Stem Cell Therapy

General Principles

Hematopoietic stem cell transplantation utilizes either allogeneic or autologous stem cells.
Allogeneic transplantation uses donor-derived stem cells to treat genetic diseases of blood cells, inherited metabolic diseases, and bone marrow failure.
Autologous transplantation uses patient-derived stem cells as a rescue strategy.
It is administered after delivering otherwise lethal doses of chemotherapy with or without radiotherapy.
The infused graft contains mature blood cells of donor origin, including T cells, B cells, natural killer cells, and dendritic cells.
These mature donor cells repopulate the recipient’s lymphohematopoietic system and establish a new immune system.
The new immune system provides a critical graft-versus-leukemia effect.
Immunocompetent donor cells help eliminate residual leukemia cells that survived the conditioning regimen.

Bone marrow originally represented the sole source of hematopoietic progenitor cells used for transplantation.
Peripheral blood hematopoietic stem cells are now widely utilized.
They are harvested after being mobilized into the peripheral circulation by cytokines alone or with cytotoxic agents.
A CXCR4 antagonist can also be extremely effective in mobilizing hematopoietic progenitors.
Umbilical cord blood serves as an additional, immediately available source of hematopoietic progenitors.

Protocols for transplantation begin with a preparative conditioning regimen.
This utilizes chemotherapy, sometimes combined with irradiation.
The primary principle is to eliminate the patient's existing hematopoietic system.
It suppresses the recipient's immune system, specifically T cells, to prevent graft rejection.
In patients with malignancies, the conditioning regimen additionally serves to significantly reduce the overall tumor burden.
Reduced-intensity conditioning regimens are frequently employed in pediatric patients.
These regimens are primarily immunosuppressive and aim to induce a state of reduced immune competence.
This avoids rejecting the donor cells without being fully myeloablative, thereby reducing toxicity.

The success of allogeneic stem cell transplantation relies heavily on minimizing the diversity between the donor and recipient in histocompatibility antigens.
Human leukocyte antigens must be matched for successful engraftment.
This includes major histocompatibility complex class I molecules and class II molecules.
Disparities in human leukocyte antigen alleles serve as independent risk factors for the development of graft-versus-host disease.
The traditionally preferred donor is an identical sibling.
Any pair of siblings has a 25 percent chance of being perfectly matched.
Alternative options include matched unrelated volunteer donors from international registries.
Full-haplotype mismatched family members and unrelated umbilical cord blood donors are also viable alternatives.

Disease Category	Specific Indications
Malignant Disorders	Acute lymphoblastic leukemia in first complete remission for patients at very high risk of relapse. Acute myeloid leukemia in first complete remission or advanced disease. Juvenile myelomonocytic leukemia. Myelodysplastic syndromes. Relapsed Hodgkin and non-Hodgkin lymphomas (autologous). Stage IV or relapsed neuroblastoma (autologous). High-risk central nervous system tumors (autologous).
Bone Marrow Failure	Severe acquired aplastic anemia. Fanconi anemia. Diamond-Blackfan anemia. Shwachman-Diamond syndrome.
Hemoglobinopathies	Thalassemia major. Severe sickle cell disease with recurrent vasoocclusive crises or strokes.
Primary Immunodeficiencies	Severe combined immunodeficiency. Wiskott-Aldrich syndrome. Leukocyte adhesion deficiency. Chronic granulomatous disease.
Metabolic Diseases	Mucopolysaccharidosis type 1 (Hurler syndrome). Adrenoleukodystrophy. Infantile malignant osteopetrosis.

Acute graft-versus-host disease occurs when alloreactive donor T cells recognize recipient tissues as foreign.
It leads to a massive inflammatory attack primarily targeting the skin, liver, and gastrointestinal tract.
Significant acute graft-versus-host disease typically manifests within the first two to eight weeks post-transplant.
Infectious complications arise because recipients experience a transient but profound state of immune deficiency.
The pre-engraftment phase features severe neutropenia placing patients at extreme risk for bacterial sepsis and invasive fungal diseases.
The post-engraftment phase predisposes patients to severe viral infections like cytomegalovirus and Epstein-Barr virus.
Primary graft failure is the failure to achieve a neutrophil count of 0.5 cells per microliter.
Secondary graft failure is the loss of peripheral counts after an initial transient engraftment.
Graft rejection is typically mediated immunologically by residual host T-lymphocytes surviving the conditioning regimen.
Venoocclusive disease, or sinusoidal obstruction syndrome, results from conditioning-induced endothelial damage within the liver.

Organ System	Late Complications
Immunologic	Chronic graft-versus-host disease functions as a systemic disorder of immune regulation. It produces severe autoimmune-like symptoms such as scleroderma, progressive bronchiolitis obliterans, and cirrhosis.
Endocrine	Severe growth impairment occurs due to total body irradiation affecting the hypothalamic-pituitary axis. Primary ovarian or testicular failure leads to delayed puberty. There is a high risk of permanent infertility. Hypothyroidism is a frequent complication.
Oncologic	The risk of developing secondary malignancies is significantly elevated. Common secondary neoplasms include myelodysplastic syndromes, secondary leukemias, thyroid carcinoma, and brain tumors.
Cardiovascular	Patients face an elevated risk for metabolic syndrome and dyslipidemia. Cardiotoxicity is prevalent if exposed to pre-transplant anthracyclines or chest radiation.
Neurologic	Neurocognitive deficits and progressive leukoencephalopathy can occur. This is particularly seen in young children who receive cranial radiation.
Other Systems	Restrictive pulmonary disease. Renal toxicity. Cataracts. Dental abnormalities.