Basics
Description
- Hematopoietic stem cell transplantation (HSCT) is the infusion of progenitor stem cells with the intention of restoring hematopoiesis and immunity. HSCT can be classified by
- Donor type: syngeneic (derived from an identical twin), allogeneic (derived from a related or unrelated donor), or autologous (derived from the patient prior to stem cell-toxic therapy)
- Product type
- Bone marrow transplantation (BMT): Stem cells are obtained by harvesting bone marrow under anesthesia.
- Peripheral blood stem cell transplantation (PBSCT): Stem cells are mobilized to the periphery with cytokines (GCSF) and collected by apheresis.
- Umbilical cord blood transplantation (UCBT): Stem cells are collected from the umbilical cord and placenta following delivery.
- Stem cells are infused in the peripheral blood of the recipient using a central venous catheter, similar to a blood transfusion. They then home to the bone marrow niche and over the next 2-4 weeks differentiate into mature blood components.
Epidemiology
- In 2010, 1,479 pediatric allogeneic (and 782 autologous) HSCTs were performed in the United States. Approximately 40% of allogeneic transplants are from matched related donors.
- The use of unrelated PBSCT and unrelated UCBT has been gradually increasing since the late 1990s, whereas the use of related BMT/PBSCT has remained stable. The use of unrelated BMT has been steadily decreasing.
Treatment
Indications
- HSCT is typically used to provide stem cell rescue following myeloablative therapy (cancers), to provide new stem cells to correct an intrinsic cellular defect (inborn errors of metabolism, other stem cell defects), or to alter the immune system to improve or correct an immunologic defect (e.g., autoimmune disease).
- Examples of diseases for which HSCT can be beneficial include the following:
- Leukemia (ALL, AML, JMML, and CML)
- High-risk ALL (indications for transplant include lack of response to chemotherapy or early relapse)
- High-risk AML (indication based on cytogenetic markers, response to therapy, or early relapse)
- All JMML patients require HSCT for cure.
- CML only if not well-controlled on tyrosine-kinase inhibitor therapy (imatinib, dasatinib)
- Solid tumors (lymphoma, neuroblastoma, brain tumors, some sarcomas)
- Severe primary immunodeficiencies (SCID, WAS, CGD, hyper IgM, XLP, Chediak-Higashi syndrome, Griscelli syndrome)
- Stem cell defects (aplastic anemia, myelofibrosis, Fanconi anemia, thalassemia major, sickle cell disease)
- Inborn errors of metabolism (Hurler syndrome, Hunter syndrome, adrenoleukodystrophy)
- Autoimmune disease (HLH, severe SLE)
Donor Selection
- Optimal major histocompatibility antigen (HLA) matching of the donor to the recipient minimizes the risks of rejection and GVHD.
- HLA matching is important at the A, B, C, and DR loci (8/8 match is recommended in most cases).
- Additional HLA matching at the DQ and DP loci (12/12) may be important in some cases.
- For nonmalignant disease, donor preference is syngeneic > matched familial > unrelated.
- Matched unrelated donor: Over 18 million potential donors registered worldwide. Disadvantages include long search time (2-3 months), lower chance of finding an 8/8 match for minorities, increased risk of graft failure and GVHD, and slower immune reconstitution.
- Alternative donors include mismatched unrelated donor (match at ≥7/8 HLA Ag), umbilical cord blood (match at ≥4/6 HLA Ag), or haploidentical (parental) donor (4/8 matching requires ex vivo manipulation of the graft to deplete T cells in order to prevent fatal GVHD).
- Other donor characteristics to consider include age, gender, and CMV status. CMV reactivation risk is based on donor/recipient serologies:
- D-/R-: very low risk
- D+/R-: intermediate risk
- R+: high risk; CMV+ donor is preferred.
Conditioning & Toxicity
- 3 goals of conditioning (depending on disease):
- Myeloablation (M): Clear space to allow stem cell engraftment.
- Immunosuppression (I): Prevent rejection and GVHD.
- Antineoplastic effect (N): Eradicate any remaining leukemia/tumor cells.
- Agents used during conditioning differ by their M/I/N effects and are used in combination to produce the desired outcome. Side effects of conditioning agents:
- Total body irradiation (M/I/N): cognitive delay, poor growth, cataracts, abnormal dental development, pulmonary and cardiac dysfunction, pituitary dysfunction, infertility, 2nd malignancy
- Busulfan (M/N): restrictive lung disease, seizures and possibly neurocognitive deficits, skin rash and hyperpigmentation, 2nd malignancy
- Thiotepa (M/I/N): skin rash, hemorrhagic cystitis, 2nd malignancy
- Melphalan (M/N): mucositis, cardiac dysfunction, 2nd malignancy
- Cyclophosphamide (I/N): cardiac dysfunction, SIADH, hemorrhagic cystitis, 2nd malignancy
- Etoposide (M/N): allergic reaction, hypotension, 2nd malignancy
- Fludarabine (I/N): cerebellar syndrome, peripheral neuropathy
- Carmustine (M/N): pulmonary toxicity, 2nd malignancy
- Alemtuzumab (Campath) (I): anaphylaxis, fever, hypotension, hives, viral and fungal infection
- Antithymocyte globulin (ATG) (I): anaphylaxis, fever, hypotension, hives, serum sickness, viral and fungal infection
- Nonmyeloablative or reduced toxicity regimens
- Goal of reduced toxicity regimens is to allow partial donor stem cell engraftment, while limiting toxic effects of conditioning agents.
- Indications include preexisting organ toxicity precluding full-dose chemotherapy; low performance status, often in the elderly; and primary DNA repair defects resulting in sensitivity to ionizing radiation and alkylating agents (Fanconi anemia, dyskeratosis congenita).
- Uses lower doses of chemotherapy or lower dose of radiation.
- Relies more heavily on the GVL effect of alloreactive donor T cells to control or eradicate any remaining neoplastic disease.
Ongoing Care
Complications
Treatment-related mortality (TRM) has been declining over time (40% in 1987-1995 to 15% in 2003-2006) and is attributable to the following complications:
- Infection
- Correlates with timing of immunologic defect (early or <100 days vs. late or >100 days from transplant)
- Bacterial
- Early bacterial infections are due to neutropenia, mucositis, or central line (Staphylococcus spp, gram-negative rods, Clostridium difficile, VRE, atypicals). Later, prolonged adaptive immunity defect and chronic GVHD are risks for mycobacteria and encapsulated bacteria.
- Treat neutropenic fever empirically with broad-spectrum antibiotics.
- Role of prophylactic antibiotics is under investigation.
- Viral
- Early viral infections are due to lymphopenia, T-cell depletion, cord blood source, and previous viral exposures. Common infections include RSV, rhinovirus, adenovirus, influenza, and herpes virus reactivation (HSV, CMV, HHV-6). Persistent defect in adaptive immunity contributes to later infections such as CMV, VZV, and EBV/PTLD.
- Acyclovir prophylaxis to prevent HSV reactivation
- At detection of CMV viremia, rule out CMV retinitis with funduscopic exam and begin preemptive therapy for CMV viremia with foscarnet or ganciclovir. For CMV organ involvement, consider Cytogam, IVIG, or intravitreal foscarnet for CMV retinitis. Continue maintenance therapy with ganciclovir or valganciclovir once viremia is cleared.
- Fungal
- Combined innate and adaptive immunity defects (early) and persistent T-cell dysfunction (late) confer risk for Candida, Aspergillus, Pneumocystis, and other fungal infection (Fusarium, Zygomycetes/Mucor, Cryptococcus, Histoplasma, Coccidioides).
- Prophylaxis: Fungal prophylaxis is with fluconazole (yeast coverage) or caspofungin; Pneumocystis prophylaxis is with cotrimoxazole before conditioning and after engraftment.
- Treatment with voriconazole empirically for sustained fever without source (strong mold/Aspergillus coverage)
- Decrease calcineurin inhibitor/sirolimus dose when starting voriconazole due to inhibition of cytochrome P450 metabolism.
- Document infection (BAL) whenever possible.
- Mucositis
- Grades 1-4 based on WHO classification (mild to severe).
- Prevention: Reduced intensity protocols, glutamine, palifermin; consider holding posttransplant methotrexate if severe mucositis
- Treatment: IV pain control, TPN, suction
- Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS)
- Due to hepatic accumulation of toxic metabolites leading to reduced hepatic venous outflow and postsinusoidal intrahepatic portal hypertension
- Overall risk of VOD is 10-25%. Risk factors include mismatched or unrelated donor, previous hepatic tumor involvement or abdominal RT, pretransplant elevation of AST, and medications such as busulfan.
- Diagnosis
- Modified Seattle criteria: Any 2 of the following present by day +20: jaundice (bilirubin >2 mg/dL); painful hepatomegaly; or ascites ± weight gain of >2% from baseline
- Baltimore criteria: bilirubin >2 mg/dL before day +21 and any 2 of the following: hepatomegaly, ascites, or weight gain (>5% from baseline)
- Reversal of portal venous flow on ultrasound (US) is characteristic but not part of diagnostic criteria.
- Prophylaxis may include ursodiol, N-acetylcysteine, or defibrotide (under investigation)
- Treatment
- Defibrotide: Porcine intestinal mucosal oligonucleotide. Anticoagulant with effects on endothelial cells, platelets, and fibrinolysis
- Supportive care: restriction of sodium and fluid intake; diuresis to keep fluid balance even (spironolactone if able to take PO)
- Complications of VOD include renal insufficiency, altered mental status, cardiac failure, and bleeding.
- Thrombotic microangiopathy
- Diagnosis: RBC fragmentation, thrombocytopenia with increased need for frequent platelet transfusions, elevated LDH, concurrent renal and/or neurologic dysfunction
- Calcineurin GVHD prophylaxis is a risk factor (CSA > tacrolimus). Combination with sirolimus triples the risk from 4.2% to 10.8%.
- Treatment: Discontinue calcineurin inhibitors; supportive care. Limited data for plasmapheresis, eculizumab (anticomplement C5), infliximab, and defibrotide.
- Engraftment syndrome
- Cytokine-mediated inflammation due to increasing neutrophil activity
- Usually occurs by day +28 (earlier for autos, later for cord blood transplants)
- Characterized by rash, fever, and pulmonary edema at the time of engraftment or before neutrophil recovery
- Treatment: rule out infection, then methylprednisolone for 3-7 days.
- Interstitial pneumonitis
- Complication of TBI, chemotherapy (busulfan, Cytoxan), or infection (fungal, CMV). Idiopathic pneumonia syndrome (IPS) if no etiology is found.
- Diagnosis:
- Cough, dyspnea, hypoxemia, fever
- CXR/CT: diffuse versus focal consolidations, nodules or cavitary lesions suggestive of fungus
- BAL: sensitive for CMV, RSV, PCP, other respiratory viruses. Less sensitive for fungus.
- Treatment: early empiric broad-spectrum antibiotics and antifungals, respiratory support. Consider corticosteroids or TNF blockade for IPS.
- GVHD
Immune Reconstitution
- Innate immunity recovers within 2-4 weeks posttransplant and includes monocytes, followed by granulocytes and NK cells.
- Adaptive immunity recovers over months to years, with peripheral expansion of donor memory T cells (1st wave) followed by thymic development of donor stem cells (2nd wave). Measurements of adaptive immune reconstitution include ALC, donor chimerism, lymphocyte phenotyping, T-cell function (proliferation to mitogen and antigen), B-cell function (serum IgA/IgM and isohemagglutinin titers), and vaccine titers before and after revaccination.
- Revaccination: Effects of conditioning require revaccination with killed vaccines when adaptive immunity has recovered (approximately 1 year posttransplant). If titers demonstrate an immunologic response, live-attenuated vaccines are administered after 2 years.
Outcomes
- Overall: 10-20% transplant-related mortality from rejection (<1-8%); toxicity (including infection, 5-20% mortality); and GVHD (5-15% mortality). Additional risk of relapse ranges from 15 to 40%. Risks are modified by several factors:
- Rejection risks: disease, donor match, cell dose
- Toxicity risks: infectious risks, conditioning, performance status/organ function.
- GVHD risks: HLA match, number of donor T cells infused, GVHD prophylaxis.
- Relapse risks: disease, disease status, conditioning regimen, donor type
Long-Term Effects
- Risk is based on doses of chemotherapy and/or TBI received and presence/severity of GVHD.
- Incidence at 10 years (and etiologies):
- Pulmonary: 20% (TBI, busulfan, GVHD/bronchiolitis obliterans)
- Ophthalmologic: 44% (TBI, steroids, GVHD)
- Hypothyroidism: 36% (TBI, busulfan)
- Osteoarticular: 29% (steroids, GVHD)
- Cardiac: 11% (TBI, Cytoxan, prior anthracyclines)
- Hepatic: 16% (iron overload, GVHD)
- Dental: 15% (TBI, GVHD)
- Secondary malignancy: 5-10% (TBI, alkylators, VP16, immunodeficiency)
- Infertility: >90% (TBI, alkylators)
- Other effects include GH deficiency, hearing loss, hypogonadism, chronic renal insufficiency, neurocognitive defects.
- Long-term follow-up should include evaluations of disease physical exam, immune status, cardiopulmonary function, endocrine function, hepatic function renal function, ophthalmologic exam, audiology, and neurocognitive evaluation.
- Immunization strategy posttransplant
Additional Reading
- Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008;41(2):119-126. [View Abstract]
- Fisher BT, Alexander S, Dvorak CC, et al. Epidemiology and potential preventative measures for viral infections in children with malignancy and those undergoing hematopoietic cell transplantation. Pediatr Blood Cancer. 2012;59(1):11-15. [View Abstract]
- Pulsipher MA, Skinner R, McDonald GB, et al. National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant. 2012;18(3):334-347. [View Abstract]
- Spellman SR, Eapen M, Logan BR, et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012;120(2):259-265. [View Abstract]
Codes
ICD09
- V42.81 Bone marrow replaced by transplant
- V42.82 Peripheral stem cells replaced by transplant
- V59.3 Bone marrow donors
- V59.02 Blood donors, stem cells
- 996.85 Complications of transplanted bone marrow
- 996.88 Complications of transplanted organ, stem cell
ICD10
- Z94.81 Bone marrow transplant status
- Z94.84 Stem cells transplant status
- Z52.3 Bone marrow donor
- Z52.001 Unspecified donor, stem cells
- T86.0 Complications of bone marrow transplant
- T86.5 Complications of stem cell transplant
SNOMED
- 161669001 History of bone tissue recipient (situation)
- 278257006 Peripheral blood stem cell graft (procedure)
- 105471006 Bone marrow donor (person)
- 430792005 Stem cell donor (person)
- 234519006 Bone marrow transplant rejection (disorder)
FAQ
- Q: Should friends and family of a patient needing a transplant be tested as a potential match?
- A: If family contacts are willing to donate for an unrelated patient in need of a stem cell transplant, they should join the National Marrow Donor Program (NMDP) registry. However, extended family members are very unlikely to be a match for a related patient.
- Q: Can transplant recipients meet their donors?
- A: The NMDP has guidelines for donor/recipient contact. If both parties agree, contact is allowed 1-2 years after the transplant.