusion of nonirradiated blood products in patients with no T-cell function. Acute GVHD presents with fever, skin rash, and severe diarrhea. Patients develop a high, unrelenting fever; a morbilliform maculopapular erythematous rash that is painful and pruritic; hepatosplenomegaly and abnormal liver function tests; and nausea, vomiting, abdominal pain, and watery diarrhea. Acute GVHD is staged from grade 1 to 4 depending on the degree of skin, fever, gastrointestinal, and liver involvement. Chronic GVHD results from acute GVHD lasting longer than 100 days and can develop without acute GVHD or after acute GVHD has resolved. Chronic GVHD is characterized by skin lesions (hyperkeratosis, reticular hyperpigmentation, fibrosis, and atrophy with ulceration), limitation of joint movement, interstitial pneumonitis, and immune dysregulation with autoantibody and immune complex formation.
HSCT can be used for any disorder of hematopoiesis such as aplastic anemia, sickle cell disease, and other hemoglobinopathies. It is also used in treatment of malignancy such as leukemia, lymphoma, and solid tumors. In some cases of solid tumor therapy, autologous bone marrow is harvested before high-dose chemotherapy, and then reinfused into the patient to rescue the hematopoietic system.
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