Rudolph's Pediatrics, 22nd Ed.

CHAPTER 133. Hematopoietic Cell Transplantation

Ann E. Woolfrey, Paul A. Carpenter, and Jean E. Sanders

Hematopoietic cell transplantation (HCT) transfers a small number of hematopoietic stem cells (HSC) from a donor to a recipient, where they are able to differentiate and proliferate to restore a normal hematopoietic and immune system (see eFig. 133.1 ). HCT is performed in patients with life-threatening hematologic disorders or as a means to restore hematopoietic function following administration of otherwise lethal doses of chemotherapy or radiation for treatment of resistant malignancies. HCT also has the potential to cure disorders resulting from defects in the pluripotent progenitor cells or in a single hematopoietic lineage.


HCT is most commonly used to treat aggressive hematopoietic malignancies that have not responded to conventional therapy (see eFig. 133.2 ). Acute lymphoblastic leukemia is the most common indication for HCT in children who fail to achieve remission following induction chemotherapy, or in those that relapse following chemotherapy. In general, 65% to 75% of patients in first remission, 40% to 50% of those in second remission, and 10% of those with more advanced disease will survive long term (see Chapter 449).1,2 In patients with acute myeloid leukemia, HCT is generally indicated at first remission if an HLA–identical sibling donor is available (see Chapter 450).3 Other hematologic malignancies, such as chronic myelogenous leukemia, juvenile chronic myeloid leukemia, myelodysplastic syndromes, and myeloproliferative syndromes, are considered appropriate candidates for HCT, and in certain instances, HCT is the only potential modality for cure.4,5

Hematopoietic cell transplantation (HCT) is also used to treat some pediatric solid tumors. The hematopoietic cells generally come from the patient, although other donors have been used. The transplant typically is performed after chemotherapy, and sometimes surgery or radiation, has reduced the tumor burden sufficiently. Neuroblastoma is the most common solid tumor for which HCT is used (see Chapter 457). Patients with relapsed Hodgkins or nonHodgkins lymphoma also may benefit from HCT, which results in approximately 50% long-term survival when performed during second remission.7 HCT also has shown promise as a component of treatment for patients with relapsed Ewing sarcoma or medulloblastoma.8,9

Life-threatening disorders of bone marrow production or immunity also may be treated with HCT. Patients diagnosed with severe combined immunodeficiency syndrome should be given HCT as soon as a suitable donor is identified (see Chapter 1).

Patients diagnosed with bone marrow failure also are considered excellent candidates for HCT. HCT may be the only potential for curing congenital marrow failure syndromes, such as Fanconi anemia or congenital neutropenias,16and has been studied for treatment of other blood disorders such as thalassemia and sickle cell anemia. Prognosis is most heavily influenced by the underlying disorder. In general, results using HLA-identical sibling donors have been encouraging, with greater than 90% of patients surviving and greater than 80% living without recurrent disease symptoms.17,18 Mortality caused by the transplant procedure, and not from disease relapse, termed transplant-related mortality, ranges from 15% to 40% for allogeneic HCT recipients compared with 5% to 10% for autologous HCT recipients. HLA-disparity between donor and recipient increases the risk of transplant-related mortality owing to the greater likelihood of developing GVHD and graft rejection.


The type of hematopoietic cell transplantation (HCT) procedure appropriate for a specific patient depends upon the patient’s diagnosis, disease stage, prior treatments, donor availability, age, and presence of comorbidities. HCT is categorized according to the source of stem cells, the type of donor, or the intensity of the preparative regimen.


HSC capable of reconstituting hematopoiesis can be obtained from three different sources: bone marrowperipheral blood and umbilical cord blood. These HSC products are characterized by distinct kinetics of engraftment and recovery of immune function after transplantation. In general, HSC products with equivalent HLA-matching may be used interchangeably, however the risks of developing infectious complications and graft-versus-host disease (GVHD) may differ for HSC from different sources.

Bone marrow was historically the most common source of stem cells for HCT but its use has lessened as other sources have become more available.

Growth factor–mobilized peripheral blood stem cells (PBSC) are now the predominant source of HSC for allogeneic HCT in adults and for autologous HCT.19 PBSC are collected from the peripheral vein of the donor by leukapheresis.

Umbilical cord blood (UCB) contains HSC sufficient for reconstitution of hematopoiesis, and can be collected from the placenta and umbilical cord immediately after delivery of a baby. UCB banking has increased donor availability for patients with rare HLA haplotypes.24 T cells contained in UCB are immunologically naïve, which allows for less stringent HLA matching between donor and recipient. The number of hematopoietic stem cells contained in a typical UCB unit is several orders of magnitude lower compared with that of typical bone marrow or PBSC harvests. The smaller number of HSC may result in delayed engraftment, increase risk for graft rejection, and infection.25 Nonetheless, UCB transplantation remains an important option with an acceptable toxicity profile for patients who would otherwise not have a suitable stem cell donor.26


Transplantation of hematopoietic stem cells (HSC) donated by the patient is termed autologous hematopoietic cell transplantation (HCT). The success of the autologous transplant procedures relies exclusively on the tumor-eradicating potential of the preparative regimen. Transplantation of autologous HSC provides a means to overcome the marrow toxicity, hence to deliver markedly higher doses of chemotherapy or radiation.

Transplantation of marrow or PBSC donated from identical (monozygotic) twins is termed syngeneic hematopoietic cell transplantation (HCT).

Transplantation of hematopoietic cells donated by another individual is termed allogeneic HCT. Allogeneic HCT requires availability of an HLA-compatible related or unrelated donor. Because of the inheritance pattern of HLA haplotypes, the likelihood of two siblings being genotypically HLA identical is 25%. Donor-recipient HLA genotypic identity is associated with the lowest risks for immunologically mediated complications such as graft rejection and GVHD.27,28 For approximately 70% of patients who do not have an HLA-identical sibling donor, a search for an unrelated donor can be considered. HCT from HLA-matched unrelated donors, however, has traditionally been associated with higher risks of transplant-related morbidity and mortality compared with HCT from HLA-identical related donors. Use of unrelated donors who are matched not only at the antigen level (HLA typing by serology) but also at the genetic level (HLA typing by molecular methods) can improve outcomes considerably, and for some diseases, survival of patients with unrelated grafts has approached that of HLA-identical sibling grafts.29

Another alternative source of HSC is a haploidentical relative, such as a parent, defined by the inheritance of one identical haplotype and mismatching of one or more HLA loci with the noninherited haplotype. Over the past decade, technological advances have improved the outcome for recipients of HLA-disparate grafts.30


In preparation for hematopoietic cell transplantation (HCT), high-dose chemotherapy alone, or combined with irradiation therapy, are used for the dual purpose of (1) eradicating the underlying disease process and (2) inducing immunosuppression to prevent graft rejection, an immunologic host-versus-graft reaction after allogeneic HCT. High-dose chemoradiation is followed by intravenous infusion of the hematopoietic stem cells (HSC) that home to the bone marrow and reconstitute the ablated hematopoietic system of the patient.

Myeloablative preparative regimens ablate the hematopoietic system of the patient. Although the regimens used for autologous HCT typically consist of drugs that provide maximum tumor eradication with tolerable toxicity to the patient, regimens used for allogeneic HCT also must provide sufficient recipient immunosuppression to prevent graft rejection. Myeloablative preparative regimens are associated with substantial risks of transplant-related toxicity and mortality, particularly among older or medically unfit patients.

Nonmyeloablative preparative regimens for allogeneic HCT are mainly immunosuppressive and aimed at preventing graft rejection. The underlying malignancy is eliminated through immunologic graft-versus-tumor effects, provided the tumor expresses antigens that make it a target for immune attack. Compared with myelo-ablative allogeneic HCT, the extrahematopoietic toxicity from nonmyeloablative preparative regimens is considerably milder. Thus, patients who would otherwise not be eligible for HCT because of age or comorbidities can take advantage of this treatment.31


Transplant-related complications are those resulting from undergoing hematopoietic cell transplantation (HCT), not from the underlying disease process. Transplant-related complications include (1) regimen-related toxicity, (2) infections, and (3) complications associated with alloimmune T cells.


Regimen-related toxicities typically occur within the first month after myeloablative conditioning, and include cytopenias and organ damage. Each of these manifests differently in the immediate transplant period versus long-term sequelae, which are discussed separately below. More intense conditioning regimens also are associated with greater risk for infection, which is also affected by the prolonged period of immune reconstitution following allogeneic grafts. The complications of allogeneic HCT that may occur irrespective of the intensity of the conditioning regimen include rejection, graft-versus-host disease (GVHD) and hemolysis.

The likelihood of developing transplant-related complications depends on patient age, the intensity of the preparative regimen, the type and stage of the underlying disease, and the presence of comorbidities.

High-dose cytotoxic chemotherapy with or without doses of total body irradiation (TBI) exceeding 6 Gy has the potential to cause regimen-related toxicity (RRT) in the skin, gastrointestinal tract, liver, bladder, lung, heart, kidney, and nervous system. RRT occurs predominantly within the first 3 to 4 weeks after conditioning and is more common after myeloablative than nonmyeloablative conditioning.32-37RRT increases the risk for opportunistic infection.32-37 Opportunistic infection or GVHD as etiologies for organ dysfunction must strongly be considered in the differential before making a diagnosis of RRT.


Reconstitution of hematopoiesis occurs in an orderly pattern; in general, neutrophil recovery occurs first, followed by recovery of platelets and red blood cells. Hematopoietic reconstitution varies according to the type of HSC product, being earlier after peripheral blood stem cells (PBSC) grafts and later after umbilical cord blood (UCB) grafts, relative to marrow grafts. Transfusions of 1500 to 3000 cGy irradiated platelets and red blood cells usually are needed to support hematopoietic function until hematopoiesis recovers. Red blood cell transfusions generally are indicated when the hemoglobin falls below 8 g/dL. Platelet transfusions are indicated when the platelet count falls below 10,000 cells/μL to minimize the risk for spontaneous bleeding.33 Patients that have become alloimmunized to platelet antigens demonstrate poor response to platelet transfusions and may achieve higher platelet counts by limiting the number of donor exposures, depleting transfused platelets of leukocytes, controlling fever or disseminated intravascular coagulation, use of platelet products that are less than 48 hours old, or use of non-pooled (single-donor) platelets or HLA-matched platelets.34

Precautions should be taken in preparation of blood products for transfusion into HCT patients because passenger lymphocytes pose a risk for generating GVHD. Except for the stem cell graft, all other components should be irradiated at a dose of 1500 to 3000 cGy to eliminate contaminating lymphocytes. Depletion of leukocytes or use of blood components that test seronegative for CMV are equally effective for prevention of CMV transmission to CMV-seronegative recipients.35 Removal of white blood cells from platelet and red blood cell products also decreases the risk for alloimmunization of the patient.36

Skin and Mucositis

Generalized skin erythema is common after doses of TBI exceeding 12 Gy but is self-limiting and rarely associated with skin breakdown. Regimens that contain cytosine arabinoside (Ara-C), thiotepa, busulfan, etoposide, and carmustine (BCNU) may also cause erythema. Hyperpigmentation typically follows the inflammatory dermatitis with skin folds often being particularly noticeable. Skin biopsies during the first 3 weeks after transplant often show nonspecific inflammatory changes irrespective of cause, making them usually unhelpful in distinguishing between RRT, drug allergies or acute GVHD.

Most patients who receive intensive conditioning regimens develop mucositis.37,38 Symptoms include inflammation, desquamation, and edema of the oral and pharyngeal epithelial tissue that typically presents within the first several days after HCT and usually resolves by the third week after HCT. Damage to the mucosa of the lower GI tract results in secretory diarrhea, crampy abdominal pain, and anorexia, and facilitates translocation of intestinal bacteria with sepsis.39 Anorexia, nausea, or other intestinal symptoms that persist after day 21 are more likely to be caused by graft-versus-host disease (GVHD) or infection.

Mucositis is treated supportively with administration of hyperalimentation and intravenous fluids to provide calories and maintain water balance, and intravenous narcotics to control pain. Octreotide or loperamide may be used if diarrhea is severe.41 It is important to recognize that an iatrogenic narcotic bowel syndrome, characterized by abdominal pain and bowel dilatation, may be a side effect of efforts to control painful symptoms of mucositis or liver toxicity.42 Esophageal bleeding conditions are treated supportively with transfusions to maintain platelet counts at more than 60,000 per μL and optimal management of emesis.

Hepatic Sinusoidal Obstruction Syndrome (SOS)

Hepatic sinusoidal obstruction syndrome (previously called veno-occlusive disease) develops in 10% to 60% of patients and is a clinical diagnosis based on the triad of tender hepatomegaly, jaundice, and unexplained weight gain usually within 30 days after HCT and in the absence of other explanations for these symptoms and signs.43,44 Once SOS is established, mathematical models can be used to predict prognosis, based on rates of increase in serum bilirubin and weight within the first 2 weeks after transplantation. The treatment for the 70% to 85% of patients who are predicted to have a mild or moderate course is largely supportive, with attention to management of sodium and water balance to avoid fluid overload.


Pulmonary complications occur in 40% to 60% of patients after HCT.45 Noninfectious pulmonary problems that may occur within 30 days from the transplant include idiopathic pneumonia syndrome (IPS), pulmonary hemorrhage, pulmonary edema due to excessive sodium and fluid administration or associated with sinusoidal-obstruction syndrome (SOS), or acute cardiomyopathy induced by cyclophosphamide, and sepsis with adult respiratory distress syndrome (ARDS).46,47 Although the incidence of life-threatening pulmonary infections has decreased over the past decade because of the introduction of routine antimicrobial prophylaxis, pulmonary complications continue to be a leading cause of death.


Cardiac complications related to chemotherapy or radiation occur in 5% to 10% of patients after HCT but death from cardiac failure is uncommon.48

Acute Renal Failure

Acute renal failure (ARF), defined by doubling of baseline serum creatinine, occurs in 30% to 50% of all patients during the first 100 days after hematopoietic cell transplantation (HCT), and most often during the first 10 to 30 days.50-52 Nephrotoxic drugs such as cyclosporine, tacrolimus, all amphothericin products, and aminoglycosides frequently cause renal insufficiency. Thrombotic microangiopathy, endothelial damage caused by chemoradiotherapy, cyclosporine, or tacrolimus, occurs in 5% to 20% of patients, more frequently in allograft recipients.


Hypertension develops in approximately 60% of patients after HCT, more often in patients given cyclosporine for GVHD prophylaxis. Most patients respond to conventional antihypertensive therapy, such as a calcium-channel blocker, angiotensin-converting enzyme inhibitor, or beta-blocker. Correction of hypomagnesemia, which often confounds cyclosporine therapy, may improve control of hypertension.55

Hemorrhagic Cystitis

High-dose cyclophosphamide is commonly used for conditioning and one of its toxic metabolites, acrolein, accumulates in the urine and may cause a hemorrhagic chemical cystitis during the conditioning regimen or later after HCT.56,57 Viral infections, particularly adeno-virus and BK virus, also have been implicated in the development of hemorrhagic cystitis and the diagnosis is established by viral culture or PCR test of a urine sample.59

Central Nervous System

Noninfectious complications include, cerebrovascular events, and encephalopathies because of metabolic, toxic, and immune-mediated causes. Focal symptoms are more indicative of infectious or cerebrovascular mechanisms, whereas diffuse symptoms such as delirium or coma may have metabolic causes. Fever is not necessarily associated with central nervous system (CNS) infections. Infection should be considered as the cause of any neurologic symptom and should prompt evaluation, including obtaining CT or magnetic resonance imaging (MRI) scans of the head and a sample of cerebrospinal fluid for appropriate cultures, cytochemistry stains, and PCR tests should be obtained.60

Cyclosporine or tacrolimus and glucocoricoids can cause a range of neurotoxicities.62,63 Essential tremor develops in most patients. Seizures have been reported in up to 6% of patients and may present in association with headaches, tremor, or visual disturbances. Seizures should be managed with anticonvulsant therapy and cessation of the drug if possible, or if not, substitution of one agent for the other.


Prevention of infection is of vital importance to the success of HCT procedures. Hospitalized patients should be housed in single rooms that have positive-pressure air flow and ventilation systems with rapid air exchange and high-efficiency particulate air filtration.66,67 Strict visitation, hand-washing, and isolation policies should be instituted to prevent introduction or spread of communicable disease. A daily program of skin and oral care should include bathing all skin surfaces with mild soap, brushing teeth with a soft brush, frequent rinsing of the oral cavity with saline, and good perineal hygiene. The diet should exclude foods known to contain bacteria or fungi, and patients should avoid exposure to dried or fresh plants or flowers. Caregivers should be trained in the proper handling of central venous catheters.68

Immunologic reconstitution after HCT can broadly be categorized into 3 phases, which are characterized by a spectrum of opportunistic infections (Fig. 133-1). Prevention strategies for the most common infections through administration of appropriate antimicrobial agents are outlined in Table 133-1.


This period is characterized by neutropenia and oral/gastrointestinal mucosal damage. The most common infections are bacterial (gram-positive and gram-negative) and fungal. Possible fungal infections that may occur during this period may be present with skin lesions (candida), sinus involvement (aspergillus and mucor), lung lesions (aspergillus), or hepatitis (candida). Herpes simplex virus is the most common viral infection in this period. Fever of unknown origin also occurs commonly during the neutropenic period.69 Prophylactic systemic antibiotics may be administered to reduce the risk of bacteremia during the neutropenic period, although improvement in survival has not been demonstrated.


This period is characterized by skin and mucosal damage, and compromised cellular immunity related to GVHD and its treatment. Viral (cytomegalovirus [CMV]) and fungal (AspergillusPneumocystis carinii) infections predominate during this period. Gram-negative bacteremias related to GVHD-associated mucosal damage and gram-positive infections due to indwelling catheters may also occur.

FIGURE 133-1. Infectious complications after hematopoietic cell transplantation (HCT). The risk for specific infections differs according to the phase of immune reconstitution following HCT.


This period is characterized by a persistently decreased cellular immunity in patients with chronic GVHD. Patients with chronic GVHD are highly susceptible to recurrent bacterial infections, especially from encapsulated bacteria, including Streptococcus pneumoniaHemophilus influenzae, and Neisseria meningitides. Bronchopulmonary infections; septicemia; and ear, nose, and throat infections often occur. Common nonbacterial infections at this time include varizella zoster, CMV, Pneumocystis carinii, and Aspergillus.


Signs and symptoms of infection may be diminished in patients who are neutropenic or receiving immunosuppressive drugs. Thus, preemptive antibiotic therapy should be instituted promptly for any fever during the neutropenic period, because infections can progress rapidly to a fatal outcome.69 The febrile patient should be examined thoroughly for source of infection, including the oral cavity, perianal tissue, and skin surrounding the central venous catheter. Cultures should be obtained of blood, urine, and stool if diarrhea is present, and chest x-ray should be performed. Antibiotic therapy should provide empiric coverage for the most common organisms, gram-positive bacteria that colonize the skin and oral cavity, as well as the less common but more virulent gram-negative bacteria that arise from the gastrointestinal tract. Broad-spectrum antibiotic therapy should be continued through the duration of neutropenia, even if fever resolves. If fever persists, the antibiotic regimen should be broadened after 4 days to provide empiric treatment of fungi. Clostridium difficile infection should be considered in patients with diarrhea and can be treated with oral metronidazole.

Table 133-1. Recommendations for Prevention of Opportunistic Infections following Hematopoietic Cell Transplantation (HCT)


Graft rejection presents as failure to recover hematopoiesis after transplantation, termed primary graft failure, or as the loss of an established donor graft, termed secondary graft failure. Failure to achieve an absolute neutrophil count of more than 100 cells/μL and neutropenia lasting after day 26 is associated with increased risk of early mortality.70-98 Although the molecular and cellular mechanisms are not completely understood, graft rejection appears to be mediated by recipient natural killer cells or T cells.99,100 Donor HLA disparity stimulates strong alloreactive immune responses in the immunocompetent recipient and increases the risk for graft rejection. Higher stem cell doses facilitate engraftment, particularly when T cell–depleted grafts are used. Graft rejection after myeloablative conditioning is a life-threatening complication because autologous reconstitution is uncommon.

When graft failure is suspected, quantitation of donor engraftment (donor chimerism) is performed in peripheral blood using sex chromosome–specific fluorescent in situ hybridization probes for sex-mismatched donors, or polymerase chain reaction (PCR)–based techniques to detect donor-specific variable nucleotide tandem repeats sequences (VNTR). Other causes of graft suppression should be ruled out, including relapse, medications such as ganciclovir or trimethoprimsulfamethoxazole, or viral infections such as cytomegalovirus (CMV), human herpes virus 6, or parvovirus B19.


The most significant immunological barrier to successful hematopoietic cell transplantation (HCT) is the GVHD reaction. Donor T cells that recognize disparate recipient alloantigens are the central mediators of GVHD. The most important alloantigens are those encoded by the major histocompatibility complex, or HLA system.


The incidence and severity of acute GVHD are determined primarily by the degree of HLA disparity.102,103 The incidence of severe acute GVHD (grades III to IV) differs according to donor source: 15% following HLA-identical sibling grafts, 25% to 35% following related donors with zero or one HLA mismatch, 50% following related donors with two or more HLA mismatches, and 35% following HLA-matched unrelated donor grafts. Acute GVHD typically begins 2 to 4 weeks after myeloablative HCT and generally occurs before day 100, but the onset may be delayed after nonmyelo-ablative HCT. The severity of acute GVHD in the skin, liver, and GI tract, is staged 1 through 4 based on criteria that include the extent of rash, hyperbilirubinemia, and diarrhea. The various combinations of skin, liver, and GI involvement can then be used to assign an overall grade of GVHD as delineated in Table 133-2.104


Chronic GVHD occurs in approximately 30% to 60% of patients, more often when the donor is not an HLA-identical sibling and when there is a history of acute GVHD.105 There is a higher risk for developing chronic GVHD with growth factor–mobilized peripheral blood stem cells (PBSC) grafts compared with marrow grafts. Prognosis depends on the presence of certain risk factors at the time of diagnosis of CGVHD, including platelet counts less than 100,000, greater than 0.5 mg/kg/day prednisone, serum total bilirubin greater than 34 μmol/L, older recipient, prior acute GVHD, older donor, and graft-versus-host HLA mismatching.106

Table 133-2. Classification of Graft-Versus-Host Disease (GVHD)

Chronic GVHD is defined by the presence of features, which resemble autoimmine diseases such as systemic sclerosis, Sjogren syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis obliterans, immune cytopenias and chronic immunodeficiency (Table 133-2).107 Chronic GVHD frequently involves the skin, liver, eyes, mouth, upper respiratory tract, and esophagus. Major causes of morbidity include scleroderma, contractures, ulceration, keratoconjunctivitis, strictures, obstructive pulmonary disease, and weight loss.


Graft-versus-host disease (GVHD) prevention strategies are almost always incorporated into the overall treatment plan, and these include optimizing the choice of allogeneic donor and stem cell product based on known risk factors for GVHD, T-cell depletion of the donor HSC graft as discussed earlier, or, most commonly, posttransplant immunosuppression. Most often, a 6-month course of cyclosporine or tacrolimus is combined with a short course of methotrexate administered intravenously on the first, third, sixth, and eleventh days after HCT.102,108 Steady-state serum cyclosporine or tacrolimus levels should be monitored and the dose reduced in the event of toxicity or when serum trough levels exceed the upper limit of the therapeutic range. Recently other agents have been explored for use as GVHD prophylaxis, such as sirolimus, and mycophenolate mofetil.109


Despite graft-versus-host disease (GVHD) prophylaxis regimens, 30% to 80% of allogeneic HCT recipients develop acute GVHD requiring additional treatment. High-dose glucocorticoids have been the standard primary therapy of acute GVHD. Initial starting doses generally range from 1 to 2 mg/kg/day methylprednisone, calibrated to the severity and extent of organ involvement. The lower dose often is combined with topical and minimally absorbed glucocorticoids, such as budesonide, for treatment of mild gut GVHD. When there is liver involvement, or when intestinal and skin GVHD is extensive, methylprednisolone is typically begun at a dose of 2 mg/kg/day for 7 to 14 days, by which time rash, diarrhea, abdominal pain, and liver dysfunction usually remit and a glucocorticoid taper is considered appropriate. In addition to methylprednisolone, primary therapy should include continuation of cyclosporine or tacrolimus. Adjunctive therapy with ursodeoxycholic acid may improve liver GVHD.110,111

Mild chronic GVHD, such as a rash covering less than 20% of the body surface or symptoms localized to oral cavity, is treated with local or low-dose systemic immune suppression. Patients with mild chronic GVHD who have high-risk features, such as thrombocytopenia or systemic steroids at the onset of CGVHD, should be given systemic immune suppression. All patients who have involvement of more than 2 organs, or moderate to severe abnormalities of a single organ with functional impairment, require systemic immunosupression. Glucocorticoids have been the standard primary therapy for clinical extensive chronic GVHD, combined with extended administration of cyclosporine or tacrolimus. After newly diagnosed chronic GVHD manifestations have been controlled by daily glucorticoids, the judicious use of glucocorticoids at the lowest effective dose and alternate-day administration can minimize steroid-related side effects. The median duration of systemic immunosuppression for the treatment of chronic GVHD approximates 3 years after PBSC allografts and 2 years after marrow allografts.106 In 27% of patients, disease manifestations resolve within 3 years with primary therapy alone, whereas 11% of patients will continue therapy beyond 3 years, and 33% require secondary immunosuppressive agents for treatment of refractory disease. Within 2 years after starting secondary therapy, approximately 35% of patients die, and 15% require more than 2 years of secondary treatment. Because infection is a major cause of mortality, antibiotic prophylaxis is an important component of management in chronic GVHD.107

Glucocorticoids often fail to control acute graft-versus-host disease (AGVHD) manifestations such that 40% to 60% of patients have steroid-refractory (SR) AGVHD, defined as the progression of GVHD symptoms beyond 3 days after starting methylprednisolone.

Alternative therapies used include: sirolimus, mycophenolate mofetil, monoclonal antibodies (mAbs), topical therapies, and extracorporeal photopheresis.112 Unfortunately, the survival at 6 to 12 months after these therapies has been only 6% to 38%.


Red blood cell hemolysis may be encountered after hematopoietic cell transplantation (HCT) and may include more than one etiology. Thrombotic microangiopathy may present as mild hemolysis with RBC fragmentation (shistocytes) or as a more severe form, with thrombocytopenia, renal insufficiency, fever, and altered mental status, similar to hemolytic uremic syndrome (HUS) or thrombotic thrombocytopenic purpura (TTP).113 Predisposing factors include endothelial cell injury triggered by chemotherapy, radiation, or calcineurin inhibitor therapy. Autoimmune hemolytic anemia occurs infrequently after HCT and may be difficult to treat, although glucocorticoids, intravenous immunoglobulin (Ig), rituximab, plasmapheresis, or splenectomy have been used with variable success. Drugs such as fludarabine and antithymocyte globulin, or infections with mycoplasma also may produce hemolysis. Hemolysis in 30% of the recipients of allografts, being mediated by major or minor blood group incompatibilities.


An increasing number of children given hematopoietic cell transplantation (HCT) have survived into adulthood and have been followed for the development of late complications. Endocrine disturbances have been documented in 20% to 80% of survivors of childhood cancer and frequently occur as late effects of therapy. Total body irradiation (TBI) frequently disturbs the hypothalamic-pituitary axis (see Chapter 521).


Growth Hormone deficiency can impair growth, as can chronic or recurrent corticosteroid therapy. Skeletal dysplasia may result from damage to epiphyseal plates as consequence of TBI and intensive chemotherapy. This contributes at least in part to growth disturbance, and to a disproportionate effect on spinal growth compared with other epiphyses.196

Growth hormone (GH) deficiency occurs after cranial irradiation in a dose and time dependent manner and is irreversible.115-122 Studies in Seattle have shown significant impairment in growth among patients who received a single dose of 1000 cGy TBI. Fractionated TBI, given at total cumulative exposures of 1200 to 1575 cGy, also compromised final adult height.

Growth hormone deficiency is less likely to develop in children who were not given TBI. Normal growth rates and height skeletal dysplasia scores have been observed in children with aplastic anemia whose transplant preparative regimen was cyclophosphamide alone.127,128 The addition of busulfan (BU) to a CY-containing preparative regimen does not appear to result in a significant incidence of growth hormone deficiency.

Growth hormone (GH) deficiency is observed in up to 85% of children following HCT, but less than half recieve GH therapy.127 Most retrospective studies have indicated that GH therapy may improve growth rates, but most children achieve a final height below their target adult height.125,130-132 Improvements in growth and final height are achieved with contemporary dosing regimens that employ daily doses in the range of 0.04 mg/kg, increasing to 0.06 mg/kg at puberty.126,135-137 The total height gained from GH therapy has been found to relate inversely to patient age at the start of treatment, and relate positively to the duration of therapy.

Concerns that GH therapy may increase the risk for recurrent malignancy have not been validated in large studies of brain tumor survivors.138,139


Radiation may also be toxic to the gonads and hypothalamic-pituitary axis, whereas chemotherapy, particularly alkylating agents, may be gonadotoxic. Therefore, puberty may be disturbed by those chemoradiotherapies administered as treatment for an underlying malignancy, transplant preparative regimen, or both (see Chapters 540 and 541). Approximately 50% of prepubertal girls given 1200 to 1575 Gy fractionated total body irradiation (TBI) entered puberty spontaneously and achieved menarche at the normal age. Almost all of the remaining prepubertal females fail to develop secondary sexual characteristics unless adequate hormone replacement is administered.127 Busulfan also appears to predispose prepubertal girls to gonadal failure, with approximately 75% incidence observed, whereas normal pubertal development, gonadotropin levels and ovarian function have been observed among most prepubertal girls given cyclophosphamide and bone marrow transplantation (BMT) for aplastic anemia.127, 141-150 Evaluation for gonadal failure in girls is advised at age 13 if there is no evidence of thelarche, at age 14 if there has been no progression to Tanner stage 2 or 3, or at age 16 if there has been no evidence of menarche. Less commonly, precocious puberty may result from prior cranial irradiation. In post-pubertal girls, radiation effects on ovarian function are dose and age dependent. Ovarian recovery, heralded by spontaneous return of menses and normalization of LH, FSH, and estradiol levels, will occur in about 10% of women between 3 and 7 years after TBI.

In males, testicular failure and delayed puberty are common following HCT. About 40% of those that received TBI, half of those treated with busulfan and 15% of those treated with cyclophosphamide. Evaluation of boys at 14 years of age for gonadal failure is recommended if there is no evidence of secondary sexual development. The promotion of sexual maturation in boys with delayed puberty is discussed in Chapters 540 and 541. Male patients who are azoospermic as a result of hypothalamic or pituitary injury may be treated with recombinant gonadotropins. In postpubertal males, sperm banking may be considered prior to chemotherapy or induction regimens. The offspring of male survivors of childhood and adolescent cancer have similar rates of birth defects as the general population or as sibling controls, but so far there has been no increased risk for perinatal mortality or for low birth weight.151-173


Approximately 10% to 40% of children will have measurable abnormalities of thyroid function following the most commonly used HCT preparative regimens.159,174-178 The most common abnormalities are compensated or overt hypothyroidism, but sick euthyroid syndrome, hyperthyroidism and autoimmune thyroiditis have occasionally been reported.176 Annual thyroid screening is recommended by examining for thyroid lumps and by measuring the serum TSH and free T4. Patients who develop overt clinical hypothyroidism, or who have an elevated TSH and low T4 should receive thyroxine replacement therapy.


Survivors of hematopoietic cell transplantation (HCT) are also at increased risk for obesity because of prior cranial irradiation, growth hormone deficiency, glucocorticoid therapy, and lower activity levels as a result of physical or other limitations.179-194 A metabolic syndrome of obesity combined with hyperinsulinemia, low HDL cholesterol levels and reduced spontaneous GH secretion has been reported in 8 of 50 childhood cancer survivors and was significantly different from no cases seen in 50 age- and sex-matched controls.195


The combination of chemotherapy and radiation to the head and neck can cause growth impairment of deciduous or permanent teeth.196,197,198-201 Micrognathia and mandibular hypoplasia may occur, especially in those less than 7 years of age.202,203 Radiation may result in diminished secretion of saliva, which may increase the risk for tooth decay. Impaired dentine and enamel formation may lead to tooth and root shortening and, in some cases, complete lack of tooth development depending on the age of the patient at the time of irradiation. Regular dental examination and attention to oral hygiene and diet are mandatory.


Temporary alopecia is universal after myeloablative chemotherapeutic or radiation-based preparative regimens, but hair regrowth is usually occurring between 4 and 6 months later. Permanent alopecia is unlikely in children transplanted for nonmalignant disease in those that do not receive prior chemoradiotherapy. Moderate to severe alopecia occurs in 18%.


These complications develop in at least 15% to 25% of all HCT recipients. Noninfectious late pulmonary complications comprise four major disease entities, the most common of which is physiologically defined restrictive lung disease. The remaining three diagnoses are clinicopathologic syndromes whose exact pathogenesis remains poorly understood: bronchiolitis obliterans (BO), BO with organizing pneumonia (BOOP), and late idiopathic pneumonia syndrome (IPS). Noninfectious late pulmonary complications may mimic infection, further causing diagnostic dilemmas. Therefore, diagnosis requires consideration of the various known temporal associations, clinical symptoms and signs, and whether there are recognizable patterns of radiographic and pulmonary function tests.

Bronchoalveolar lavage with the use of fluorescent antibody stains, and shell vial cultures, is usual in the work-up of noninfectious late pulmonary complications other than restrictive lung disease, and permits sensitive and specific detection of viral, bacterial and Pneumocystis carinii infections, although negative results neither exclude the presence of fungal infection nor confirm a diagnosis of noninfectious late pulmonary complications.204-212Thorascopic lung biopsy is often required to continue the workup of a focal pulmonary infiltrate after a negative bronchoalveolar lavage, with the likely diagnoses being BOOP or infection.

Patients with BOOP present with fever, cough, dyspnea, and crackles on auscultation, with disease severity ranging from a mild illness to respiratory failure and death. Histologically, BOOP is defined by plugs of granulation tissue that fill distal airway lumina, extending in to the alveolar ducts and sacs. Idiopathic pulmonary syndrome is a diffuse lung injury for which no infectious etiology is identified. It occurs in 6% to 8% of HCT recipients with a median onset during the second to third week, although late onset IPS has been reported 3 to 24 months after HCT.47,207,213-232 The clinical presentation of idiopathic pneumonia syndrome is usually dramatic and marked by dyspnea, fever, and hypoxemia. Chest radiographs are diffusely abnormal, and in cases where the patient was not too ill pulmonary function tests have indicated a pattern of restriction and impaired diffusing capacity. Grade IV acute GVHD has been strongly associated with IPS, and TBI-containing preparative regimens appear to increase the risk of IPS in patients who have received prior chest radiotherapy.233-235 Overall, the major risk factors for idiopathic pneumonia syndrome include high-dose radiotherapy and multiorgan dysfunction associated with allore-activity.47 Mortality rate approaches 70% for the idiopathic pneumonia syndrome, almost 100% if mechanical ventilation is required.47


Survivors of childhood malignancy represent one of the largest risk groups for premature cardiovascular disease.236,237 Subclinical abnormalities in the electrocardiograms and myocardial contractility of children have been reported in children evaluated between six months and 16 years posttransplant.238,239 Treadmill testing appears to be the most sensitive test and detects abnormal cardiac output and oxygen consumption during exercise. Because only about 25 years have elapsed since the first decade of HCT in children and young adults, it is conceivable that cardiovascular complications may not yet have presented. Therefore, it is wise for physicians to fully evaluate suspicious cardiovascular symptoms.

Radiation may directly affect all structures of the heart including the pericardium, myocardium, valves, conduction tissues and coronary blood vessels causing functional abnormalities.237 Two children who are surviving more than 10 years following TBI-containing preparative regimens have coronary artery disease (J. Sanders, personal communication).


Two important posttransplant sequelae that involve the skeleton are iatrogenic complications of reduced bone mineral density and avascular necrosis.243-246 Radiation, chemotherapy, and corticosteroid exposure may all affect BMD. The only study that has reported BMD in children following HCT has indicated that median BMD z-scores were significantly lower, –0.5 (–2 to 1.0) SD, than in adults, 1.0 (–2 to 3; P < 0.03)243 but it remains unknown to what extent radiation and chemotherapy contribute to reduced BMD. One study showed that GH-deficient children who were osteopenic at 3 years post transplant improved significantly following treatment with GH.247-255 Dual energy x-ray absorptiometry (DEXA) scans are advised for children at 3 months and 1 year post transplant to enable early detection of reduced BMD. It is reasonable to check a serum calcium, magnesium, and 1,25-hydroxyvitamin D level in those patients who are shown to have osteoporosis. Supplementation with calcium, vitamin D, and weight-bearing exercise based on guidelines of national organizations are recommended, although alone, these measures have not proven effective in preventing osteopenia, osteoporosis, or fractures.256,257 Wherever possible, glucocorticoid therapy should be tapered to an alternate-day steroid regimen. Sex hormone replacement therapy has increased bone mass in both women and men.258,259 Prospective studies evaluating the impact of bisphosphonates, sex hormone therapy, and GH replacement on posttransplant BMD and fracture rates are required.


Avascular necrosis (AVN) develops in 4% to 10% of allogeneic hematopoietic cell transplantation (HCT) survivors, most frequently in the hip (88%), followed by the humerus, at a median of 12 months (range 2 to 132 months) after transplantation.245,246,260 In the largest reported study of posttransplant AVN, multivariate analysis identified three major risks: age older than 16 years, an initial diagnosis of aplastic anemia or acute leukemia, and GVHD.245Glucocorticoid therapy (not duration of use) also appears to be associated with increased risk for developing AVN.261,262 AVN presents with persistent or progressive pain in a typically affected joint, especially in a patient who has received glucocorticoids for GVHD. Plain film radiography findings are usually insufficient to detect the early lesions of AVN,261such that diagnosis is best confirmed by MRI imaging of the suspected joints.260


Prior chemotherapy and total body irradiation (TBI) may cause skeletal dysplasia as the result of epiphyseal plate damage. Less commonly, osteochondromata may develop in the long-term survivors of TBI. In our series of more than 400 children surviving long term, 14 have reported exostosis and 32 have reported osteochondromata. Lesions developed in long bones, digits, ankles, and scapulae. Radiation osteochondromata are more often multiple than single and are indistinguishable from the more common idiopathic type.


The most common late complications of HCT include lens cataracts and the ocular sicca syndrome, which are the sequelae of TBI and chronic graft-versus-host disease (GVHD). Less commonly occurring infectious sequelae, such as ophthalmic herpes zoster and symptomatic CMV retinitis, need to be remembered, particularly in high-risk seropositive patients with chronic GVHD. Following TBI, posterior subcapsular cataracts are first evident by slit lamp evaluation at approximately 1 year after BMT and most are visible by 3 to 4 years.263-270 Following fractionated TBI cumulative doses of more than 1200 cGy, the incidence is 50% lower, and 30% to 35% lower for doses of 1200 cGy or below. Close follow-up with an ophthalmologist is especially recommended for children younger than age 2 in whom the assessment of vision can be difficult. Older children should continue regular standard checks for visual acuity and cataracts up until age 6 to 7, after which neurovisual pathways become fixed.

The development of ocular sicca syndrome (dry eyes associated with insufficient tear production) is seen in about one third of patients with and about 10% of those without chronic GVHD. Untreated ocular sicca syndrome can be associated with infection, scar formation and corneal damage. In patients with clinical extensive chronic GVHD systemic immuno-suppression is an essential component in the prevention of progressive sicca. Meticulous ocular hygiene, use of artificial tears, and follow-up with an ophthalmologist are essential.


A preliminary analysis of 145 children studied immediately before and 1 or more years after TBI and BMT suggests that there is no significant impairment of fine-motor hand-eye coordination. Evaluation of full-scale, performance, and verbal-intelligence quotient (IQ) demonstrates a significant decrease in full-scale and performance IQ with increasing number of years after transplant.274-276 Significant risk factors were age at time of initial cranial irradiation, total dose of cranial irradiation, and number of years after radiation. One practical implication of these observations is that children who performed well in elementary school may begin to have difficulty in high school.

Recognition that a child may develop learning disabilities after HCT is important to facilitate appropriate and timely psychological testing and placement of the child in special education classes if necessary. Deficits can be subtle learning difficulties or attention deficits. Parents should be told of this risk before the HCT, and inquiry regarding school performance should occur with each long-term follow-up visit. Neuropsycho-metric testing may be warranted and assessment by a multidisciplinary team is often helpful for the detection of specific learning disability.


After TBI and hematopoietic cell transplantation (HCT) for leukemia, a 7% incidence of leukoencephalopathy has been observed among patients who received pretransplant CNS treatment and posttransplant intrathecal therapy.278Symptoms often become evident 4 to 6 months after TBI. A cerebral MRI scan will be abnormal. Reversible neurotoxicity has occasionally been reported in patients treated with cyclosporine, tacrolimus or high-dose acyclovir.279


Two very large studies have reported the increased incidence of solid tumors and post-transplant lymphoproliferative disease (PTLD) based on data collected from more than 14,000 patients by the International Bone Marrow Transplant Registry (IBMTR) and more than 4000 patients by the Seattle group.280-285 Using these combined data, Socié and colleagues recently reported the separate analysis of 3182 children transplanted before age 17 for acute leukemia.140 A 34-fold increased risk of solid tumors at a median of 6 years (range 0.3 to 14.3 years) was observed posttransplant. Types of solid tumors in order of frequency included brain tumors, thyroid papillary carcinoma, melanoma, squamous cell carcinoma of the tongue, salivary gland mucoepidermoid carcinomas, osteosarcomas, and malignant fibrous histiocytoma. Of children surviving 10 years post transplant, the cumulative incidence for solid tumors was 1.7% and 3.9% at 10 and 15 years, respectively. Multivariate analyses showed an almost 4-fold greater risk for the development of solid tumors in children ages infant to 9 years compared to children ages 10 to 16. Children who received high-dose TBI were approximately 3 times more likely to develop solid tumors than children who received no or low-dose TBI. Brain and thyroid tumors occurred in 14 children, accounting for more than half of the solid tumors; 9 of these 14 children had received cranial irradiation in addition to TBI. The association of brain and thyroid tumors with children ages infant to 9 years at transplantation was even stronger than for solid tumors as a group, suggesting that brain and thyroid are highly sensitive to the effects of irradiation at very young ages. Interestingly, no solid tumors developed in the 416 children who received non-radiation–based preparative regimens (315 received BU/CY).

Anticipatory guidance and ongoing surveillance are crucial for early detection and effective treatments for secondary neoplasms.


The analysis by Socié et al. showed a 182-fold increase in risk for B-cell posttransplant lymphoproliferative disease (PTLD).140 The overall actuarial incidence of PTLD was 1.0% at 5 years post transplant. The prognosis of PTLD in marrow transplant patients has been dismal.287,288 This is partly because discontinuation of immunosuppression, which has helped to control PTLD after solid organ transplants, is usually not feasible in marrow transplant recipients because of the potentially serious risk for flares of GVHD. More recently, promising treatment approaches have included alpha-interferon, anti-IL-6 antibody, cellular therapy and anti-B-cell antibodies.289-291

Table 133-3. Classification of Graft-Versus-Host Disease (GVHD)


The approach to monitoring for potential complications of hematopoietic cell transplantation (HCT) are listed in Table 133-3. Anticipatory guidance regarding potential complications is essential. The evaluation of the HCT survivor should include a thorough physical exam and a particularly detailed inspection of the skin, oral cavity, and thyroid gland for neoplastic growths. Benign melanocytic nevi have frequently been observed after chemoradiotherapy and may have an increased risk for melanoma.304 Investigations should include periodic complete blood counts to monitor for myelodysplasia and secondary leukemias.


Pediatric transplant recipients may acquire the immunity of the donor, or may lose serologic evidence of immunity. Because recovery of immune function after HCT is variable, it is unwise to rely on a generalized schedule for immunization. The approach to immunization should be individualized and guided by the patient’s transplant center. Similarly, immunization of household members should also be guided by the transplant center. Generally, healthy survivors can be immunized with inactivated bacterial and viral vaccines 6 months to 1 year after HCT, and they can receive live vaccines, including MMR and varicella, 2 years after HCT. Patients with chronic graft-versus-host disease (CGVHD) should not receive live virus vaccines because of concern about resulting latent virus infection and its sequelae. Passive immunization is recommended for susceptible children with known exposure to varicella. Only IPV vaccine should be given to transplant recipients and their household contacts. Household and health care worker contacts of stem cell and solid organ transplant recipients should have immunity to or be immunized against poliovirus, measles, mumps, rubella, varicella, influenza, and hepatitis A.


Two studies pertaining of pediatric bone marrow transplantation demonstrate overall improvement in quality of life by 6 months post transplant.280,281 Family cohesion and the child’s adaptive functioning were highly predictive of quality of life and behavioral adjustment. However, when compared with age- and sex-matched siblings or friends, survivors of childhood marrow transplant appear to have more health care needs as adults. Major illness was more often reported by marrow transplant survivors (21%) compared with chemotherapy patients (3.5%), and control subjects and marrow transplant recipients perceived themselves as having more limited physical function, poorer general health, and increased bodily pain.