11.1 Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is CPHON Domain III.A.5 and III.B.7. Items test graft type, why a child is transplanted, what conditioning does, when neutrophils return, which infections appear in which window, and the complications that are named here but fully staged later. A 3-year-old finishing induction for high-risk neuroblastoma, a 7-year-old with high-risk AML, and a 9-year-old with severe aplastic anemia and a matched sibling are three different grafts. Mixing autologous marrow rescue with allogeneic graft-versus-leukemia on one consent form is how families leave thinking "bone marrow transplant" is a single procedure.

Autologous versus allogeneic grafts

Autologous HSCT uses the child's own hematopoietic stem cells, collected from peripheral blood after mobilization or, less often, from marrow, cryopreserved, then reinfused after myeloablative high-dose chemotherapy. There is no graft-versus-host disease (GVHD) because the graft is self. There is also no graft-versus-leukemia effect. The point is marrow rescue after otherwise lethal chemotherapy. The pediatric solid-tumor exemplar is high-risk neuroblastoma, often tandem autologous consolidations on contemporary cooperative-group pathways. Selected other relapsed or high-risk solid tumors may use auto HSCT on protocol. Do not import adult myeloma indication lists as pediatric CPHON fact.

Allogeneic HSCT uses another person's hematopoietic stem cells. The graft reconstitutes hematopoiesis and immunity and, in leukemia, can provide graft-versus-leukemia. Name the donor types:

• Matched sibling donor (MSD): an HLA-identical sibling. Preferred when available for many nonmalignant indications and for selected high-risk malignant disease.
• Matched unrelated donor (MUD): a volunteer from a registry, matched at high-resolution HLA.
• Haploidentical (haplo): typically a parent, matched at one haplotype. Post-transplant cyclophosphamide (PTCy) is a common GVHD-prevention platform that made haplo a realistic pediatric option when no MSD or MUD exists.
• Umbilical cord blood (UCB): a banked unit, more permissive HLA mismatch, slower neutrophil recovery, and a longer early-infection window.

Indications you will actually see

High-risk or relapsed leukemia—especially high-risk or relapsed AML, and relapsed or very-high-risk ALL after salvage—is the classic malignant allogeneic indication. Severe aplastic anemia is directed to MSD first-line when a sibling exists (see the marrow-failure section). Hemoglobinopathies, including transfusion-dependent thalassemia and selected sickle cell disease, can be cured by allogeneic HSCT. Primary immunodeficiencies such as severe combined immunodeficiency need immune reconstitution, not another year of supportive transfusions. The solid-tumor sentence to keep is autologous HSCT for high-risk neuroblastoma. Do not transplant every solid tumor by habit.

Conditioning: intensity and the drugs

Myeloablative conditioning (MAC) uses high-dose chemotherapy with or without total body irradiation (TBI) to empty marrow and, in allogeneic transplants, immunosuppress the host so the graft is not rejected. Reduced-intensity conditioning (RIC) is less marrow-toxic and more immunosuppressive; it is chosen when comorbidity, prior therapy, or protocol design does not support full ablation. RIC is not a "gentle" transplant: mucositis may be milder, but infection, GVHD, and graft failure still happen.

TBI causes mucositis, parotitis, infertility, growth and endocrine injury, cataracts, and secondary-malignancy risk—survivorship language belongs on the roadmap. Attach these chemo agents to a bedside watch:

• Busulfan: hepatic sinusoidal obstruction syndrome / veno-occlusive disease (SOS/VOD) risk and seizures from CNS irritability. Give seizure prophylaxis (commonly levetiracetam or another protocol anticonvulsant) through the busulfan window. Many programs use therapeutic drug monitoring. Do not invent a target area-under-the-curve as ONCC fact.
• Cyclophosphamide: hemorrhagic cystitis from acrolein—mesna plus hydration as in the chemotherapy chapter; high-dose cyclophosphamide is also cardiotoxic.
• Fludarabine: a lymphodepleting nucleoside analog used heavily on RIC and haplo platforms.
• Melphalan: severe mucositis; a workhorse in many autologous neuroblastoma regimens.

A 4-year-old receiving busulfan who seizes on day −3 is a missed-prophylaxis event until proven otherwise, not "hospital anxiety."

Engraftment, mucositis, and infection windows

Engraftment is commonly defined as absolute neutrophil count (ANC) recovery—often the first of three consecutive days at or above the protocol threshold (many programs use 500/µL). Platelet independence follows. Teach the concept: donor or rescued autologous neutrophils that can fight bacteria again. Do not treat one printed ANC cutoff as the only ONCC definition.

Mucositis peaks around the nadir and early engraftment after MAC. Opioid analgesia, nutrition support including parenteral nutrition when the mouth and gut cannot keep up, and infection through broken mucosa are expected work.

Infection timing is high-yield:

• Pre-engraftment (neutropenic): bacterial bloodstream and gastrointestinal translocation infections; HSV reactivation; Candida.
• Early post-engraftment through about day 100: cytomegalovirus (CMV) (especially allogeneic, mismatched serostatus), Pneumocystis jirovecii pneumonia without prophylaxis (PCP/PJP), other viruses.
• Later, or during prolonged steroids for GVHD: Aspergillus and other molds.

Protective environment, visitor restrictions, masks, and diet (a strict "neutropenic diet" versus food-safety teaching) are institutional. Follow the unit policy. Do not invent a national ONCC rule that no child may ever eat a washed apple.

GVHD prophylaxis and the two timeframes

Allogeneic grafts need GVHD prophylaxis. Common tools: calcineurin inhibitors (cyclosporine, tacrolimus—drug levels, nephrotoxicity, magnesium wasting, posterior reversible encephalopathy risk), methotrexate (adds mucositis and delayed clearance), and PTCy after haploidentical grafts. Autologous transplants do not need GVHD prophylaxis.

Acute GVHD classically involves skin (maculopapular rash, often palms, soles, and ears), gut (secretory diarrhea, cramping, bleeding), and liver (conjugated hyperbilirubinemia). Chronic GVHD is later: sicca (dry eyes and mouth), bronchiolitis obliterans, sclerodermatous skin, fasciitis, and joint contractures. High-level recognition is enough here.

Graft failure, hemorrhagic cystitis, and SOS/VOD as a signpost

Graft failure is failure of ANC recovery in the expected window, or falling counts after brief engraftment with aplasia. In allogeneic transplants think rejection or poor graft function; in autologous transplants think inadequate collection or residual marrow injury. This is a same-day transplant-team call, not "give another day of filgrastim and see."

Hemorrhagic cystitis splits in time: cyclophosphamide (early, acrolein) versus BK virus (later, after engraftment, more often allogeneic). Gross hematuria, clots, and bladder spasm need hydration, platelet support, pain control, and urology—not a wait-and-see pink-urine note.

SOS/VOD presents with tender hepatomegaly, rapid weight gain or ascites, and jaundice. Defibrotide is the disease-directed therapy concept. Fluid, renal, and ultrasound staging live in the later emergency SOS/VOD chapter. Name the triad and the drug here; do not duplicate that algorithm.

A 9-year-old on day +12 after MSD transplant with a new palm rash, eight watery stools, and rising bilirubin has acute GVHD until the team says otherwise. The same child with a tender liver, two kilograms of overnight gain, and jaundice is SOS/VOD until proven otherwise. Those two syndromes are not interchangeable.

The CPHON product is a family that can name auto versus allo and the donor type, a child on busulfan seizure prophylaxis, a nurse who times bacterial versus CMV versus mold risk, and a unit that treats tender hepatomegaly plus weight gain as VOD until the emergency chapter's workup is running.