Introduction to Hematopoietic Stem Cell Transplantation in Children

Hematopoietic Stem Cell Transplantation (HSCT) is a potentially curative treatment for various malignant and non-malignant disorders in children. It involves the infusion of hematopoietic stem cells to reestablish hematopoietic function in patients with damaged or defective bone marrow or immune systems.

Key points:

• HSCT can be used to treat both malignant (e.g., leukemias, lymphomas) and non-malignant (e.g., severe aplastic anemia, immunodeficiencies) conditions.
• The procedure involves replacing the patient's hematopoietic system with healthy donor stem cells.
• HSCT in children requires special considerations due to their developing immune systems, growth potential, and long-term effects on quality of life.
• Advances in HSCT techniques have significantly improved outcomes in pediatric patients over the past few decades.

Indications for HSCT in Children

HSCT is indicated for a wide range of pediatric conditions. The decision to proceed with HSCT is based on the underlying disease, its stage, the patient's overall health, and the availability of a suitable donor.

Malignant Conditions:

• Acute Lymphoblastic Leukemia (ALL)
• Acute Myeloid Leukemia (AML)
• Chronic Myeloid Leukemia (CML)
• Myelodysplastic Syndromes (MDS)
• Non-Hodgkin's Lymphoma
• Hodgkin's Lymphoma
• Neuroblastoma

Non-malignant Conditions:

• Severe Aplastic Anemia
• Fanconi Anemia
• Thalassemia Major
• Sickle Cell Disease
• Severe Combined Immunodeficiency (SCID)
• Wiskott-Aldrich Syndrome
• Hurler Syndrome and other storage disorders

Types of Hematopoietic Stem Cell Transplantation

HSCT can be classified based on the donor source and the relationship between the donor and the recipient.

1. Autologous HSCT:

The patient's own stem cells are collected, stored, and reinfused after high-dose chemotherapy. This is commonly used for:

• Neuroblastoma
• Some brain tumors
• Hodgkin's lymphoma

2. Allogeneic HSCT:

Stem cells are obtained from a donor. Types include:

• Matched Sibling Donor (MSD): Ideal scenario, with a fully HLA-matched sibling donor.
• Matched Unrelated Donor (MUD): Donor found through registries, matched at 8/8 or 10/10 HLA loci.
• Haploidentical: Parent or sibling who is a half-match (4/8 HLA match).
• Cord Blood: Stem cells from umbilical cord blood, allowing for more HLA disparity.

Donor Selection for Allogeneic HSCT

Selecting the appropriate donor is crucial for the success of allogeneic HSCT. The process involves several considerations:

HLA Typing:

• High-resolution typing for HLA-A, -B, -C, -DRB1, and -DQB1 is standard.
• A 10/10 match is ideal, but 9/10 or 8/10 matches can be considered based on urgency and availability.

Donor Hierarchy:

1. HLA-identical sibling (if available, this is usually the first choice)
2. Well-matched unrelated donor
3. Cord blood unit(s)
4. Haploidentical family donor

Other Factors:

• CMV status of donor and recipient
• Blood group compatibility
• Donor age and gender
• Donor health status

The choice of donor can significantly impact outcomes, including engraftment, graft-versus-host disease (GVHD) risk, and overall survival.

Conditioning Regimens for Pediatric HSCT

Conditioning regimens are designed to eradicate the underlying disease, create space in the bone marrow for donor cells, and provide immunosuppression to prevent graft rejection.

Types of Conditioning:

1. Myeloablative Conditioning (MAC):
   • High-dose chemotherapy with or without total body irradiation (TBI)
   • Examples: Busulfan + Cyclophosphamide, TBI + Cyclophosphamide
   • Used for malignant diseases and some non-malignant conditions
2. Reduced Intensity Conditioning (RIC):
   • Lower doses of chemotherapy and/or radiation
   • Examples: Fludarabine + Melphalan, Fludarabine + Busulfan (reduced dose)
   • Used for some non-malignant diseases and in patients who cannot tolerate MAC
3. Non-myeloablative Conditioning:
   • Minimal intensity, relies more on graft-versus-tumor effect
   • Example: Fludarabine + low-dose TBI
   • Used in specific scenarios, less common in pediatrics

The choice of conditioning regimen depends on the underlying disease, donor type, patient's age, and comorbidities. In pediatrics, there's a growing trend towards chemotherapy-based regimens to avoid the long-term effects of TBI on growth and development.

Transplantation Procedure

The HSCT procedure involves several key steps:

1. Stem Cell Collection:
   • Bone marrow harvest: Surgical procedure under general anesthesia
   • Peripheral blood stem cell collection: Apheresis after G-CSF mobilization
   • Cord blood: Collected at birth and stored
2. Conditioning Regimen: Administration of chemotherapy ± radiation as per the selected protocol
3. Stem Cell Infusion: Typically performed through a central venous catheter
4. Engraftment Period:
   • Neutrophil engraftment: Usually occurs 14-28 days post-transplant
   • Platelet engraftment: Can take up to 30-40 days
5. Supportive Care:
   • Prophylactic antimicrobials
   • Blood product support
   • Nutritional support
   • Management of mucositis and other toxicities
6. GVHD Prophylaxis: Typically includes calcineurin inhibitors (cyclosporine or tacrolimus) ± methotrexate or mycophenolate mofetil

Complications of HSCT in Children

HSCT is associated with significant risks and potential complications, which can be categorized as early or late:

Early Complications:

• Infections: Bacterial, viral (especially CMV, EBV), and fungal
• Acute Graft-versus-Host Disease (aGVHD): Typically occurs within 100 days post-transplant
• Veno-Occlusive Disease (VOD): Hepatic sinusoidal obstruction syndrome
• Engraftment Syndrome: Fever, rash, and organ dysfunction during neutrophil recovery
• Graft Failure: Primary (failure to engraft) or secondary (loss of graft after initial engraftment)

Late Complications:

• Chronic Graft-versus-Host Disease (cGVHD): Can affect multiple organ systems
• Endocrine Dysfunction: Growth hormone deficiency, thyroid disorders, gonadal failure
• Secondary Malignancies: Increased risk, especially with TBI-based conditioning
• Chronic Organ Toxicities: Pulmonary, cardiac, renal, hepatic
• Neurocognitive Effects: Especially in young children who received cranial radiation
• Infertility: Risk depends on conditioning regimen and age at transplant

Follow-up and Long-term Care

Long-term follow-up is crucial for pediatric HSCT survivors due to the potential for late effects and the need for ongoing monitoring.

Key Components of Follow-up:

1. Regular Health Assessments:
   • Annual physical examinations
   • Growth and development monitoring
   • Psychosocial evaluations
2. Screening for Late Effects:
   • Endocrine function tests
   • Pulmonary function tests
   • Cardiac evaluations
   • Bone density scans
   • Ophthalmologic examinations
3. Immunizations: Re-vaccination post-transplant as per guidelines
4. Cancer Screening: Heightened awareness for secondary malignancies
5. Educational and Vocational Support: Addressing any cognitive or learning difficulties
6. Fertility Counseling: As appropriate for age and risk factors
7. Psychosocial Support: For patients and families

The frequency and specifics of follow-up care should be tailored to the individual patient, considering their age, underlying disease, type of transplant, and conditioning regimen used.