Principles and Clinical Indications

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Chapter 129 Principles and Clinical Indications

Andrea Velardi, Franco Locatelli

Thousands of children have received an infusion of either allogeneic or autologous (from the same individual) hematopoietic stem cells to cure both malignant and nonmalignant disorders. Autologous transplantation is employed as a rescue strategy after delivering otherwise lethal doses of radiotherapy and chemotherapy in children with hematological malignancies or solid tumors. Allogeneic transplantation is used to treat children with genetic diseases of blood cells, such as thalassemia and primary immunodeficiency diseases, as well as hematologic malignancies, such as leukemia and lymphoma. Bone marrow has traditionally represented the source of hematopoietic progenitors employed. Growth factor (G-CSF)-mobilized peripheral blood hematopoietic stem cells and umbilical cord blood hematopoietic progenitors have been introduced in the clinical practice to perform hematopoietic stem cell transplantation (HSCT).

In addition, a human leukocyte antigen (HLA)-matched sibling had been the only type of donor employed. Currently, matched unrelated volunteers, full-haplotype mismatched family members, and unrelated cord blood donors have also been employed to transplant patients lacking an HLA-identical relative.

Protocols for allogeneic HSCT consist of 2 parts: the preparative regimen and transplantation itself. During the preparative conditioning regimen, chemotherapy, often associated with irradiation, is administered to destroy the patient’s hematopoietic system and to suppress the immune system, especially T cells, so that graft rejection is prevented. In patients with malignancies, the preparative regimen also serves to significantly reduce the tumor burden. The patient then receives an intravenous infusion of hematopoietic cells from the donor. The intrabone injection of cord blood cells has been pioneered to optimize stem cells homing in the marrow niches.

The immunology of HSCT is distinct from that of other types of transplant because, in addition to stem cells, the graft contains mature blood cells of donor origin, including T cells, natural killer (NK) cells, and dendritic cells. These cells repopulate the recipient’s lympho-hematopoietic system and give rise to a new immune system, which helps eliminate residual leukemia cells that survive the conditioning regimen. This effect is known as the graft versus leukemia (GVL) effect.

The donor immune system exerts its T cell–mediated GVL effect through alloreactions directed against not shared recipient histocompatibility antigens displayed on recipient leukemia cells. Because some of these histocompatibility antigens are also displayed on tissues, however, T cell–mediated alloreactions may ensue. Specifically, donor alloreactive cytotoxic CD8+ effector T cells may attack recipient tissues—in particular, the skin, gastrointestinal tract, and liver—causing acute graft versus host disease (GVHD), a condition of varying severity, that, in some cases, can be life-threatening (Chapter 131).

The success of allogeneic HSCT is undermined by diversity between donors and recipients in major and minor histocompatibility antigens. Major histocompatibility complex (MHC) molecules, the HLA-A, HLA-B, and HLA-C MHC class I molecules, present peptides to CD8+ T cells, while the HLA-DR, HLA-DQ, and HLA-DP MHC class II molecules present peptides to CD4+ T cells. There are hundreds of variant forms of each class I and class II molecule, and even small differences can provoke alloreactive T-cell responses that mediate graft rejection and/or GVHD. Disparities for HLA-A, -B, -C, or -DRB1 alleles in the donor-recipient pair are independent risk factors for both acute and chronic GVHD.

Minor histocompatibility antigens derive from differences between the HLA-matched recipient and donor in peptides that are presented by the same HLA allotype. They are due to polymorphisms of non-HLA proteins, to differences in the level of expression of proteins, or to genome differences between males and females. An example of the latter is represented by the H-Y antigens encoded by the Y chromosome, which can stimulate GVHD when a female donor is employed to transplant to an HLA-identical recipient. Thus, GVHD may occur even when the donor and recipient are HLA identical.

The optimal donor for any patient undergoing HSCT is an HLA-identical sibling. Because polymorphic HLA genes are closely linked and usually constitute a single genetic locus, any pair of siblings has a 25% chance of being HLA identical. Thus, also in view of the limited family size in the developed countries, approximately only 25-30% of patients in need of an allograft can receive their transplant from an HLA-identical sibling.

Hsct from an Hla-Identical Sibling Donor

Allogeneic HSCT from an HLA-compatible sibling is the treatment of choice for children with hematological malignancies and congenital diseases (Table 129-1). Best results are achieved in patients with congenital or acquired nonmalignant disorders because the risk of disease recurrence is low and the cumulative transplant-related mortality is lower than in children transplanted for hematological malignancies.

Table 129-1 INDICATIONS FOR ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR PEDIATRIC DISEASES

• Acute myeloid leukemia in first complete remission or in advanced disease phase

• Philadelphia chromosome-positive chronic myeloid leukemia

• Myelodysplastic syndromes

• Hodgkin and non-Hodgkin lymphomas

• Selected solid tumours

• Metastatic neuroblastoma

• Rhabdomyosarcoma refractory to conventional treatment

• Very high risk Ewing sarcoma

• Severe acquired aplastic anemia

• Fanconi anemia

• Congenital dyskeratosis

• Diamond-Blackfan anemia

• Thalassemia major

• Sickle cell disease

• Variants of severe combined immunodeficiency (SCID)

• Hyper-lgM syndrome

• Leukocyte adhesion deficiency

• Omenn syndrome

• Wiskott-Aldrich syndrome

• Chédiak-Higashi syndrome

• Kostmann syndrome (infantile malignant agranulocytosis), chronic granulomatous disease, and other severe neutrophil defects

• X-linked lymphoproliferative disease (Duncan syndrome)

• Hemophagocytic lymphohistiocytosis

• Selected severe variants of platelet function disorders (e.g., Glanzmann thromboasthenia, congenital amegakaryocytic thrombocytopenia, or Bernard-Soulier syndrome)

• Selected types of mucopolysaccharidosis (Hurler disease) or other liposomal/peroxisomal disorders (Krabbe disease, adrenoleukodystrophy)

• Infantile malignant osteopetrosis

• Life-threatening cytopenia unresponsive to conventional treatments

Acute Lymphoblastic Leukemia (ALL)

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