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Prepublished online as a Blood First Edition Paper on January 2, 2003; DOI 10.1182/blood-2002-07-2231.
REVIEW ARTICLE
From the Hematology/Stem Cell Transplantation,
Hôpital Saint Louis, Paris, France; Hematology Department,
Hammersmith Hospital, London, United Kingdom; Department of Pediatrics,
Saint Paul Hospital, Savona, Italy; Pediatric Bone Marrow
Transplantation Unit, Ospedale San Gerardo, Monza, Italy; Institute of
Hematology, Hospital Clinic, Barcelona, Spain; Hematology/Stem Cell
Transplantation, San Camillo Hospital, Roma, Italy; Department of
Pediatric Immunology/Hematology, and Stem Cell Transplantation, Leiden
University Medical Center, Leiden, the Netherlands; Tumor Biology
Center, University of Freiburg, Freiburg, Germany; Departement
Bioinformatique Medicale, Hospital Saint Louis, Paris, France;
Hematology Department, University Hospitals, Basel, Switzerland.
Large numbers of patients now survive long term following stem
cell transplantation (SCT). The late clinical effects of SCT are thus of major concern in the 21st century. Secondary malignant diseases are of particular clinical concern as more patients survive the early phase after transplantation and remain free of their original
disease.1,2 These malignant complications have
been previously reviewed in Blood3 and
recently updated.4 Nonmalignant late effects are
heterogeneous, and although often not life threatening they
significantly impair the quality of life of long-term
survivors.5 The main aims of this review by the Late
Effects Working Party of the European Study Group for Blood and Marrow
Transplantation (EBMT) are to present physicians with an overview of
these nonmalignant late complications and provide some recommendations
regarding their prevention and early treatment. The major risk factors
for nonmalignant complications after SCT are chronic graft-versus-host disease (cGVHD) and/or its treatment and the use of irradiation in the pretransplantation conditioning. The interrelationship between cGVHD, total body irradiation (TBI), and nonmalignant late
effects are summarized in Figure 1.
Chronic GVHD, and its
associated immune-deficiency state, is the prime cause of
transplant-related mortality late after marrow grafting and contributes
directly or indirectly to most nonmalignant complications. Because
cGVHD has recently been reviewed in Blood,6 only the main points relating to nonmalignant complications will be
highlighted here. Following HLA-identical marrow transplantation, the
5-year probability of transplant-related mortality following discharge
is more than 20% in patients with and around 5% in patients without
chronic GVHD.7 Despite the advent of new treatment modalities, the incidence of cGVHD is being sustained by changes in
clinical SCT practice as follows: (1) the expanded use of matched unrelated as well as mismatched related donors,6,8,9 (2) the increasing use of SCT in older patients, (3) the increasing use of
donor lymphocyte infusions to treat relapsed disease or to achieve full
donor chimerism after nonmyeloablative transplantation, and (4) current
evidence that suggests patients receiving allogeneic peripheral blood
stem cell transplants have an equally high or a higher incidence of
chronic GVHD compared with patients receiving marrow grafts. Long-term
follow-up data from Seattle indicated that, although the cumulative
incidence of chronic GVHD at 3 years was similar in patients whose stem
cells came from marrow versus peripheral blood, cGVHD after peripheral
blood SCT was more protracted and less responsive to treatment than
cGVHD after marrow SCT.10
Whereas the prophylactic use of multiagent immunosuppression has
reduced the incidence and severity of acute GVHD, the incidence of
chronic GVHD remains unchanged. The incidence of chronic GVHD after
sibling-matched related, unrelated, and peripheral blood stem cell
transplantation lies between 27% to 50%, 42% to 72%, and 54% to
57%, respectively.11 Factors that increase the
development of chronic GVHD include increased donor and recipient age,
prior acute GVHD, use of alloimmune female donors, type of GVHD
prophylaxis, and history of recipient herpes virus infection. There are
several grading schemes that predict survival of patients with chronic GVHD. In these grading schemes, poor prognostic variables include lichenoid skin changes, extensive skin involvement (> 50% body surface area), elevated bilirubin, progressive onset, thrombocytopenia, and prior steroid refractory/dependent acute GVHD (reviewed in Lee et
al11).
Immune reconstitution has a pivotal role in the long-term issue of
allogeneic SCT. Several studies have characterized the immune
reconstitution in the few months following allogeneic SCT, but data on
long-term immune reconstitution involving large numbers of patients are
scarce.12-15 A large number of variables related to
patient or transplant characteristics, such as age of recipients, stem
cell engineering, type and duration of their disease, or conditioning
regimen, may influence the recovery of immunity after SCT. Other
posttransplantation variables, and in particular chronic GVHD and the
consequent administration of immunosuppressive drugs, also have an
effect. Chronic GVHD is the major factor affecting immune
reconstitution of B cells and CD4
Late bacterial and viral infections have been extensively reviewed, and
guidelines for preventing and treating these opportunistic infections
after SCT are proposed in a document published under the hospice of the
Centers for Disease Control and Prevention (CDC), the Infectious
Disease Society of America, and the American Society of Blood and
Marrow Transplantation.16 Susceptibility to encapsulated
bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis) has been well
documented, especially in patients with current or previous chronic
GVHD. Late (> 2 years) fungal or cytomegalovirus (CMV)
infections are rare and almost invariably occur in patients with
ongoing immune suppression for GVHD. Varicella-zoster, in contrast, is
extremely frequent even in patients without GVHD, but it usually occurs within several months of SCT after acyclovir prophylaxis has been discontinued. Finally, of the parasitic infections, late
Pneumocystis carinii pneumonia (PCP) and
Toxoplasma gondii infections are more common in patients
receiving active treatment for cGVHD. Because PCP prophylaxis with
trimethoprim-sulfamethoxazole is highly active, this regimen should be
given to all patients receiving treatment for cGVHD and/or those with
CD4+ cells less than 0.2 × 109/L. Probably,
PCP prophylaxis should be continued for several weeks after the
cessation of immunosuppressive therapy given the long-lasting T-cell
defects characteristic of patients who have developed cGVHD.
Ocular complications of the posterior segment
Ocular complications of the anterior segment The 2 most common late complications affecting the anterior segment are cataract formation and keratoconjunctivitis sicca syndrome. Cataract formation, particularly posterior subcapsular cataracts, has long been recognized in recipients of SC transplant as one of the most frequent late complications of TBI.26,27 After single-dose TBI almost all patients develop cataracts within 3 to 4 years, and most if not all need surgical repair. Although the probability of developing cataracts after fractionated TBI lies around 30% at 3 years, the incidence may reach more than 80% in 6 to 10 years post-SCT27,28 (Table 1; Figure 3A). In a multivariate analysis, the use of TBI, fractionation of its dose (Figure 3B), and the use of steroid treatment for longer than 3 months were associated with a significant risk of cataract development.27 The effect of the dose rate of irradiation on the subsequent development of cataracts is also established.29,30,32 In the largest series evaluating a cohort of 1064 patients,30 factors independently associated with an increased risk of cataracts were older age (> 23 years), higher dose rate (> 0.04Gy/minute), allogeneic SCT, and steroid administration. Finally, in prospective studies comparing cataract incidence rate and risk factors it has been shown that patients who receive cyclophosphamide and TBI (Cy/TBI) have a higher incidence of cataract formation than those treated with busulfan and cyclophosphamide (BuCy).31 Although the total dose of TBI is the most important factor for cataract formation, the incidence, severity, and time course of cataract formation differ depending on the number of fractions, dose rate of irradiation, the age of the patient, and the use of steroids. The only treatment for cataract is to surgically remove the opacified lens from the eye to restore transparency of the visual axis. Today, cataract surgery is a low-risk procedure and improves visual acuity in 95% of eyes that have no other pathology. Results of surgical repair in patients who have received a transplant are not yet available.
Keratoconjunctivitis sicca syndrome is usually part of a more general syndrome with xerostomia, vaginitis, and dryness of the skin.33 All these manifestations are closely related to cGVHD34 that may lead in its most extensive forms to a Sjögrenlike syndrome.35 The ocular manifestations include reduced tear flow, keratoconjunctivitis sicca, sterile conjunctivitis, corneal epithelial defects, and corneal ulceration.36-40 The incidence of late-onset keratoconjunctivitis sicca syndrome may reach 20% in 15 years after SCT41-43 but reaches nearly 40% in patients with cGVHD, compared with less than 10% in those without GVHD. Risk factors for late-onset keratoconjunctivitis include cGVHD, female sex, age older than 20 years, single-dose TBI, and the use of methotrexate for GVHD prophylaxis.41 Treatment is based on the management of cGVHD with repeated use of topical lubricants. Topical corticosteroids may improve symptoms but can cause sight-threatening complications if used inappropriately in herpes simplex virus or bacterial keratitis. Topical retinoic acid may also be used.44
Significant late toxicity involving both the airways and lung parenchyma affects at least 15% to 40% of patients after SCT. Most of the studies have been performed in adult patients, and results are still conflicting because of varying selection and evaluation criteria, limited sample size, and short follow-up. Moreover, clinical syndromes are not well defined or definable because of overlapping mechanisms and/or because they represent a continuum rather than a distinct disorder. Sensitivity to cytotoxic agents and irradiation, infections, and immune-mediated lung injury associated with GVHD are the most prominent factors that contribute to late respiratory complications.45 Impaired growth of both lung and chest can be an additional factor in children. Restrictive lung disease Abnormal pulmonary function tests (PFTs) with loss of lung volume and diffusing capacity may exist prior to SCT as a result of the intensification of front-line treatment.46 Although the relevance of pretransplantation PFTs is still debated, some studies indicate that PFTs can be predictive of complications and outcome after SCT and should, therefore, be included within the pretransplantation investigation program.47-49 Restrictive lung disease is frequently observed 3 to 6 months after SCT in patients conditioned with TBI and/or receiving an allogeneic SCT, but in most cases it is not symptomatic. Restrictive disease is often stable and may recover, partially or completely, within 2 years.46,50,51 However, some patients do develop severe late restrictive defects and may eventually die of respiratory failure.52Chronic obstructive lung disease Chronic obstructive pulmonary disease with reduced forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) and FEV1 can be detected in up to 20% of long-term survivors after SCT.53-55 Its pathogenesis is not yet well understood. It has been mainly associated with cGVHD, but other potential risk factors, including TBI, hypogammaglobulinemia, GVHD prophylaxis with methotrexate, and infections, have been described. Although direct immune-mediated damage by donor T lymphocytes and cytokines is classically the main mechanism, airflow obstruction can also be due to indirect consequences of cGVHD, for example aspiration secondary to esophageal GVHD, sicca syndrome, abnormal mucociliary transport,56 and recurrent infections. Mortality is high among these patients, particularly in those with an earlier onset and rapid decline of FEV1. Symptoms consist of nonproductive cough, wheezing, and dyspnea; chest radiography is normal in most cases. High-resolution computed tomography (CT) scanning may reveal nonspecific abnormalities.57 Symptomatic relief can be obtained in some patients with bronchodilators; however, in most cases obstructive abnormalities are not improved by this treatment. Patients with low IgG and IgA levels should receive immunoglobulins to prevent infections, which may further damage the airways. Immunosuppressive therapy may be of benefit, but typically improvements occur in less than 50% of cases probably because the damage has already become irreversible or because other pathogenetic factors persist. Asymptomatic patients with abnormal PFTs should be closely monitored for the development of respiratory symptoms; an early recognition of airflow obstruction allows the initiation of treatment at a potentially reversible stage.Obliterative bronchiolitis (OB), the best characterized obstructive syndrome, has been reported in 2% to 14% of allogeneic SC transplant recipients and carries a mortality rate of 50%.56,58-61 OB is strongly associated with cGVHD and low levels of immunoglobulins. GVHD is probably responsible for the initial epithelial injury to the small airways62 with further damage caused by repeated infections. Initial symptoms often resemble those of recurrent upper respiratory tract infections, and then persistent cough, wheezing, inspiratory rales, and dyspnea appear. PFTs gradually deteriorate with severe and nonreversible obstructive abnormalities. Chest radiographs and CT scanning may reveal hyperinflation with or without infiltrates and vascular attenuation; however, radiologic findings do not correlate with lung function changes probably because of the patchy nature of the disease.63 Bronchoscopy with transbronchial biopsy can help to rule out infection and may reveal obliteration of bronchioles with granulation tissue, mononuclear cell infiltration, or fibrosis. It is not clear to what extent combined immunosuppressive treatment can be effective in the treatment of this disease, which typically does not respond to treatment with steroids. Azathioprine and mycophenolate may lead to improved symptoms in some cases. Prophylaxis and prompt treatment of infections are the most important elements of clinical management and may help to alter the clinical course of a disease whose pace can vary from slow progression to rapidly fatal respiratory failure. Single or double lung transplantation has been suggested for patients with advanced disease,64 although the transplanted lung may also be a target for immune-mediated damage.
Unraveling the cause of liver dysfunction can pose difficulties, first, because several causes of liver disease may coexist and, second, because patterns of viral serology may be atypical. Furthermore, in addition to the most important hepatotropic viruses, other agents, like herpesviruses (including CMV), adenoviruses, and Epstein-Barr virus, may be implicated, sometimes leading to life-threatening fulminant hepatitis.65 Useful tools for differential diagnosis are timing posttransplantation, type of clinical and biochemical deterioration, previous evidence of liver complications, including veno-occlusive disease (VOD), acute or chronic GVHD, and infection. Liver biopsy is often difficult to interpret, but histologic examination can be helpful in discriminating between an acute exacerbation of viral hepatitis and an episode of GVHD. Hepatitis B and hepatitis C infections Hepatitis B (HBV) or hepatitis C (HCV)66 may be nonsymptomatic or may progress to fulminant hepatitis or evolve to chronic active hepatitis and cirrhosis. Today, the risk of acquiring HBV and HCV infection from blood transfusion is greatly reduced. A recent prospective study of the EBMT, which included patients transfused in the "post-screening" era, showed that the prevalence of serum hepatitis B surface antigen (HBsAg)- and HCV-RNA-positive SCT patients was 3.1% and 6.0%, respectively. The prevalence of "de novo" infection in patients receiving HBsAg and HCV-RNA-negative SC transplant was 2.0% and 7.4%, respectively; the prevalence of donors positive for HBsAg and HCV-RNA, was found to be 2.6% and 3.6%, respectively.67 Chronic viral hepatitis still remains an important clinical problem in this setting.68,69Patients infected with HBV generally show mild to moderate liver disease on long-term follow-up, but cirrhosis as a result of chronic hepatitis B has not been reported to date. Chronic hepatitis C is often asymptomatic with fluctuating transaminases levels and no signs or symptoms of uncompensated liver disease at least during the first decade following SCT.68-70 Progression to cirrhosis or advanced liver disease in patients surviving more than 10 years does occur, however71 (G.S., unpublished observations, 2003). These observations indicate that, although the outcome of chronic hepatitis was thought to be benign, it may represent an important clinical problem in very long-term survivors. Careful tapering of immunosuppressive therapy posttransplantation, with monitoring of biochemical parameters and viral load, is crucial to prevent and allow early treatment of hepatitis reactivation. Increasing HBV viral load may need treatment with lamivudine.72 However, prolonged therapy with this drug is followed by the emergence of HBV DNA polymerase mutants. As the selection of these mutants is a function of time, the indication for long-term therapy should be reviewed. The combination of lamivudine and anti-HBs immunoglobulins may also be of value. In patients with active chronic HCV, hepatitis treatment with interferon, with or without nucleotide analogues, is indicated.73 Iron overload On the basis of serum ferritin levels, the diagnosis of iron overload can be made in up to 88% of long-term survivors of SCT.74 Prolonged dyserythropoiesis and increased iron absorption both contribute to the accumulation of iron. Liver biopsies performed early after SCT show siderosis in most patients.75 Autopsies performed in patients dying early after SCT show iron accumulation in a range equivalent to that of patients suffering from hereditary hemochromatosis.76 Iron deposition has also been demonstrated in others tissues, such as the myocardium or bone marrow.76,77 Iron overload may be associated with a number of clinical consequences, but these consequences have not been extensively evaluated in patients posttransplantation. A clear correlation exists between iron deposition and persistent hepatic dysfunction, probably as a consequence of intracellular iron accumulation and the toxic effect of free radicals. In heavily transfused patients, such as those with thalassemia, iron can contribute to hepatic fibrosis, cirrhosis, and hepatocellular carcinoma as well as to cardiac dysfunction.77,78 Hepatic iron overload may also worsen the natural course of chronic hepatitis, in particular hepatitis C, and the response to antiviral therapy.79 Finally, iron overload increases the risk of opportunistic infections in immunocompromised patients, mucormycosis being the infection most usually observed in SCT.80 Although iron overload spontaneously decreases in the years following SCT,78 the true effect of iron overload on post-SCT complications such as diabetes mellitus, impotence, hypogonadism, or growth retardation has not yet been established. All survivors (even if asymptomatic) should, therefore, be assessed for iron overload by measuring serum ferritin. Iron overload should be treated by means of phlebotomy and/or chelation therapy, especially when iron overload coexists with chronic viral hepatitis. Phlebotomy has the advantage over chelation of better compliance, fewer side effects, and lower costs. The use of recombinant human erythropoietin may facilitate this strategy in patients who have low hemoglobin levels.81,82
Avascular necrosis of bone (AVN) The published incidence of AVN varies from 4% to more than 10% in the largest series.83-87 The mean time from transplantation to AVN is 18 months (range, 4-132 months), and pain is usually the first sign. Early diagnosis can rarely be made using standard radiography alone, and magnetic resonance imaging is the investigation of choice (Figure 4). The hip is the affected site in more than 80% of cases, with bilateral involvement occurring in more than 60% cases. Other locations described include the knee (10% of patient with AVN), the wrist, and ankle. Symptomatic relief of pain and orthopedic measures to decrease the pressure on the affected joints are of value, but most adult patients with advanced damage will require surgery. The probability of total hip replacement following a diagnosis of AVN is approximately 80% at 5 years.88,89 Although short-term results of joint surgery are excellent in the majority (> 85%) of cases, it is clear that long-term follow-up of the protheses are needed in young patients who have a long life expectancy. Studies evaluating risk factors for AVN have clearly identified steroids (both total dose and duration) as the strongest risk factor. Thus, unnecessary long-term low-dose steroids for nonactive chronic GVHD should be avoided. The second major risk factor for AVN is TBI, the highest risks being associated with receipt of single doses of 10 Gy or higher or more than 12 Gy in fractionated doses.87 Finally, some underlying conditions may predispose a patient to develop AVN after SCT, in particular patients receiving transplants for severe aplastic anemia90 or acute lymphoblastic leukemia.
Osteoporosis Hematopoietic SCT can induce bone loss and osteoporosis via the toxic effects of TBI, chemotherapy, and hypogonadism (reviewed in Weilbaecher91 and Schimmer et al92). Osteopenia and osteoporosis are both characterized by a reduced bone mass and increased susceptibility to bone fracture. These conditions are further distinguished by the degree of reduction in bone mass and can be quantified by T and Z scores on dual photon densitometry. The Z score is similar to the T score but uses mean bone mass from an age- and sex-matched control population as a reference value. The relative risk of fracture doubles for every standard deviation below the control adult peak bone mass. The incidence and clinical course of bone mineral density (BMD) abnormalities following hematopoietic SCT have been studied in 2 large series.93,94 In both, the cumulative dose and number of days of glucocorticoid therapy and the number of days of cyclosporine or tacrolimus therapy showed significant associations with loss of BMD. Nontraumatic fractures occurred in 10% of patients. These results indicate that loss of BMD after allogeneic SCT is common and is accelerated by the length of immunosuppressive therapy and cumulative dose of glucocorticoid. With the use of World Health Organization (WHO) criteria, nearly 50% of the patients have low bone density, a third have osteopenia, and roughly 10% have osteoporosis, 12 to 18 months posttransplantation. The true incidence and morbidity rate of osteoporosis in very long-term SCT survivors is currently unknown. Preventative measures of osteoporosis must include sex-hormone replacement in patients with gonadal failure; the efficacy of new treatments for osteoporosis in long-term survivors of SCT requires evaluation.
Both TBI-based regimens and those without irradiation can result in severe damage to the enamel organ and developing teeth. These defects may be prolonged or permanent.95,96 After TBI in children, underdevelopment of the mandible and anomalies in the mandibular joint may also occur.96 In children, long-term clinical and radiologic follow-ups reveal hypoplasia and microdontia of the crowns of erupted permanent teeth and thinning and tapering of the roots of erupted permanent molars or incisors.97-100 Caries are found more frequently in patients who have received a transplant compared with age-matched healthy children. The defects in dental elements post-SCT may occur at any age of tooth development, and only the severity seems to depend on age at SCT. Recommendations to minimize this adverse effect aim to preserve the enamel layer and prevent, by active oral hygiene, dental plaque, periodontal and oral mucosal infections, and xerostomia, all of which contribute to the development of caries. Specialist dental consultation before SCT and yearly posttransplantation examinations should be requested to register any specific dental problems, to provide treatment, and to give instruction on oral and dental care. In the long-term, 3 key elements to reduce dental complications are brushing teeth, application of fluoride, and the use of antiseptic mouthwashes. Brushing teeth should be done twice daily, with a soft brush and fluorinated toothpaste.
Thyroid dysfunction Thyroid dysfunction has long been recognized as one of the most frequent late complications of SCT.101 The most common thyroid abnormalities can be classified into 3 distinct patterns: subclinical-compensated hypothyroidism, overt hypothyroidism, and autoimmune thyroid disease.Subclinical-compensated hypothyroidism. Between 7% and 15.5% of patients will develop subclinical hypothyroidism (slightly high serum thyroid-stimulating hormone [TSH] and normal free-T4 levels) in the year post-SCT.102-104 It is not yet clear if patients who develop subclinical hypothyroidism should be treated with L-thyroxin because most of these cases are mild, compensated, and may resolve spontaneously.102,105,106 Furthermore, treatment with L-thyroxin might induce early osteoporosis, especially if given to those women after SCT with gonadal failure. It is also not clear if a relationship exists between high TSH levels and carcinogenesis.107 One possible approach is to monitor TSH and free-T4 levels twice yearly and to consider L-thyroxin treatment only if TSH concentration remains high or is increasing.108 Overt hypothyroidism. The great majority of cases of overt hypothyroidism following SCT are due to direct damage to the thyroid gland. Secondary hypothyroidism, caused by pituitary damage, is rare following SCT. Hypothyroidism is usually diagnosed after a median period of 50 months posttransplantation. The frequency of hypothyroidism requiring L-thyroxin replacement therapy is highly variable,109,110 depending to a large extent on the type of pretransplantation conditioning applied as follows: nearly 90% in patients who have received 10 Gy single-dose TBI,110 14% to 15% of patients following fractionated TBI,103 and smaller numbers after conditioning with BuCy.32,109-111 Treatment with L-thyroxin is indicated in all cases of frank hypothyroidism (elevated TSH with low free-T4 blood levels). Thyroid hormone levels should be measured 4 to 6 weeks after commencement of replacement therapy, and dosage should be tailored thereafter to the individual patient and adjusted according to thyroid function evaluation every 6 months. Elderly patients should have an electrocardiogram (ECG) prior to commencing treatment to exclude associated ischemic heart disease and/or arrhythmias. Autoimmune thyroid disease. Autoimmune thyroiditis, presumably transferred via donor cells, has been reported.112 This same autoimmune mechanism can also lead to hyperthyroidism if the donor is affected with Grave disease.113 Growth Linear growth is an intricate process that may be affected by several systems, including genetic (ie, midparental height), nutritional, hormonal, and psychological factors. Intensive anticancer therapy during childhood may influence all or some of these factors resulting in decreased growth. Children who undergo SCT form a heterogeneous group because of the different treatment protocols used. In addition, posttransplantation factors such as GVHD and its treatment, especially the use of long-term steroids, may induce growth failure in childhood.104,114-119Final height achievement has been reported in some
studies.115-117,120-122 Decreased growth has been
described in patients who underwent SCT during childhood. The mean loss
of height (as estimated by the standard deviation score [SDS]) is
estimated to be approximately 1 height SDS (equivalent to 6 cm)
compared with both the mean height at the time of SCT and mean genetic
height.115-117,120,121,123 Nevertheless, nearly 80% of
the children will achieve adult height values above the 3rd percentile
(or Puberty and gonadal failure Gonadal failure (both testicular and ovarian) is a common long-term consequence of the chemotherapy given prior to SCT and of the pretransplantation conditioning. The major cause of gonadal damage leading to hypergonadotropic-hypogonadism is irradiation.128,129 Similar damage can also be caused by busulfan. Among patients who have received a transplant, it is uncommon to find either a condition of hypogonadotropic-hypogonadism or precocious puberty because of irradiation damage to the hypothalamic-pituitary area.120,130In males, the testicular germinal epithelium (Sertoli cells) where spermatogenesis occurs is more vulnerable to radiation and chemotherapy than the testicular Leydig cell component, which is involved in testosterone secretion. Therefore, testosterone levels are usually normal even when spermatogenesis is reduced or absent. The serum follicle-stimulating hormone (FSH) is typically elevated, whereas luteinizing hormone (LH) levels may remain in the normal range. The great majority of patients will not, therefore, require testosterone replacement to ensure sexual activity, libido, erection, and ejaculation. Furthermore, boys transplanted during childhood will usually spontaneously start and complete puberty. Patients transplanted before puberty, however, might achieve a reduced testicular volume as a result of damage to the germinal epithelium.131 Sex hormone replacement therapy (SHRT) with testosterone derivatives in males is indicated in patients with severe uncompensated hypogonadism. In females, the ovaries are more vulnerable to irradiation and chemotherapy than the testes, and hypergonadotropic-hypogonadism is almost the rule. Busulfan is one of the most gonadotoxic agents, whereas cyclophosphamide is usually associated with only minor effects on gonadal function. Prepubertal patients conditioned with cyclophosphamide alone for SAA usually have normal puberty.114 The age at transplantation is of major importance because the younger the age, the better will be the chances for gonadal recovery. In fact, ovarian failure in adult women is usually irreversible, whereas in prepubertal girls, although uncommon, there is still a greater possibility for a subsequent spontaneous recovery and achievement of spontaneous menarche.131-134 Fractionation of the irradiation reduces the effect on the ovaries114,135; girls treated with 12 Gy fractionated TBI are 5 times more likely to have a spontaneous recovery to normal ovarian function than girls receiving single-dose TBI. With the increasing utilization of BuCy in pediatric pretransplantation conditioning, it becomes clear that most girls of any age at transplantation develop ovarian failure.136,137 Most females will need SHRT, both for the induction of puberty in girls who have had SCT prior to the menarche and for maintaining menstrual cycles and bone turnover/mineralization in adult women. In prepubertal girls who do not undergo puberty spontaneously post-SCT, estrogen treatment should be started at the age of 12 to 13 years to promote breast and uterine development and the pubertal growth spurt. The dose of estrogen treatment will need to be gradually increased, and a combination of cyclical estrogen-progesterone treatment introduced after 1 to 2 years to initiate menstruation and to reduce the risk of future osteoporosis. SHRT can be interrupted once every 2 to 3 years, for a period of 6 months, to evaluate possible spontaneous recovery of ovarian activity, which occurs in a minority of women. Because of the high incidence of gonadal dysfunction and early menopause in patients after SCT, an annual clinical and biologic gynecologic assessment is recommended.
Despite the potential gonadotoxicity of pretransplantation
conditioning (see "Puberty and gonadal failure"), gonadal
recovery and pregnancies following SCT are well described (Tables 2 and 3). The precise incidence of fertility
following SCT is hard to establish.
Unpublished data from the EBMT Late Effects Working Party (LEWP)
pregnancy database relating to incidence of pregnancy in patients
transplanted prior to 1994 who survived for a minimum of 2 years is
given in Table 2. These data are not comparative because the patients
within the groups were not age matched. Nonetheless, it is clear that
the overall incidence of pregnancy is low (< 2%) except for patients
transplanted for SAA and this is in accordance with the available
literature. Such data are limited in their ability to accurately
predict the likely return of fertility post-SCT, however, because many
patients do not wish to become parents following the diagnosis of a
potentially life-threatening illness.
Other studies have looked at clinical and laboratory indicators of gonadal function in post-SCT patients. In women these include amenorrhea, menopausal symptoms, raised gonadotrophin levels, and low estrogen. In men, sperm quality (motility and morphology) and quantity can be assessed, and the typical biochemical profile would be raised FSH with normal LH and normal/low testosterone levels. Fertility following SCT for nonmalignant disease Return of gonadal function following cyclophosphamide conditioning for SAA was noted in 56 of 103 adult female survivors in Seattle (as indicated by return of menstruation and normal gonadotrophin and estradiol levels); 28 (27%) women subsequently conceived.138 Of 109 adult male survivors in the same study, 61% had return of sperm production an | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Introduction
Chronic GVHD, late infections,...
and CD8
2 height SDS) for the healthy general population.