Pediatric Hematopoietic Stem Cell Transplantation

Indications and patient selection: 1) Malignant indications - acute lymphoblastic leukemia (high-risk MLL rearranged, induction failure, hypodiploid, MRD-positive, T-cell, Ph+ resistant; relapsed especially early or extramedullary), acute myeloid leukemia (high-risk MRC, MRD-positive, secondary AML, relapsed), juvenile myelomonocytic leukemia (JMML), high-risk neuroblastoma (autologous, often tandem), high-risk brain tumors (medulloblastoma, AT/RT - autologous), sarcomas, lymphomas (relapsed Hodgkin, refractory non-Hodgkin); 2) Non-malignant indications - severe aplastic anemia (matched sibling preferred), Fanconi anemia, dyskeratosis congenita, sickle cell disease (severe phenotype), beta-thalassemia major, severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, chronic granulomatous disease, hemophagocytic lymphohistiocytosis (HLH); 3) Inborn errors of metabolism - mucopolysaccharidoses (Hurler), adrenoleukodystrophy, Krabbe, metachromatic leukodystrophy, Niemann-Pick C; benefits cognitive and somatic disease in MPS; 4) Patient evaluation - performance status (Lansky/Karnofsky), comorbidities, organ function (cardiac echo, pulmonary function), infectious workup (HSV, CMV, EBV, hepatitis), HLA typing, financial and social assessment, neurodevelopmental, dental, fertility preservation discussion (sperm/egg/ovarian tissue), psychosocial support; 5) Donor selection - matched sibling preferred, matched unrelated (8/8 or 10/10 HLA match) extensive search, haploidentical family donor, umbilical cord blood (lower HLA matching threshold but slower engraftment), autologous (for solid tumors); 6) Centers - pediatric HSCT centers must meet FACT/JACIE accreditation, multidisciplinary expertise, infection control, transfusion, intensive care.

Conditioning regimens and procedure: 1) Myeloablative conditioning - busulfan + cyclophosphamide, total body irradiation (TBI) + cyclophosphamide, busulfan + fludarabine; provides intense disease eradication and immunosuppression; intense toxicity but better disease control; 2) Reduced-intensity conditioning - lower toxicity for fragile patients (older children with comorbidities, second transplants), relies more on graft-vs-tumor effect; 3) Specific regimens - busulfan + cyclophosphamide + ATG (Hurler, MPS), busulfan + fludarabine (sickle cell), TBI + cyclophosphamide (ALL), Mel-cyclophosphamide-thiotepa (autologous neuroblastoma); 4) GVHD prophylaxis - calcineurin inhibitors (tacrolimus, cyclosporine) with methotrexate (matched), or post-transplant cyclophosphamide (haploidentical); ATG (anti-thymocyte globulin) for T-cell depletion; 5) Stem cell infusion - peripheral blood, bone marrow, or cord blood; bone marrow harvested under anesthesia from posterior iliac crest; PBSC mobilized with G-CSF and collected by apheresis (5-10 x 10^6 CD34+ cells/kg target); 6) Engraftment - neutrophil engraftment ANC >500 typically day 14-21 (faster with PBSC); platelet engraftment day 18-30; immune reconstitution months to year+; 7) Post-transplant care - protective isolation initially, transfusion support, prophylaxis (HSV, fungal, PCP, CMV monitoring with PCR), nutritional support including parenteral if mucositis severe, growth monitoring.

Complications, outcomes, and survivorship: 1) Acute GVHD - clinical syndrome of immune-mediated injury to skin, GI tract, liver; develops day 0-100; staged I-IV based on extent; treatment - first-line corticosteroids; second-line ruxolitinib, MMF, mycophenolate, ECP, ATG; 2) Chronic GVHD - develops after day 100; sclerodermatous skin, sicca syndrome (eyes/mouth), GI, lung (BOS), liver; pediatric incidence 20-40%; treatment with steroids, ruxolitinib, ibrutinib, ECP, biologics; 3) Infections - bacterial early, viral (CMV, EBV, HHV-6, adenovirus) intermediate, fungal (Aspergillus, Mucor) and parasitic (PCP); requires aggressive prophylaxis and treatment; 4) Organ toxicity - sinusoidal obstruction syndrome (SOS, formerly VOD), pulmonary toxicity (idiopathic pneumonia, BOS), cardiac, renal; 5) Engraftment syndrome, transplant-associated thrombotic microangiopathy (TA-TMA); 6) Survival outcomes - 5-year overall survival: matched sibling AML 65-80%, ALL 60-75%, sickle cell 90-95%, severe aplastic anemia 80-95%, SCID 80-90%, Hurler 70-85%; alternative donor outcomes have improved closer to matched sibling in modern era; 7) Late effects - secondary malignancies (5-15% by 20 years post), endocrine (growth hormone deficiency, gonadal failure, thyroid, diabetes), neurocognitive, cardiac, pulmonary, infertility, ocular (cataracts), bone (avascular necrosis, osteoporosis); 8) Long-term survivorship - lifelong follow-up at survivorship clinic, secondary cancer screening, endocrine assessment, fertility, cardiovascular risk reduction, vaccine reimmunization, school/career support, psychosocial; 9) Modern advances - reduced-intensity conditioning, alternative donors expanding options, post-transplant cyclophosphamide, bispecific antibodies (blinatumomab) and CAR-T as alternatives, gene therapy emerging; 10) CAR-T cell therapy - tisagenlecleucel for B-ALL refractory/relapsed, may avoid HSCT in some children, but HSCT often considered in high-risk; CAR-T is autologous and engineered, not HSCT but sometimes preceding.