eMedicine Specialties > Pediatrics: General Medicine > Oncology

Bone Marrow Transplantation, Long-Term Effects

Author: Girindra G Raval, MD, Staff Physician, Department of Internal Medicine, University of Arkansas Medical School
Coauthor(s): John R Wingard, MD, Associate Director of Clinical and Translational Research Cancer Center, Director of Bone Marrow Transplant Program, Professor, Departments of Pediatrics and Medicine, Division of Hematology/Oncology, University of Florida; Paulette Mehta, MD, Chief, Hematology-Oncology Firm, VA Hospital of Arkansas, Professor, Department of Pediatrics, Departments of Internal Medicine, Pediatrics, Bone Marrow Transplantation, University of Arkansas for Medical Sciences
Contributor Information and Disclosures

Updated: Jul 31, 2006

Introduction

Many children are surviving hematopoietic stem-cell transplantation (HSCT) and require long-term follow-up care. The number of late HSCT survivors is expected to increase as new indications for transplantation emerge, as donor pools expand, and as supportive care improves. Long-term survivors have special risks and need particular types of screening, prevention, and treatment. Risks for long-term survivors are related to their underlying malignancy, which places them at life-long risk for recurrent disease. Other risks are related to the high-dose chemotherapy and/or radiation therapy used as conditioning for HSCT. These therapies place patients at risk for organ damage, secondary malignancy, endocrinopathies, reproductive failure, and psychosocial adverse sequelae. For patients undergoing allogeneic transplantation, graft versus host disease (GVHD) and autoimmunity are other late problems for many survivors.

The number of long-term survivors of HSCT will increase as the unrelated donor pool continues to expand and as use of umbilical-cord blood gains further acceptance. Use of umbilical-cord blood for transplantation has increased since this article was first reviewed. More children with primary immunodeficiency states, such as Wiskott-Aldrich syndrome, severe combined immunodeficiency, or X-linked hyper-immunoglobulin (Ig) M have received cord-blood transplants from unrelated donors. The present authors and others have described increasing use of such transplants for children with sickle cell disease (Adamowitz, 2004). These children have had outcomes comparable to those of children receiving human leukocyte antigen (HLA)–matched stem cells from related donors (Tsuji, 2006).

Patients who are receive HLA-haploidentical T cell–depleted stem cells remain at high risk for a lack of engraftment, posttransplantational complications, and relapse of disease. A study of prognostic markers after transplantation in 113 patients who underwent HSCT for malignant and nonmalignant diseases showed that patients with eosinophil counts >500 X 10⁶/L on at least 2 consecutive days after HSCT) had an overall survival rate higher than that of patients who did not have eosinophilia (88.7% vs 43.0%, P = .0034). For the group who underwent HSCT for malignant diseases event-free survival rates (81.1% vs 44.6%, P = .0025) and relapse rates (16.0% vs 43.0%, P = .0287) were better for those with eosinophilia than for those without eosinophilia (Sato, 2005).

Another reason for increasing numbers of stem-cell transplantations (SCTs) is the growing readiness of insurance companies to fund these procedures because the costs relative to those of conventional therapy are not excessive, particularly when peripheral blood is used instead of bone marrow. One study showed that the cost of peripheral blood SCT (PBSCT) was 29% less than that of bone marrow transplantation (BMT) among children with solid tumors or lymphomas. This analysis was limited to direct costs incurred during the patient's hospital stay for the transplantation (Hartmann, 1997). Although most cost analyses of HSCT have involved adults or mixed samples of children and adolescents, derivations related to the pediatric population indicate that early transplantation during a first remission of malignancy are more cost-effective than transplantation done later (Barr, 2003).

Many of the special concerns of long-term survivors were highlighted in a recent study of the European Bone Marrow Transplant Registry. Of 798 patients who survived > 5 years after transplantation, 328 were children. Although most were apparently well, survivors at 10 and 15 years after HSCT continued to have an increased risk of death compared with age- and sex-adjusted population norms. Causes of death were related to relapse of the underlying cancer or the development of a new cancer, chronic GVHD, or transfusion-acquired viral infection. Certain patients were at higher risk for late morbidity and mortality than others; high-risk patients including male subjects, recipients of stem cells from female donors, patients younger than 10 years, those with nonidentical donors, and those who received radiation therapy. The types of health problems these late survivors had are listed in the table below and discussed later.

Table 1. Health Problems in Long-Term Survivors after BMT

Open table in new window

^* 50-100% is very common, 20-50% is common, <20% is uncommon.

Increasing indications, acceptance, and survival after SCT will all contribute to growing numbers of children and adult survivors of SCT. This review highlights the special needs of children who survive long term after HSCT. The clinical manifestations of late complications are discussed so that the physician can recognize them early. Specific screening and prevention measures that can lessen the risk of disease recurrence, infections, secondary malignancy, and other complications are suggested. Summary schemas displaying screening and revaccination schedules, pathogenesis of complications, and relative frequency and duration of complications after different types of HSCT are provided.

Immunosuppression and GVHD After Transplantation

Immunosuppression

Immunity, conditioning before transplantation ablates, returns only slowly after engraftment. The speed with which immune function recovers after HSCT depends on many factors: the type of graft (allogenic, autologous, syngenic, T-cell repleted, T-cell depleted), the presence or absence of acute or chronic GVHD, the conditioning regimen used, the type of postgrafting immunosuppression, and the underlying disease for which HSCT was undertaken. Immune function is impaired for the f4-5 months after HSCT with non–T cell–depleted irrespective of these factors.

Cytotoxic and phagocytic functions are recovered around 100 days after non–T cell–depleted transplantation . The recovery of suppressor T-cell function follows, and the finely tuned function of helper T cells is the last to recover after 1 year or longer. Full reconstitution is completed within 1-2 years, but chronic GVHD and its treatment can cause a delay (Lum, 1987). Therefore, patients are at risk for bacterial, viral, and fungal infections during the entire first year after HSCT and sometimes longer.

Immunization with protein antigen immediately or soon after HSCT cause levels of antibodies to rise but only transiently. In contrast, delaying immunization until the time of T-lymphocyte recovery (ie, 6-12 mo after HSCT) allows for sustained antibody production.

A prospective study of 64 children undergoing transplantation with T lymphocyte–depleted marrow from matched family donors or matched unrelated donors showed that the postprocedural T-lymphocyte response to T-cell alloantigen normalized after 9 months. The response to nonspecific antigen (eg, phytohemagglutinin, concanavalin A) stayed impaired until 12 months after transplantation, and the response to specific antigen (eg, tetanus toxoid, Candida albicans antigen) was delayed and did not normalize until 36 months. The CD3⁺ count, and not the CD4/CD8 ratio, was related to the recovery of the T-cell response. Acute cytomegaloviral (CMV) infection after transplantation delayed recovery of the lymphocytic mitogenic response (Kook, 1997). In addition, young recipients and donors had increased mitogenic responses and lymphocyte counts after transplantation (Kook, 1996).

Severe hypogammaglobulinemia, which occurs as a part of chronic GVHD, can increase the frequency of infections. Treatment with Igs can reduce the frequency of infections in patients with severe hypogammaglobulinemia (Copelan, 2006).

Types of GVHD

GVHD can be divided in 2 classes depending on when it occurs after transplantation. Acute GVHD is defined as GVHD occurring within 100 days after transplantation, and chronic GVHD is GVHD occurring after 100 days.

Chronic GVHD

Certain patients, including those who received transplants from HLA-nonidentical donors, those with previous acute GVHD, and those older than 20 years at the time of transplantation are more predisposed to develop chronic GVHD than others (Atsuta, 2006; Sohn, 2006). Methods to reduce GVHD, particularly T-cell depletion, continue to be used, though posttransplantational infections remain problematic (Lynch, 2003).

Predictive factors of chronic GVHD include the type of prophylaxis administered and ongoing chronic viral infections. Recipients of peripheral blood allografts are at increased risk for chronic GVHD. Findings from a recent meta-analysis from 9 randomized trials of 1111 patients supported this risk. The overall incidence of chronic GVHD among patients who underwent PBSCT was 62% compared with 52% among those who underwent BMT (odds ratio [OR] = 1.92; 95% confidence interval [CI], 1.47-2.49; P <.001) (Stem Cell Trialists' Collaborative Group, 2005).

Negative prognostic factors of chronic GVHD after allogeneic PBSCT includes a donor positive for CMV, acute GVHD after transplantation, and non-lymphomatous underlying disease for which the transplantation was undertaken. Also, a duration of disease of > 3 years after the diagnosis of chronic GVHD, a platelet count of <100 X⁹/L ( <100 X³/mm³), and a history of acute hepatic GVHD was associated with worsened survival in 66 patients (95% CI, 65-93%; P < .001) (Pavletic, 2005).

Many organs and systems can be involved, especially the skin, liver, eyes, mouth, lungs, GI tract, and neuromuscular system. Histology of samples of affected skin shows markedly decreased numbers of Langerhans cells, deposition of lymphocytes, and Ig complexes. Hepatic involvement is less common in chronic GVHD than in acute GVHD and usually reflects cholestatic abnormalities, with hyperbilirubinemia and, in rare cases, cirrhosis. Keratoconjunctivitis sicca also occurs; patients present with ocular burning, irritation, and photophobia. Keratoconjunctivitis sicca can be diagnosed by performing the Schirmer test for tear production.

Although chronic GVHD can resemble Sjögren syndrome because of the presence of xerostomia, xerophthalmia, and probable enlargement of the salivary glands. Laboratory evidence of autoantibodies, ie, anti-Ro (SS-A) and anti-La (SS-B), along with high percentage of CD8 lymphocytes compared with CD4 lymphocytes help to differentiate these 2 entities. Anti-La had a high diagnostic specificity of 83% (n = 35) in the detection of Sjögren syndrome (Venables,1989). An uncommon but particularly severe manifestation is bronchodilator-resistant obstructive lung disease, which sometimes progresses to bronchiolitis obliterans. This disease more commonly occurs in patients previously treated with methotrexate, in those who have hypogammaglobulinemia, or in those who received GVHD prophylaxis with methotrexate.

Although GI involvement is less common in chronic GVHD than in acute GVHD, it can result in severe dysphagia, pain, and weight loss. Multiorgan chronic GVHD is associated with more weight loss than GVHD confined to 1 organ. Multiorgan chronic GVHD often results in growth retardation (Browning, 2006).

In rare instances, nephrotic syndrome, bullous esophagitis, hemolytic anemia, and unexplained effusions can occur. Also, patients who have chronic GVHD, especially those receiving immunosuppressive therapy for chronic GVHD, are at increased risk for Pneumocystis carinii pneumonia (PCP) or Toxoplasma gondii infection. Patients receiving treatment for chronic GVHD and those with CD4⁺ count <0.2 x 10⁹/L should receive trimethoprim-sulfamethoxazole prophylaxis. This prophylaxis should be continued for several weeks after immunosuppressive therapy is discontinued. Cardiac involvement is distinctly uncommon, though findings consistent with chronic GVHD have been identified in the myocardium of some patients. Also reported is complete heart block in an infant, which was presumably secondary to chronic GVHD. Thrombocytopenia may occur, and autoimmune hemolytic anemia (AIHA) or eosinophilia occasionally occurs in association.

No specific laboratory tests are available to detect, monitor, or follow up chronic GVHD. Definitive diagnosis of GVHD is possible with histopathologic examination of the biopsy material, along with clinical correlation. However, some patients may have serum evidence of autoimmunity or altered cytokine production.

Ongoing studies are being conducted to prophylactically decrease the risk and the severity of GVHD after SCT. A pilot study to evaluate the effects of prophylactic metronidazole showed that the incidence of acute GVHD among 19 patients treated with metronidazole from 14 days before to 35 days after allogenic HSCT was lower than that of 85 subjects in the control group who were not treated with metronidazole. The relative risk (RR) for GVHD in the treated group was 0.36 (95% CI, 0.13-0.997; P = .05) (Guthery, 2004).

Another interesting finding was that patients with Fanconi anemia who underwent SCT had a lower-than-expected rate of GVHD when they received CD34-selected progenitor cells from peripheral blood (Boyer, 2005).

Methotrexate and cyclosporine A continue to be the mainstays for GVHD prophylaxis. Incidences of GVHD are similar with both the regimens (Koga, 2003). Also, a regimen of cyclosporine and mycophenolate mofetil (n = 21) for GVHD prophylaxis was associated with hastened hematopoietic engraftment (11 vs 18 d; P <.001), a decreased incidence of mucositis (21% vs 65%; P = .008), and equal incidence of acute GVHD compared with a regimen of cyclosporine and methotrexate (n = 19) (Bolwell, 2004).

Different treatments have had variable success in managing chronic GVHD. These treatments include prednisone in combination with tacrolimus or cyclosporine, mycophenolate mofetil, psoralen–UV-A (PUVA), extracorporeal photopheresis, ursodeoxycholic acid, antithymocyte globulin (ATG), azathioprine, thalidomide, daclizumab, hydroxychloroquine, infliximab, and others.

A survey of the management of chronic GVHD in 92 adult and pediatric transplantation programs participated showed that only systemic corticosteroids, cyclosporine, and mycophenolate mofetil were successful in >10% of the responders (Lee, 2002). Pentostatin has some activity in patients with steroid-resistant acute GVHD.

A preliminary trial of the efficacy of pentostatin in chronic GVHD was performed in 5 pediatric patients. The investigators found an early improvement in the skin and oral symptoms in all 5 patients and no increase in the incidence of infection in patients treated with pentostatin. These positive results need further confirmation in other trials

For skin involvement, only PUVA may be successful. Photopheresis (a derivative of PUVA therapy in which lymphocytes are treated with psoralen and UV light) may be effective in refractory, systemic, chronic GVHD. Artificial tears may alleviate dryness, and sunscreen lotion can prevent activation of skin GVHD. For patients with fascial thickening, range-of-motion exercises are important to prevent contractures.

Secondary Malignancies After Transplantation

Secondary malignancy is a risk after radiation therapy alone, chemotherapy alone, and combined chemotherapy and radiation therapy. These risks also apply to patients who undergo HSCT. Whether the risk is higher in these patients than in patients undergoing standard high-dose chemotherapy and/or radiation therapy has not yet been well defined. Secondary malignancies, especially lymphomas, can occur after HSCT.

One type of lymphoma, which is associated with Epstein-Barr virus (EBV), is called B-cell lymphoproliferative disease (BLPD). It may be fatal and occurs with the highest frequency in patients who receive T cell–depleted bone-marrow donor cells. Although T cell–depleted HSCT is associated with a decreased incidence of acute GVHD, it is also associated with increased risk for monoclonal BLPD.

Post-HSCT treatment with antilymphocyte globulin (ALG) and ATG can also be given as prophylaxis for GVHD. ATG is associated with increased depletion of T lymphocytes, including those active against EBV-infected cells. It was associated with an increased incidence of monoclonal BLPD compared with ALG for the GVHD prophylaxis (hazard ratio, 3.57; P = .001) (Lynch, 2003).

In a recent review, Faye and Vilmer (2005) suggested that anti-EBV cytotoxic T lymphocytes (CTLs), cytokine inhibitors, and anti–B-cell antibodies (eg, Campath) might reduce risk for these lymphoproliferative diseases. The present authors and others have demonstrated the treatment benefit of rituximab in B-cell that does not responding to the cessation of immunosuppression alone (Skoda-Smith, 2001). Subsequent reports showed that rituximab can be helpful in patients with a high EBV viral load and in EBV-associated lymphoproliferative disease after HSCT (Gruhn, 2003). The risk of monoclonal is reported to be 0.6% after allogeneic BMT (Zutter, 1988). Amplified copies of the EBV genome reside within lymphocytes.

B-cell posttransplantational lymphoproliferative disorder (PTLD) can be monoclonal, oligoclonal, or polyclonal. Patients with the monoclonal form have survival rates poorer than those of patients with the polyclonal form. Polyclonal EBV lymphoproliferative disorder may resolve with a suspension or decrease of immunosuppression with or without the use of Ig, acyclovir, or interferon. However, monoclonal disease usually does not respond to such simple measures, and chemotherapy with or without radiation therapy may be required.

Monoclonal antibody therapy that targets B-cell antigens, such as rituximab (anti-CD20), can also be effective. Survival rates for patients with monoclonal EBV lymphoproliferative disease who receive donor lymphocyte infusions are associated with sustained remissions in patients with relapsed or residual lymphoid malignancy after allogenic SCT (Russell, 2005).

PTLD is usually associated with EBV and is B-cell type in origin. T-lymphocyte dysfunction after transplant secondary to immunosuppression, allows the EBV-infected B lymphocytes to proliferate in uncontrolled fashion. This proliferation allows B-cell PTLD to develop.

T-cell PTLD is rare, with only a few cases reported in the literature. The incidence is higher after solid-organ transplant than after SCT (10-12% vs 1-2%) (Yufu, 2000). In a recent report, Tatsuya et al suggested that EBV can infect B and T cells and induce clonal proliferation in immunocompromised patients after allogenic HSCT. Anti-EBV CTLs and anti-CMV CTLs may have a role in the prevention or treatment of PTLD, and trials to study this possibility are underway.

Approximately 1-2 cases of B-cell PTLD per 100 exposure-years occur in the first year after BMT (Kolb, 1992). In addition to lymphoid malignancies, solid tumors also occur after SCT. Curtis et al (1997) reported a higher-than-expected rate of malignancies. These primarily affected patients who were younger than 10 years at the time of treatment, those who received total-body irradiation (TBI), and those who developed GVHD. Skin and oropharyngeal cancers are especially common.

Endocrine Abnormalities

The endocrine system suffers a disproportionate toll after HSCT. Gonadal, growth, and thyroid failure are the most common sequelae. These disturbances are often underappreciated, yet they seriously disrupt the patient's quality of life.

Growth problems

Growth problems are most common and severe in patients receiving TBI-containing regimens. Patients with neuroblastoma who undergo autologous transplantation that includes TBI often have growth failure that is more persistent and severe than that observed in patients treated for leukemia. In addition, these patients are unlikely to catch up or to respond to growth-hormone treatment, probably because of radiation therapy to the spine and pelvis that they receive at an early age. Some patients have growth retardation immediately after SCT. This is often due to steroids and/or TBI exposure. Other children develop growth retardation after many months or years. This type is most likely to be associated with impaired puberty development and may be most amenable to pharmacologic adjustments, such as sex-hormone replacement therapy (Narumi, 2006).

Gonadal failure

High-dose alkylator and radiation therapy invariably affect ovarian and testicular function. The degree and the duration of gonadal failure depends on the dose of radiation therapy received and the age at which it is received. Pubertal and postpubertal female patients at the time of transplantation almost always develop ovarian failure manifested by high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) with or without decreased estrogen levels. These females patients are at risk for early osteoporosis, bone fractures, lipid disorders, and atherosclerotic heart disease. Associated use of steroids and radiotherapy potentiates the risk of osteoporosis.

Ovarian failure after HSCT responds well to estrogen replacement. Known risks of estrogen (ie, predisposition to endometrial and breast cancer) must be weighed against the risks of bone and heart disease. The role of bisphosphonates to help prevent osteopenia and to reduce the risk of fractures in patients with osteopenia may be promising in patients undergoing chemotherapy. However, bisphosphonates have not been systematically studied in patients undergoing HSCT.

In prepubertal female patients, the risk of ovarian failure is approximately 50%, whereas the risk is about 90% in older female patients, depending on the dose of radiation used in the preparative regimen. For example, Sarafoglou et al (1997) showed that 9 (56%) of 16 prepubertal girls (mean age of 6.1 y at the time of HSCT) progress to normal puberty with a normal onset of menses and normal estrogen levels after undergoing HSCT with high-dose chemotherapy and hyperfractionated TBI. However, many patients continue to have high LH and FSH levels, which represent subclinical early ovarian failure. The remaining 7 girls (mean age, 8.6 y) required hormone-replacement therapy for biochemical and hormonal ovarian failure after HSCT. Hormonal suppression of the ovaries before transplantation may increase the recovery of ovarian function afterward (Dann, 2005). Whether prepubertal female patients regain normal fertility is not yet known; also unknown is the duration of fertility if it is achieved.

Female patients who regain their reproductive potential and who become pregnant after HSCT have a high risk for pregnancy complications, including premature deliveries (20% in patients vs 6% in the healthy population) and low-birth-weight infants (23% in patients vs 6% in the healthy population), and cesarean delivery (42% in patients vs 16% in the healthy population) (Salooja, 2001). However, rates of infant congenital anomalies and malignancies are not increased. In the converse, women partners of men who have undergone and survived HSCT do not have high risk of having pregnancy complications.

About 90% of prepubertal male patients undergo puberty normally and maintain testosterone levels in the reference range. The resistance of male gonads to chemotherapy and radiation therapy is a function of increased numbers of Sertoli cells in prepubertal boys compared with that in postpubertal male adolescents and men. However, men may develop testosterone deficiency. The decline in the male gonadal function is less recognized than its counterpart in female patients, but is likely to involve medical and psychosocial complications.

Other hormone abnormalities

Other hormone abnormalities include thyroid dysfunction with decreased thyroid hormone production and increased thyroid-stimulating hormone (TSH). These patients may present with signs of hypothyroidism and require replacement therapy. A study of survivors of 72 HSCT aged 16-56 years with no history of thyroid dysfunction showed that 6% of male patients and 5% of female patients had overt hypothyroidism (basal TSH level >8 µIU/mL, free thyroxine [T4] level <0.8 ng/dL) after a mean follow-up of 1.5 years (range, 0.2-9.8 y). About 13% of male patients and 5% of female patients were having subclinical hypothyroidism (basal TSH level of 4-8 µIU/mL with a low normal free T4 level of 0.8-1.9 ng/dL) (Somali, 2005).

Organ Dysfunction After Bone Marrow Transplantation

A major concern after HSCT is long-term residual damage to organs from chemotherapy and radiation therapy. Because tissue damage due to chemoradiation may result in permanent organ damage, many patients are likely to have long-term organ damage after transplantation.

Pulmonary abnormalities

Few children surviving HSCT have clinically significant pulmonary symptoms, yet 25-50% of surviving children have abnormal pulmonary function test (PFT) results. Etiologic factors for pulmonary restrictive syndrome are chemotherapy, scoliosis, kyphosis, thoracotomy, post-HSCT interstitial pneumonitis, and GVHD. Pulmonary restrictive syndrome is most common in patients who treated with TBI. CMV pneumonitis is associated with a mortality rate of approximately 30-40%. This rate may decrease with improved screening for CMV activation and with improved antiviral agents (de Medeiros, 2000). Interstitial pneumonitis occurs in 20-50% of patients after allogeneic HSCT and in 10% of patients treated with autologous HSCT. It generally occurs in the first 4 months after HSCT, but it can occur later than this.

The mechanism of noninfectious pulmonary abnormalities appears to be immunologic, similar to GVHD, as manifested by the increased severity of these changes when transplants are obtained from allogenic donors (Cooke, 2006).

Diffuse alveolar hemorrhage (DAH) is a noninfectious complication and occurs within 1-4 weeks after transplantation. It manifests with dyspnea, hemoptysis, hypoxemia, a decreased hematocrit, diffuse chest infiltrates, an increased alveolar-arterial (A-a) gradient, and restrictive ventilatory defects (De Lassence, 1995). Early treatment with high-dose corticosteroids is beneficial in these patients (Haselton, 2000).

In different studies, the incidence of DAH was 1-21% in autologous transplant recipients and 2-17% among recipients of allogenic HSCT. The diagnosis is suggested by alveolar and interstitial infiltrates on chest radiographs and by blood- or hemosiderin-laden macrophages on bronchoalveolar lavage (BAL) specimens (Afessa, 2002). DAH is associated with intensive pretransplantation chemotherapy, TBI, and old age at the time of transplantation (Robbins, 1989; Crilley, 1995).

Researchers comparing the efficacy of low- and high-dose corticosteroids for the treatment of DAH showed that high-dose methyl prednisone >30 mg/day decreased the mortality rate and the incidence of mechanical ventilation compared with low-dose steroids (methyl prednisone £ 30 mg) (Metcalf, 1995; Haselton, 2000).

Among patients undergoing unrelated-donor SCT, the incidence of late-onset noninfectious pulmonary complications (LONIPCs) such as bronchiolitis obliterans organizing pneumonia (BOOP) and interstitial pneumonia was 26% (n = 39). Advanced-stage disease at time of transplantation and the presence of chronic GVHD are associated with an increased risk of these late-onset complications (Patriarca, 2004). Also, the overall cumulative incidence of BOOP 2 years after allogenic SCT was lower in patients who receive a reduced-intensity conditioning regimen (fludarabine, busulphan and/or cladribine) compared with patients who receive a myeloablative conditioning regimen (busulphan, TBI, and/or cyclophosphamide), with rates of 17% versus 2.3% (n = 144, P = .024). The development of BOOP within 200 days of transplantation is associated with a worsened prognosis, compared with BOOP occurring after 200 days (P = .003) or a lack of BOOP (P = .002) (Yoshihara, 2005).

Bronchiolitis obliterans (BO) carries a mortality rate of 50% among recipients of allogenic HSCT (Au, 2001). Symptoms are persistent cough, wheezing, and recurrent respiratory tract infections. Chest radiography and CT may reveal patchy infiltrates, though a definitive diagnosis is established by means of bronchoscopy with transbronchial biopsy. Treatment is based on immunosuppressive therapy, such as mycophenolate-azathioprine and prompt treatment of infection (Socie, 2003).

Cerveri et al (2001) prospectively examined 75 pediatric patients with leukemia who underwent allogenic or autologous HSCT. At 3-6 months, a restrictive pattern on PFT was the most frequent abnormality. Predictors for late PFT abnormalities were advanced primary disease at the time of transplantation, (P = .005) and bronchopulmonary infections after transplantation (P <.05).

Obstructive lung disease can be detected in as many as 20% of survivors after HSCT, and they are frequently associated with IgG and IgA deficiency, chronic GVHD, infections, methotrexate use, and TBI (Clark, 1989). Patients with Ig deficiency should be given IVIg infusions, and asymptomatic patients with abnormal PFT results should be closely monitored for the development of overt pulmonary disease. Pulmonary complications also correspond to the total radiation dose given during conditioning, the dose rate, and the dose fractionation scheme of TBI (Morgan, 1996; Chen, 2001).

Cardiac abnormalities

The major risks of long-term cardiotoxicity are related to treatment before HSCT, particularly anthracycline therapy at doses >300 mg/m² (Fujimaki, 2001; Sakata-Yanagimoto, 2004), ablative-dose cyclophosphamide >150 mg/kg, chest radiation therapy, TBI (especially if not fractionated), and high-dose steroids. Most patients have some cardiac dysfunction during and immediately after HSCT, and as many as 50% have persistent abnormalities. However, these abnormalities are usually subclinical and rarely limit the patient's quality of life.

Cardiac dysfunction may not be identified with conventional testing at rest. For example, Larsen et al (1992) found significant cardiotoxicity during exercise stress echocardiography in 50% of their pediatric patients at 7 years after HSCT. Abnormalities included decreased exercise time, decreased maximal oxygen consumption, and decreased ventilatory anaerobic thresholds. Only 10% had abnormalities after echocardiography at rest, and none had abnormalities on ECG alone. The degree of cardiac abnormalities varied with the underlying disease. Akahori et al (2003) suggested that prolongation of the QTc interval before HSCT was strongly associated with onset of acute heart failure after HSCT. Cardiac reserve (ie, increased cardiac output with exercise) was an important prognostic factor for peritransplantional mortality among patients younger than 43 years (Zangari, 1999).

In 1 study, patients who received little or no therapy before HSCT (eg, those with aplastic anemia) had significantly fewer abnormalities than those who were heavily pretreated with thiotepa plus cyclophosphamide and TBI (Fujimaki, 2001). This finding suggesting that the damaging effects may be related to cumulative chemotherapy and radiation toxicity rather than to the HSCT itself. However, almost all HSCT regimens contain ablative-dose cyclophosphamide, which can cause hemorrhagic myocarditis, especially in patients with preexisting cardiac injury. Radiation therapy further enhances this toxicity.

Cardiotoxicity increases over time, even without further therapy for the underlying disease for which transplantation was done. Larsen et al (1992) showed that children who survived HSCT for <3 years had fewer abnormalities than those who had survived for >3 years, even when they were treated with similar preparative regimens. The authors speculated that this discrepancy over time is related to loss of reserve of heart muscle, early progression of atherosclerosis, or even chronic GVHD.

Heart attack was reported to be a potential manifestation of GVHD after HSCT. Myocardial GVHD is exceedingly uncommon (Kupari, 1990). Hormonal changes may predispose patients to heart disease. Almost all postpubertal women and one half of prepubertal girls develop estrogen deficiency and lose the normally protective effects of estrogen against coronary artery disease. Deficiency of estrogen accelerates coronary artery disease. Some suggest that anthracycline-induced cardiotoxicity may be reduced with the concurrent use of dexrazoxane (Erlaky, 2006). Responses to low-dose dobutamine stress echocardiography were better in patients treated with doxorubicin and dexrazoxane than among patients treated with doxorubicin alone (Paiva, 2005). Amifostine also may have a cardioprotective effect when used with anthracyclines (Catino, 2003).

Renal complications

Kumar et al (1996) showed that most children undergoing HSCT have normal renal function years after treatment. Of children examined for more than 6 years from the time of transplantation, 89% had normal renal function. The other 11% were asymptomatic but were had hemofiltration abnormalities or hyposthenuria on testing.

Hemorrhagic cystitis is a rare but serious complication after HSCT. Risk factors for hemorrhagic cystitis are a relatively old age at the time of transplantation, vesical irradiation, use of cyclophosphamide or busulfan in the pretransplantation regimen, and prolonged aplasia after transplantation (Thomas, 1987; Brugieres, 1989; Morgan, 1991). Early development is associated with use of high-dose cyclophosphamide before transplantation, and it can be prevented with use of sodium 2-mercaptoethane sulfonate (mesna) and abundant hydration.

Late-onset hemorrhagic cystitis is sometimes associated with BK virus, JC virus, adenoviruses and/or polyoma viruses, though a cause-effect relationship has not been proven. Vidarabine has been used to successfully treat hemorrhagic cystitis caused by JC virus and BK virus (Seabra, 2000). Vidarabine decreases urinary excretion of adenovirus and BK virus, and it improves hematuria associated with cystitis caused by these viruses in patients undergoing HSCT (Kawakami, 1997). Case reports have described the successful treatment of BK virus–associated hemorrhagic cystitis with cidofovir (Held, 2000).

Infectious complications

Sepsis is a known complication in patients with HSCT and is associated with immunosuppression after HSCT. Several acute-phase reactants may be useful in predicting the outcome of infection, including C reactive protein, procalcitonin, and endotoxin (Sauer, 2003). Immunosuppression also increases the risk of opportunistic infections, such as CMV and invasive fungal infections. HSCT involving an unrelated donor and increased age at the time of transplantation are associated with an increased risk of CMV disease. A polymerase chain reaction (PCR) for CMV DNA can be used to detect CMV in the early stages of disease and thereby allow for an early start of treatment and improved results (Ljungman, 1998).

Infections with human herpes virus (HHV) has emerged as a possible complication after STC. In 1 recent study, Khanani et al (2006) found HHV-7 in 9 children undergoing allogeneic transplantation. The infection was associated with increased risk of acute GVHD. Manifestations ranged from GI disease to septicemia to septic shock.

GI complications

Mucositis is a common complication after HSCT. A study was done to compare glutamine and glycine 2 g/mg twice a day for 28 days after transplantation showed that this preventive therapy decreased mucositis severity (n = 120, P = .07). Glutamine reduced the duration of IV narcotic use (P = .03), and decreased use of total peripheral nutrition (TPN) (P = .01) compared with glycine (Aquino, 2005). However, studies have not been definitive.

Keratinocyte growth factor has been used to prevent conditioning-related mucositis. Radtke et al (2005) recently reviewed use of the recombinant form of keratinocyte growth factor, ie, palifermin. Grade 3 or 4 oral mucositis was significantly reduced in patients who received the growth actor before transplantation (63% vs 98% in the control group, P <.001). Moreover, in patients who developed grade 3 or 4 oral mucositis, the duration was significantly shortened when they were pretreated with palifermin (6 vs 9 d).

Hematologic abnormalities

AIHA and alloimmune hemolytic anemia are recognized complications of HSCT. AIHA occurs with increasing frequency in patients receiving an unrelated-donor transplant and in those undergoing transplantation for nonmalignant diseases (O'Brien, 2004).

Harvesting of peripheral stem cells is associated with engraftment earlier and better than that of bone-marrow harvesting, and it is becoming frequently used.

Dental, cranial, and facial abnormalities

Many patients have dental complications after SCT. Vaughn et al (2005) reviewed dental complications in 27 patients aged 1-18 years who underwent HSCT. The rate of dental abnormalities was high. Abnormalities included serious gingivitis in 60% of patients, parodontal involvement in 4%, dentofacial abnormalities in 56%, tooth agenesis in 63%, and dental root hypoplasia in 33%. Patients who received and those who did not receive radiation therapy were affected equally. A young age at time of HSCT was a risk factor. Causative factors included drug and irradiation toxicity, difficulty in maintaining adequate active oral hygiene, frequency of bacterial infections of the oral mucosa, and xerostomia (which occurred in most patients after HSCT). Other investigators have shown similarly high rates of dental abnormalities in the long-term follow-up care of children after HSCT.

One proposed reasons for dental complications is reduced salivary-gland secretion after SCT. Dahllof et al (1997) showed that salivary secretion was decreased in 26 patients for as long as 4 years after HSCT, especially in those who received TBI. Decreased salivary secretion resolved within 4 years in most patients who received conditioning with chemotherapy, but it persisted in all who received TBI as preparation. This finding suggested that the damage to salivary glands may be permanent after radiation. Patients with impaired salivary secretion also had concomitant increased counts of mutans streptococci and lactobacilli compared with patients with normal salivary flow and healthy age- and sex-matched children. However, despite these abnormalities, children receiving chemotherapy alone, those receiving chemotherapy plus irradiation, and healthy children had similar rates of dental caries. Therefore, patients may not develop serious caries if oral hygiene is sufficient.

Neurologic abnormalities

Encephalopathy is a known complication of HSCT. It may be due to irradiation of the CNS, chemotherapy crossing the blood-brain barrier, infections, hypoxia, or other factors. It is often associated with immunosuppression and multiorgan failure. Many cases progress to dementia, permanent neurologic deficits, and death. MRI, CSF analysis, and brain biopsy may help in identifying the cause of the disease (Woodard, 2004).

Eye abnormalities

Visual defects are common in children after HSCT. In a study of 100 children surviving >5 years after HSCT, almost one third had long-term visual defects (Ng, 1999).

The most common defect was subcapsular posterior cataracts or other cataracts secondary to irradiation and/or steroid treatment. The incidence of cataract after TBI is less after hyperfractionated TBI than after single-dose TBI (Aristei, 2002). The second most common problem is dry-eye syndrome, which can be a sign of chronic GVHD. Infrequent eye complications include retinal hemorrhages and panuveitis.

Early after HSCT, cortical blindness and microvascular retinopathy are the 2 main causes of deteriorating vision. Cyclosporine has been implicated in the pathogenesis of these problems. The exclusion of organic brain disease, meningitis, and encephalitis, as well as MRI and funduscopic examination, are usually sufficient for diagnosis. However, in patients who have normal results on these tests and who continue to have visual defects, electroretinograms and visually evoked cortical potentials can be used to diagnose retinal damage.

Diagnostic tests include the Schirmer test for tear production and function and corneal microscopy to detect lymphocytic deposition.

Hearing abnormalities

The incidence of ototoxicity is increased in patients with breast cancer who are treated with cyclophosphamide, thiotepa, and carboplatin as a part of the conditioning regimen for HSCT (Jillella, 2000). Hearing abnormalities are common, affecting >50% of children with neuroblastoma who survive >5 years after transplantation.

Skeletal abnormalities

Osteonecrosis, osteoporosis, and avascular necrosis of the hip or other joints or bones can occur in long-term survivors. These complications are secondary to high-dose steroids, radiation therapy, and estrogen depletion. A review of 77 patients with avascular necrosis revealed the following risk factors: acute or chronic GVHD, patient age of >16 years at time of transplantation, and an underlying diagnosis of aplastic anemia or acute leukemia. Patients who develop aseptic necrosis after HSCT respond well to joint replacement when indicated. Increasing evidence suggest that the use of bisphosphonates is associated with osteonecrosis of the jaw (Dimitrakopoulos, 2006).

Psychosocial and Cognitive Adaptation After Bmt

Children receiving HSCT are at risk for neurologic and psychological problems because of chemotherapy, radiation therapy, prolonged isolation away from home, and feelings of guilt about consuming the family's resources.

In many patients, the intelligence quotient (IQ) substantially declines between baseline and 1 year after transplantation. The decline in cognitive skills is probably related to radiation therapy and chemotherapy with agents such as cytosine arabinoside. Busulfan can cause seizures, loss of consciousness, and abnormal electroencephalographic (EEG) findings when used for myoablation, but it has not been associated with cognitive defects. Therefore, busulfan is being used to replace radiation therapy in selected protocols (Shah, 2004). Children younger than 3 years are at highest risk for decreased cognitive abilities, as measured 2 years after transplantation. Little or no decline in cognitive skills is observed in children older than 3 years after transplantation (Simms, 2002).

Posttraumatic stress disorder (PTSD) has been diagnosed in some patients. This PTSD is similar to that described in children receiving chemotherapy for cancer (Packman, 1999).

Siblings who donate bone marrow can have posttraumatic stress reactions, feelings of guilt when the HSCT does not cure the sibling, and self-esteem lower than that of control subjects. Siblings of patients with HSCT who are not selected to donate also have evidence of low self-esteem (Packman, 1999).

Several investigators have observed psychosocial distress in parents of children undergoing SCT. This distress can include anxiety as well as PTSD, especially in mothers (Manne, 2004).

Implications for Follow-up Care

The most important long-term complications in HSCT survivors include immunosuppression, relapse of primary malignancy with or without secondary malignancy, endocrinopathies, organ failure, and cognitive and psychological sequelae. Thus, physicians must be well versed in monitoring for these complications and in providing prevention and treatment for these complications when possible. Table 2 shows a schema for screening for these problems.

Table 2. Health Measures for Complications in Long-Term Survivors of BMT

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^* PCP prophylaxis is with trimethoprim-sulfamethoxazole (Bactrim) or pentamidine during first 6 months after transplant or longer if the patient is receiving immunosuppressants.

Immunosuppression

In the first year after transplantation, immunity is beginning to develop and becomes fully functional only after about 1-1.5 years in the absence of chronic GVHD. Although B-cell function usually returns within 3-6 months after transplantation, long-term immunity after vaccination requires T-cell engraftment, which occurs relatively late. Hence, it is best to vaccinate the patients a year after transplantation. Also, restimulation with specific antigens is required to regain antigen-specific immunity. Therefore, bacterial and viral infections are common, as is nonbacterial interstitial pneumonias and sinusitis.

Varicella zoster develops in at least 50% of marrow transplant recipients within the first year, and the risk of disseminated varicella zoster is high. Therefore, patients with varicella zoster should receive systemic acyclovir. Also, varicella zoster Ig prophylaxis is usually administered to patients who are seronegative for varicella and who are exposed to the virus any time within the first year after transplantation or within the first 2 years after HSCT involving an unrelated donor.

Leung et al (2000) investigated the incidence of varicella zoster infection among children after HSCT and showed that seropositivity before transplantation was the only risk factor associated with varicella zoster after transplantation on multivariate analysis. Also, acyclovir reduced the rate of posttransplantational varicella zoster infection among patients with leukemia from 36% to 25%.

The CDC has made recommendations for immunizations and prophylaxis of infections after BMT (Centers for Disease Control and Prevention [CDC], 2000). Infections by encapsulated bacteria are common and life threatening in patients with chronic GVHD because of impaired opsonizing antibody and decreased reticuloendothelial function. Antibiotic prophylaxis is recommended for patients with late GVHD. However, the CDC and other agencies have recommended that the specific type of antibiotics be selected on the basis of local antibiotic-resistance patterns.

Immunizations with protein antigen in the immediate post-HSCT period increases specific antibody levels only transiently. Delaying immunization until T-lymphocyte immunocompetence recovers (ie, 6-12 mo after HSCT) allows for sustained antibody production. Transplant recipients without chronic GVHD can be immunized with inactivated polio vaccine 6-12 months after HSCT; however, immunization with live vaccines (ie, MMR) should be delayed 2 years in most patients.

Sauerbrei et al (1997) reported that varicella vaccination in children after HSCT was effective and safe when administered 12-23 months after HSCT. In concept, such vaccination may be similarly effective and safe when administered 6 months after HSCT.

Immunization according to recommendations of the CDC is shown below (see Table 3). Because most cases of post-HSCT herpes zoster and varicella infections occur within the first 18 months after HSCT, an early vaccination regimen may be attractive. Patients who have chronic GVHD do not have adequate responses to immunizations; therefore, immunizations should be delayed in this setting in favor of passive immunity (ie, intravenous [IV] Ig [IVIg]) if they have contact with the disease.

Patients should be reimmunized only after adequate T-lymphocyte immunocompetence recovers, after about 3-6 months or preferably 12 months. Table 3 shows a recommended reimmunization schedule.

Table 3. Schedule of Immunizations after HSCT

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Patients are at risk for PCP infections during the first 6 months after HSCT and should receive trimethoprim-sulfamethoxazole or pentamidine prophylaxis. Such prophylaxis should continue >6 months in those with chronic GVHD. Vigilance for recurrent or secondary malignancy is necessary.

A variety of malignancies can occur after HSCT. They may be detected with regular physical examinations, early screening programs, self-examinations (eg, of the breast, skin), routine yearly mammography, and Papanicolaou tests (Pap smears) for women or prostate examinations and PSA tests for men. History taking and physical examination must be focused on obtaining as much information as possible to rule out or to rule in second malignancy. In obtaining a history, questions related to weight loss, malaise, anorexia, fever, night sweats, and other symptoms are important. In conducting physical examination, any evidence of skin lesions, bruising, organomegaly, lymphadenopathy or other findings must be investigated fully as clinically indicated.

Patient behaviors to prevent secondary malignancy or to decrease the risk for secondary malignancy should be encouraged. These include avoidance of tobacco; protection from sun exposure; avoiding weight gain (The ideal body mass index [BMI] 18.5-25.); regular moderate physical activity for 30 minutes for several days a week; and increase fiber, vegetable, and fruit consumption (400-800 g [15-30 oz.]) or 5 or more servings of a variety of vegetables and fruits per day (Go, 2004).

Vigilance for chronic GVHD

Patients with chronic GVHD can present in a myriad of ways, and GVHD can mimic different syndromes. Careful history taking and physical examination focused on findings consistent with GVHD are needed. The history should focus on anorexia, nausea, vomiting, and weight loss; skin, nail, or hair changes; changes in vision; dryness of the eyes or mucous membranes; and other symptoms. Physical examination should focus on subtle skin findings, sinus pain or drainage, wheezing or dyspnea, dysphagia, heartburn, vomiting, diarrhea, joint contractures, organomegaly, and lymphadenopathy.

Endocrinopathies

Physicians must be alert to testing for endocrinopathies in patients who undergo HSCT. Growth and growth-velocity measurements should be performed at 6- to 12-month intervals. Any decrease of > 2 standard deviations from age- and sex-expected means should alert the physician to the possibility of growth-hormone deficiency. Assessment of gonadal function is necessary in all children aged approximately 11 years who undergo transplantation. In female patients who undergo transplantation before puberty, the risk of ovarian failure is approximately 10-40%, whereas the risk of gonadal failure in male patients who undergo transplantation before puberty is 10%.

Female patients who have ovarian failure, as reflected by high gonadotropin or low estrogen (late finding) levels, should probably receive estrogen-replacement therapy with a low-dose daily oral contraceptives. However, the decision to begin estrogen replacement to prevent osteoporosis and early atherosclerotic heart disease must be weighed against the potential risk of breast or endometrial cancer and hypercoagulability. The long-term effects of hormone replacement in this high-risk category of patients are not yet known.

In patients who received radiation therapy as part of the preparative regimen, thyroid-hormone deficiency is common. Approximately 15% of such children have clinical hypothyroidism, and approximately 30% have compensated hypothyroidism (ie, high TSH level but triiodothyronine [T3] and T4 levels in the reference range). The incidence is relatively low in patients who received fractionated TBI and even lower in patients treated with chemotherapy alone (Sanders, 1991; Borgstrom, 1994).

Euthyroid sick syndrome is more common than tertiary hypothyroidism after HSCT, but overt hypothyroidism can develop several years after HSCT. Therefore, long-term follow-up of thyroid function is necessary in individuals with these conditions (Ishiguro, 2004; Matsumoto, 2004).

In children who undergo transplantation after puberty, the risk of gonadal failure is higher than the risk in patients treated before 11 years of age. Moreover, replacement must take place soon after transplantation. Therefore, children should be tested for gonadal function after they are discharge from the BMT unit.

Female patients who are estrogen depleted (ie, high gonadotropin and low estrogen levels) need estrogen replacement, as outlined above. Males who have high serum gonadotropin or low serum testosterone levels should receive testosterone replacement at puberty.

Some patients may recover gonadal function spontaneously, even after years. Therefore, hormone replacement treatment should be discontinued after every 3-5 years for at least 6 months, and retesting should be performed. Replacement should be continued only if deficiency persists. In all patients, thyroid-hormone screening should be performed after HSCT. Growth hormone needs to be assessed only if a delay or drop-off in the patient's growth curve is observed.

Women who become pregnant after receiving HSCT require high-risk obstetric care because their incidence of spontaneous abortions, premature labor, and other complications is high.

Finally, diabetes insipidus can also occur after SCT, especially in children younger than 4 years who receive HLA-mismatched transplants, those given steroids, and/or those undergoing cord-blood transplantation (Kobayashi, 2004).

Summary

Long-term survivors of HSCT are at risk for many complications. These complications are related to the underlying disease for which transplantation is performed, as well as to previous therapy, conditioning therapy, immunosuppression, and transplantation. Each of these components increases the risks for specific complications, as shown in Table 1. For example, patients with an underlying malignant disease may have a relapse at any time after transplantation. Myeloablative therapy and conditioning before transplantation predisposes the patient to organ toxicity, and immunosuppression, and secondary malignancies. Also, transplantation can lead to GVHD in its many manifestations. Finally, the combination of these components (ie, disease, treatment, transplantation) potentially increases the risks of long-term cognitive and psychosocial consequences.

Awareness of these potential risks is the first step toward preventing and/or treating them. After the risks are identified, important preventive measures or treatment modalities may begin. Specific preventive-care measures include vaccinations; awareness of complications; screening for secondary malignancies; and assessing for cognitive, psychosocial, and organ function. Family physicians who are aware of these potential problems and informed about preventive and treatment options can help long-term survivors live long and healthy lives.

Keywords

transplantation, bone marrow transplantation, HSCT, stem cell transplantation, malignancy, high-dose chemotherapy, radiation therapy, organ damage, secondary malignancy, endocrinopathies, reproductive failure, psychosocial adverse sequelae, graft versus host disease, GVHD, autoimmunity

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