Keywords

Introduction

Hematopoietic stem cell transplant (HSCT) is a curative therapeutic option for patients not only with malignancies but also with many nonmalignant conditions such as beta thalassemia, sickle cell disease, metabolic disorders, and many primary immunodeficiencies. Continued advances in the use of alternative donors, manipulation of the hematopoietic stem cell product, expansion of indications for HSCT, and tremendous progress in supportive care strategies and management of HSCT-related complications have collectively resulted in an expanding population of survivors of HSCT. Progress and expansion of alternative donor hematopoietic stem cell (HSC) sources (e.g., umbilical cord blood, haploidentical donors) are resulting in a continually increasing number of HSCTs performed in children and adolescents each year. These survivors are at risk of developing treatment-related late effects; two-thirds of the HSCT survivors will develop at least one chronic health condition.

Survivors of childhood and adolescent HSCT carry a significantly greater burden of morbidity not only compared with the non-cancer populations but also compared with the conventionally treated cancer patients, proving the need for close monitoring of this high-risk population [1]. The type of HSCT (i.e., matched sibling donor versus matched unrelated donor versus umbilical cord blood), HSC source (i.e., bone marrow, umbilical cord blood, and peripheral blood stem cells), and the conditioning regimen used determine the type and severity of long-term complications in the HSCT patients. 70–80% of those who survive at least 2 years after an allogeneic HSCT are expected to become long-term survivors [2,3,4].

The Bone Marrow Transplant Survivor Study (BMT-SS) which is one of the most comprehensive and largest studies of HSCT survivors to date, studied 1479 patients who were alive at least 2 years post their allogeneic HSCT and found that allogeneic HSCT patients had a 9.9-fold increased risk of early death [3]. Though relapse of primary disease and chronic graft versus host disease (GvHD) remained the leading cause of premature death, treatment-related causes such as GvHD secondary malignancies, cardiac toxicity, and pulmonary complications attributed to 25% of the deaths.

A multi-institutional study comparing long-term health outcomes in survivors of childhood cancer treated with HSCT to survivors of childhood cancer treated with conventional therapy showed that survivors of HSCT were more likely to have a severe or life-threatening condition (Relative Risk [RR] = 3.9) [1]. They were more likely to have multiple chronic conditions (RR = 2.6) and more likely to have functional impairment (RR = 3.5) and activity limitations (RR = 5.8) than the conventionally treated patients. HSCT survivors were drawn from the BMT-SS study and conventionally treated patients were drawn from the Childhood Cancer Survivor Study (CCSS) . The results of this study highlight the need for timely screening for these health-related complications and appropriate interventions.

While screening guidelines have been developed by the Center for International Blood and Marrow Transplant Research (CIBMTR), European Group for Blood and Marrow Transplantation (EBMT), American Society for Blood and Marrow Transplantation (ASBMT) [5,6,7], and other societies, these are not pediatric focused. In 2011, the NCI and NHLBI held the first international consensus conference on late effects after pediatric HSCT and recommended a coordinated effort through the Pediatric Blood and Marrow Transplant Consortium (PBMTC), the Children’s Oncology Group (COG)-SCT committee, the Children’s Cancer and Leukemia group (CCLG) BMT group, the EBMT Pediatric Diseases Working Group, and other pediatric-oriented HSCT-specific groups, to work alongside larger pediatric cancer late effects groups such as the COG Late Effects Task Force to formulate formal guidelines.

Secondary Malignancies After HSCT

One of the most devastating complications after HSCT is the development of a secondary malignancy. Many host and clinical factors are associated with the increased risk of secondary malignant neoplasms after HSCT. These risk factors are summarized in Table 27.1.

Table 27.1 Risk factors for secondary malignancies after HSCT
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The risk of secondary malignancy for children undergoing HSCT is increased not only compared to age-matched controls but also compared to patients undergoing HSCT at older ages [8]. Table 27.2 lists the most common types of secondary malignancies seen in post-HSCT recipients. Curtis, et al. showed that cancer survivors who were transplanted at less than 10 years of age had a risk of new malignant neoplasms 36.6 times higher than the general population [9]. This risk decreased to 4.6-fold for those transplanted between the ages of 10 and 29 years. Table 27.3 summarizes the causative agents and screening recommendations for secondary malignant neoplasms. These secondary malignant neoplasms are often due to exposure to alkylators , topoisomerase II inhibitors , and TBI.

Table 27.2 Most common types of secondary malignant neoplasms in HSCT patients
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Table 27.3 Risk factors and screening recommendations for second malignant neoplasms (SMN)
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Treatment-Related Myelodysplastic Syndrome/Acute Myelogenous Leukemia

Treatment-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are major causes of non-relapse mortality of HSCT. These disorders have very poor prognoses with conventional antileukemia therapies with a median survival of 1 year or less [10]. This outcome is related to several factors including older age at HSCT, pre-HSCT therapy with alkylating agents, topoisomerase II inhibitors and radiation, HSC mobilization with etoposide, use of peripheral blood HSCs, TBI-containing conditioning regimens, the number of CD34+ hematopoietic stem cells infused, and history of multiple HSCTs [11]. Patients presenting with t-MDS often progress to t-AML. Two types of t-MDS/t-AML (which are related to the therapeutic exposure) are generally identified: those due to alkylating agents/radiation and those due to topoisomerase II inhibitors. t-MDS/t-AML related to alkylating agents typically develops 4–7 years postexposure. Cytopenias are common and approximately 65% present with MDS. The remainder present with AML but have myelodysplastic features. Cytogenetic abnormalities associated with a poor prognosis in non-therapy-related MDS and AML, such as del (7/7q) or a complex karyotype, are common in t-MDS and t-AML [12]. AML secondary to topoisomerase II inhibitors often presents as overt AML. The latency is very short (6 months to 5 years), and there is usually no antecedent myelodysplastic phase and is associated with balanced translocations involving chromosome 11q23 or 21q22. These disorders are also described after autologous HSCT [13]. HSCT should be considered promptly after a diagnosis of t-AML/t-MDS is made. However, allogeneic HSCT for t-MDS/t-AML is associated with a high risk of treatment-related mortality.

Lymphoma

Posttransplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein–Barr virus-related (EBV) clinical diseases, ranging from a benign mononucleosis-like illness to a fulminant non-Hodgkin’s lymphoma. In the setting of HSCT, PTLD is an often fatal complication with the highest chance of occurrence in the first 5 years after HSCT [14, 15] with 80% of the cases occurring within the first year of HSCT [15]. Risk factors for PTLD are summarized in Table 27.4. PTLD is significantly associated with T-cell depletion of the donor bone marrow, use of antithymocyte globulin (ATG), and unrelated or HLA-mismatched grafts. Older age at the time of HSCT, second HSCT, and GvHD (both acute and chronic) increase the risk of developing post-HSCT PTLD by several folds. T-cell depleted grafts decrease the risk of acute GvHD but increase the risk of PTLD. In the majority of cases, PTLD is associated with EBV infection of B cells, either as a consequence of reactivation of the virus post-HSCT or from primary EBV infection. Primary infection with EBV may be acquired from the donor graft or, less commonly, from environmental exposure. The majority of the PTLD cases are due to B-cell proliferation, with only 5% of cases being of T-cell or T/NK cell origin. A vast majority of the B-cell PTLD cases (approximately 70%) are EBV-related. It is believed that EBV most likely predisposes infected B cells to uncontrolled proliferation which may result in the accumulation of (epi)genetic aberrations. Also, T-cell dysfunction caused by immunosuppressive treatment further allows uncontrolled proliferation of the EBV-infected B cells. The 2008 World Health Organization (WHO) classification divides PTLD into four categories based on morphologic, immunophenotypic, and molecular criteria: [1] early lesions, [2] polymorphic PTLD, [3] monomorphic PTLD, and [4] Hodgkin lymphoma.

Table 27.4 Risk factors for PTLD
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Reduction of immunosuppression remains the cornerstone for treatment of EBV-driven B-cell PTLD. It allows the patient’s natural immunity to recover and gain control over proliferating EBV-infected B cells. Additional therapeutic measures include immune-based therapies such as monoclonal antibodies like rituximab (anti-CD20 monoclonal antibody), EBV-specific donor T cells, IVIG, and alpha interferon.

Lymphomas distinct from PTLD, such as Hodgkin lymphoma, can occur late post-HSCT (usually >2.5 years) and are associated with moderate and severe chronic GvHD. These late-onset lymphomas do not have an association with the risk factors typically associated with PTLD [16].

Non-hematologically Derived Tumors

A study investigating the incidence of secondary malignancies in a cohort of 3182 children who underwent allogeneic HSCT for leukemia revealed the cumulative risk of invasive solid tumors to be 0.9%, 4.3%, and 11% at 5 years, 10 years, and 15 years post-HSCT, respectively [14]. The risk was highest among children transplanted under the age of 5 years and those who received high-dose TBI with a significantly increased risk for developing tumors of the tongue, salivary glands, brain, thyroid, and skin/connective tissue. In patients exposed to radiation at less than 30 years of age, the risk of developing a non-squamous cell carcinoma is ninefold higher than that of the general population, while for those older than 30 years of age when exposed, the risk approaches that of the general population [17].

Skin cancer : Allogeneic HSCT recipients have an increased risk of developing basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Leisenring et al. demonstrated that the incidence of BCC and SCC is approximately 6.5% and 3.4% at 20 years post-HSCT, respectively [18]. Exposure to TBI increases the risk of BCC, particularly in younger children. GvHD is correlated with the development of secondary skin cancers. The risk of SCC is increased in patients with acute GvHD, while chronic GvHD is correlated with both BCC and SCC.

Breast cancer : Female survivors of HSCT are at increased risk of developing breast cancer with a 25-year cumulative incidence of 11% [19]. The risk is higher among those who received TBI (17%) compared to those who did not (3%). The increased risk is directly related to the patient’s age at the time of HSCT (hazard ratio [HR] = 9.5 for HCT < 18 years), exposure to TBI, and time since HSCT with the median time to development of breast cancer being 12.5 years.

Thyroid cancer: Cohen et al. showed that HSCT patients have a 3.3-fold increased risk of developing thyroid cancer as compared to age- and sex-matched controls from the general population [20]. Young age at HSCT (<10 years) confers the strongest risk with neck irradiation, female gender, and chronic GvHD being other risk factors.

System-Based Health Complications

Cardiac Dysfunction

HSCT survivors are at risk for long-term cardiotoxicity due to a combination of factors. These include pre-HSCT therapeutic exposure (especially anthracycline dosage greater than 300 mg/m2 [21, 22]), HSCT conditioning regimens with high-dose chemotherapy and TBI, and post-HSCT GvHD. It presents as either a structural (valvular abnormalities, coronary artery disease) or functional (e.g., cardiomyopathy, arrhythmias, congestive heart failure) problem.

A prospective study evaluating the outcome of cardiac late effects in 162 children who underwent an allogeneic HSCT showed that the 5-year cumulative incidence of cardiac impairment was 26%. TBI alone and TBI with pre-HSCT anthracycline exposure were significant risk factors for decreased cardiac function [23]. The cumulative risk of cardiac late effects increases over time. Female gender, exposure to anthracyclines at a young age, and mediastinal radiation with exposure to the heart are well-established modifying factors for cardiac health among survivors of childhood cancer [23]. TBI and prolonged immunosuppressive therapy post-HSCT are HSCT-specific unique risk factors that contribute to diabetes and hypertension in this population further modifying the risk of cardiac late effects.

Another serious long-term complication is the development of therapy-related cardiovascular disease (CVD) . This includes cerebrovascular disease (stroke, transient ischemic attack, carotid artery occlusion) and coronary artery disease both of which have an increased incidence and early occurrence rate among survivors of HSCT. At 25 years after HSCT, the cumulative incidence of CVD approaches 23% in certain high-risk populations. Endothelial injury provoked by GvHD is thought to contribute to the atherosclerotic changes after HSCT that lead to premature cardiovascular events. Girls with estrogen deficiency resulting from gonadotoxic therapy used in HSCT lose the normally protective effects of estrogen against coronary artery disease. Hence, prompt hormonal replacement for gonadal dysfunction in the girls and women who underwent HSCT at a young age is important for heart health. A study of long-term HSCT survivors who had survived for one year or more after a HSCT identified the presence of two or more of the following risk factors: obesity, dyslipidemia, hypertension, and diabetes to be associated with 4.6-fold risk of late CVD (p < 0.01). Chest radiation prior to HSCT was associated with a 9.3-fold risk of coronary artery disease [24].

Compared to the general population, HSCT survivors are at a 2.3- to 4.0-fold increased risk of death due to cardiac reasons [3], emphasizing the need for lifelong monitoring for cardiac late effects in this patient population. The Children’s Oncology Group (COG) long-term follow-up guidelines give specific recommendations for echocardiographic screening of these individuals ranging from annual to every 5 years based on their total cumulative anthracycline exposure, age at exposure, and exposure to mediastinal radiation (see Tables 27.5 and 27.6). Patients who have received chest radiation should be screened for early onset atherosclerosis. Pregnant women with past exposure to anthracyclines should be monitored very closely as the markedly increased blood volume during the pregnancy, especially during the third trimester, can add considerable stress to the heart that has already received cardiotoxic exposure. Survivors should be encouraged to participate in a healthy exercise program with aerobic activity and avoid isometric exercises that put strain on the heart. They should be counseled on ways to maintain heart health including dietary guidance and timely and appropriate screening for hypertension, dyslipidemia, and diabetes.

Table 27.5 Children’s Oncology Group (COG) long-term follow-up guidelines for frequency of cardiac monitoring
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Table 27.6 Recommended frequency of echocardiogram
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Pulmonary Complications

Approximately 35–45% of HSCT survivors have abnormal pulmonary function test results and suboptimal lung function; however, very few have clinical disease [23, 25]. Pulmonary complications post-HSCT can be divided into two broad categories: late-onset infectious pulmonary complications (LOIPCs) and late-onset noninfectious pulmonary complications (LONIPCs).

The infectious complications are influenced by the immune suppression following HSCT. These patients are at an increased risk for fungal, bacterial, and viral infections. These are discussed in depth in Chaps. 17 and 21.

The noninfectious pulmonary complications include bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans with organizing pneumonia (BOOP), and idiopathic pneumonia syndrome (IPS). These noninfectious complications, which are addressed in much more depth in Chap. 21, usually appear after approximately 100 days from HSCT and are related to chronic GvHD. In a retrospective review of pediatric patients who had survived more than 3 months from an allogeneic HSCT, Nishio et al. found that the incidence rate of LONIPCs to be about 10.3% [26]. That study identified high risk underlying disease and extensive chronic GvHD to be significant risk factors associated with the development of the LONIPCs. Another study identified chronic GvHD and compromised pulmonary function existing prior to HSCT to be independently associated with a late decline in lung function. Patients with chronic GvHD and low pre-HSCT diffusion capacity for carbon monoxide (DLco) or low forced expiratory volume (FEV1) in the first second were more affected [27]. LONIPCs have been associated with a significantly worse mortality rate, especially after unrelated donor allogeneic HSCT.

Bronchiolitis obliterans syndrome: Bronchiolitis obliterans syndrome (BOS) presents as nonspecific inflammatory injury to the small airways and is strongly associated with chronic GvHD. Its incidence is approximately 8% in allogeneic HSCT recipients but is increased to approximately 13% in those with chronic GvHD. It typically occurs within the first 2 years post-HSCT with a median of 1.5 years. BOS initially presents as an obstructive disease and then gradually progresses to a restrictive disease due to peribronchiolar fibrosis. Other factors associated with an increased risk of BOS are the use of peripheral blood stem cells, busulfan-based conditioning regimen, 14 months or greater interval from diagnosis to transplant, sex match of female donor to male recipient, past history of interstitial pneumonitis, and an episode of grade 2 or higher acute GvHD [28]. High-resolution CT scan of the chest with imaging in inspiration and expiration typically demonstrates air trapping. However, PFTs needed to establish the diagnosis demonstrating an FEV1 decreased >20% from baseline. Patients at risk for developing BOS should have PFTs performed every 3 months for the first 2 years post-HSCT because changes in PFTs will occur before changes on CT scan or the development of clinical symptoms, and early intervention, particularly before a patient becomes symptomatic, may blunt the progression of BOS. See Chap. 21 for further discussion of BOS.

Bronchiolitis obliterans organizing pneumonia: Bronchiolitis obliterans organizing pneumonia (BOOP) has an incidence of less than 2%. It usually occurs in the first year following a HSCT and presents as an interstitial pneumonia with sudden onset cough, shortness of breath, and fever. It has a restrictive pattern on pulmonary function tests, and chest x-ray shows ground glass attenuation with nodular opacities. See Chap. 21 for further discussion of BOOP.

Idiopathic pneumonia syndrome: Idiopathic pneumonia syndrome occurs in the first 4 months after HSCT. Conditions which predispose patients to developing IPS are TBI, pretransplant chemotherapy, GvHD, and increasing age at the time of HSCT [29]. See Chap. 21 for further discussion of idiopathic pneumonia syndrome.

Risk factors associated with restrictive lung disease (RLD) include the conditioning regimen, indication for HSCT, scleroderma/contracture, and donor relation (sibling, parent/relative, unrelated, autologous). Patients with single fraction TBI have the highest risk of RLD. Risk factors for obstructive lung disease (OLD) include chronic GvHD, time after HSCT, and the conditioning regimen [25].

All patients who have undergone a HSCT and have had exposure to bleomycin or pulmonary radiation are recommended to have baseline screening pulmonary function tests on entry to long-term follow-up. They should also be counseled about risk of smoking.

Endocrine-Related Complications

Common endocrine-related long-term complications of HSCT include thyroid dysfunction (most commonly hyperthyroidism and secondary thyroid cancers), metabolic syndrome, impairment of growth and development, and pubertal delay or failure. Table 27.7 summarizes the frequency and recommended screening for some of these common endocrine-related long-term complications.

Table 27.7 Screening for endocrine complications after HSCT
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Thyroid dysfunction: Thyroid dysfunction is a common problem seen following a HSCT. It often presents as subclinical or overt hypothyroidism . Subclinical hypothyroidism is defined as elevated thyroid stimulating hormone (TSH) but normal T4 levels, while overt hypothyroidism is reflected by low T4 levels and elevated TSH. Hypothyroidism is directly related to radiation of the thyroid gland (as part of neck/mediastinal radiation or TBI) [30]. A study of 791 patients who were transplanted before the age of 18 years demonstrated that age < 10 years and the use of Busulfan or TBI for conditioning are the greatest risk factors for development of hypothyroidism post-HSCT (see Table 27.8). In this study, 30% of the patients developed hypothyroidism with 20% needing thyroid hormone replacement [31]. Although the latency period is variable, the majority of patients will develop hypothyroidism within the first 2 years post-HSCT. There is some thought that a subclinical GvHD-like phenomenon may play a role in the development of some cases of thyroid dysfunction, as it has been observed that children who receive an unrelated donor HSCT are more likely to develop hypothyroidism than those who receive matched sibling donor HSCT (36% vs 9%) [30]. Other thyroid disorders such as hyperthyroidism, thyroiditis, and benign thyroid nodules can occur in some patients but are uncommon.

Table 27.8 Risk factors for hypothyroidism after HSCT
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In addition to thyroid dysfunction survivors of HSCT are also at an increased risk of developing thyroid cancers. Though rare in absolute number, thyroid cancer is one of the most common second neoplasms after HSCT along with malignant tumors of the brain [14]. However, its prevalence is less than 1% [14]. The majority of patients with thyroid tumors have a history of TBI [31].

It is recommended that HSCT survivors be screened annually for thyroid disorders by checking thyroid function tests (TSH and free T4) and a thyroid ultrasound if a thyroid nodule is palpated.

Metabolic syndrome: Metabolic syndrome is comprised of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension. It is associated with an increased risk of developing type 2 diabetes mellitus and atherosclerotic cardiovascular disease. A study looking at the prevalence and risk factors for metabolic syndrome in young adult survivors of childhood leukemia treated both with and without HSCT showed that, among the HSCT recipients, the prevalence of metabolic syndrome was 5.9% among the patients who did not receive TBI and was 18.6% for those who did receive TBI [32]. Furthermore, HSCT with TBI was associated with a higher rate of hypertriglyceridemia, high-fasting glucose and a low level of high-density lipoprotein cholesterol, supporting that TBI is a major risk factor for the development of metabolic syndrome.

Direct damage to the vascular endothelium by both chemotherapy and radiation, insult to the hypothalamic-pituitary axis due to radiation with resultant deficiency of growth hormone and hypogonadism, and prolonged immune suppression post-HSCT all contribute to the development of metabolic syndrome. A study comparing the late effects for glucose and lipid metabolism in three patient populations (long-term survivors of HSCT who were 3–18 year post-HSCT for leukemia, a subset of leukemia patients who were in remission. And matched healthy controls) revealed that 39% of the HSCT survivors had core signs of metabolic syndrome as compared to 8% of the leukemia in remission controls and 0% of the healthy controls [33]. Fifty-two percentage of the HSCT patients had developed hyperinsulinemia, and 43% had abnormal glucose metabolism. Furthermore, this study showed that long-term survivors of HSCT are at a significantly increased risk of developing insulin resistance, glucose intolerance, and type 2 diabetes even at a normal weight and young age.

The Bone Marrow Transplant Survivor Study (BMT-SS) evaluated the prevalence of late occurrence of diabetes, hypertension, and cardiovascular disease in survivors of HSCT by self-report as compared to matched sibling controls. Survivors were required to be at least 2 year post-HSCT and off immune suppression. After adjusting for age, sex, race, and body mass index (BMI), survivors of allogeneic HSCT were 3.65 times more likely to report diabetes than their siblings and 2.06 times more likely to report hypertension [34]. Allogeneic HSCT survivors were also more likely to develop hypertension than autologous HSCT recipients. TBI exposure was associated with an increased risk of diabetes, supporting the notion that HSCT survivors have a higher age- and BMI-adjusted risk of diabetes and hypertension which could contribute to a higher than expected risk of cardiovascular events with age.

HSCT survivors should be screened periodically for cardiovascular risk factors, such as lipid abnormalities, and monitored for development of diabetes and hypertension.

Growth and development: Growth impairment is a frequent complication following HSCT. Insult to the hypothalamic-pituitary axis due to radiation (cranial radiation or TBI) is the primary cause with other modifying factors such as nutritional status, gonadal failure with impaired sex hormone production, hypothyroidism, prolonged exposure to corticosteroids for GvHD management, and genetic causes. TBI can have damaging effects on the epiphyseal growth plates causing direct impairment of growth. It can also impact growth secondarily by affecting growth hormone secretion or by causing gonadal failure leading to estrogen deficiency in girls or due to hypothyroidism . A study looking at 181 patients who underwent bone marrow transplantation for various hematologic disorders during childhood revealed that 80% of the patients attained an adult height within the normal range for a healthy population [35]. Irradiation, male gender, and younger age at the time of the bone marrow transplantation were directly related to long-term loss in height. Prior cranial radiation and single-dose, unfractionated TBI had the greatest negative effect on final height achievement. Fractionated TBI had significantly less effect on final adult height, and alternate conditioning with cyclophosphamide and busulfan had no effect on height loss.

The maximum benefit of growth hormone (GH) therapy has been demonstrated for patients transplanted before 10 years of age and with documented growth hormone deficiency [36]. Risk of relapse of the original cancer with growth hormone therapy has not been shown, but there is some suggestion that it may be linked with an increased risk of second malignancies [37].

Puberty and fertility : Gonadal failure, pubertal failure, and infertility are well-known late effects of HSCT and are related primarily to the high-dose alkylator therapy and radiation (TBI) used for HSCT conditioning.

Undergoing HSCT can result in pubertal delay or, rarely, complete failure due to disruption of the hypothalamic-pituitary-gonadal axis. Delayed or incomplete puberty occurs in approximately 57% of females and 53% of males [38]. High doses of radiation to the hypothalamus and pituitary cause impaired gonadotropin secretion and hypogonadism. Lower doses of radiation (<20 Gy), however, can lead to an earlier onset of puberty. Early puberty combined with impaired GH secretion can result in severe stunting of growth. Boys who receive >24 Gy testicular radiation have a very high risk of pubertal failure and often need testosterone replacement to develop secondary sexual characteristics. The risk of delayed puberty is related to the conditioning regimen used (see Table 27.9).

Table 27.9 Risk of pubertal delay based on conditioning regimen
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Pubertal development affects the self-esteem and the social integration of adolescents. Hence, it must be monitored appropriately with timely hormone replacement if pubertal signs are not occurring after 13 years of age in girls and after 15 years of age in boys.

Gonadal failure is related to the pubertal status at the time of HSCT. One of the first signs of impaired sex hormone production is delayed puberty in prepubertal patients, while the postpubertal patients may demonstrate incomplete pubertal development, primary or secondary amenorrhea, and infertility due to premature menopause or azoospermia.

Premature ovarian failure is observed in approximately 65–84% of females after HSCT [38]. Ovarian failure is considered partial when plasma estradiol level is normal and complete when the plasma estradiol is low. Ovarian failure impairs both fertility and estradiol production. Risk factors include pubertal development at the time of HSCT, busulfan-/cyclophosphamide-based conditioning regimens, and single-dose, unfractionated TBI. Prepubertal patients are more resistant to the gonadotoxic effects of cyclophosphamide and are likely to retain or recover ovarian function. Prepubescent females can tolerate as high as 25–30 g/m2 of cyclophosphamide and retain ovarian function, while for women between 30 and 39 years of age, a dose of 9 mg/m2 causes a similar effect [39]. Fertility is more likely to be preserved in patients who undergo HSCT at a young age and those who receive non-TBI-based conditioning regimens. Several cases have reported the resumption of ovarian function after initial ovarian failure following HSCT. HSCT survivors who do get pregnant have an increased risk of preterm delivery and delivery of low birth weight infants if they received TBI as part of conditioning due to the radiation-induced structural changes of the uterus.

Testicular failure is seen in 45–85% of males after HSCT [40]. Younger age offers protection for boys as well. Similar to females, the risk of gonadal failure is dependent upon the conditioning regimen and dose (cyclophosphamide and TBI are more toxic). The germinal epithelium of the testes is more vulnerable to chemotherapy and radiation than the Leydig cells. Spermatogenesis is also exquisitely sensitive to radiation and even 2–3 Gy can cause significant impairment in function. In a prospective study of 64 male patients undergoing HSCT with various conditioning regimens, the overall rate of azoospermia was about 70% [41]. Recovery of spermatogenesis was directly related to the conditioning regimen. Among the patients who received cyclophosphamide alone, the recovery of spermatogenesis was seen in 90%, and those conditioned with cyclophosphamide plus busulfan or thiotepa, the recovery was seen in 50%. In contrast, for those who received cyclophosphamide plus TBI, spermatogenesis recovery was seen in just 17% of patients. The sperm quality and functional recovery time were better with cyclophosphamide alone as compared to other regimens. Thus, since the testosterone production is independent of spermatogenesis and even if fertility is impaired, the testosterone production may be normal.

Ovarian failure should be treated with hormone replacement therapy, and boys with Leydig cell failure should get testosterone replacement.

Pubertal stage should be assessed every 3–6 months until puberty is completed. The Children’s Oncology Group (COG) long-term follow-up guidelines recommend baseline estradiol, FSH, and LH testing at age 13 years for girls and baseline testosterone, FSH and LH testing for boys at age 14 years, and then as clinically indicated. The high prevalence of infertility among HSCT survivors highlights the importance of discussion of options for fertility preservation with patients and families prior to HSCT. Embryo cryopreservation is the standard option for adult females with a committed partner, while oocyte cryopreservation and ovarian tissue cryopreservation are currently available experimental options for females without a partner. Sperm cryopreservation is the best option for adolescent and young adult males with cancer and/or plan to undergo HSCT.

Musculoskeletal-Related Complications and Bone Health Post-HSCT

Long-term survivors of HSCT are known to have musculoskeletal problems including decreased bone mineral density , avascular necrosis (AVN) , and osteonecrosis. The major predisposing risk factors are radiation therapy (especially TBI), prolonged use of high-dose steroids, and low-estrogen secondary to therapy-related gonadal failure. Interplay of other modifying factors such as gender, age, physical activity status, nutritional status, race, family history, and intake of calcium and/or vitamin D plays an important role in overall bone health as well (see Table 27.10).

Table 27.10 Risk factors for reduced bone mineral density (BMD) after HSCT
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A prospective study involving children between 5 and 18 years of age who underwent HSCT showed that the incidence of osteopenia increased from 18% at baseline to 33% at 1 year post-HSCT. The most significant loss of bone density occurred in the first 6 months after HSCT. Bone-specific alkaline phosphatase decreased by 30% by day 100 post-HSCT and recovered to near baseline levels by 6 months, demonstrating that bone mineral density (BMD) can recover post-HSCT. Osteocalcin levels at day 100 post-HSCT predicted recovery of initial bone loss by 1-year post-HSCT [42]. Myeloablative therapy is known to affect the osteoprogenitor cells within the bone marrow and also cause a cytokine storm which stimulates bone resorption. As peak bone mineral accretion occurs in adolescence and young adulthood, children who were transplanted at a very young age should still be able to regain BMD.

AVN develops in approximately 4–10% of the HSCT survivors at a median of 12 months after allogeneic HSCT. It can cause significant morbidity and sometimes requires surgery including total joint replacement. A retrospective study of 1346 HSCT survivors revealed that the cumulative incidence of AVN was 2.9% at 10 years after an autologous HSCT, 5.4% after an allogeneic matched-related donor HSCT, and 15% after an unrelated donor HSCT. Among the allogeneic HSCT recipients, male sex, chronic GvHD, and exposure to immunosuppressants such as cyclosporine, tacrolimus, prednisone, and MMF (Cellcept) increase the risk of AVN, especially with exposure to three or more of these drugs [43]. In children, knees are the most common site of AVN followed by hips. Morbidity results from progressive joint damage and includes pain, decreased range of motion, arthritis, and articular collapse. If left untreated, joint destruction occurs within 1–5 years after onset of symptoms.

The pathogenesis of osteonecrosis is often multifactorial, and several mechanisms have been proposed including increased intraosseous pressure or intraluminal obliteration that can compromise intramedullary blood flow, causing marrow ischemia and then necrosis. Contributing mechanisms include defective bone repair due to damage to the bone marrow stroma, immunosuppression, and injury to the vessel wall and vasculitis related to radiation and drug.

MRI imaging has high sensitivity and specificity for detection of early lesions of AVN. Various interventions including Vitamin D and calcium supplementation, treatment with bisphosphonates, and hormone replacement therapy in females with gonadal failure are often implemented. Early referral to a pediatric orthopedic surgeon with expertise in surgery related to AVN is recommended for timely surgical intervention. Core decompression to relieve the intramedullary compartment syndrome is sometimes tried as a temporizing measure before joint replacement.

The COG long-term follow-up guidelines recommend a baseline DEXA (dual-emission x-ray absorptiometry) scan upon entry to long-term follow-up.

Renal Dysfunction

Nowadays, most children who undergo HSCT do not develop clinically significant renal dysfunction . A retrospective study of 121 long-term survivors of HSCT who were transplanted between 1991 and 1998 demonstrated a 24% prevalence rate of chronic renal failure (CRF) among these long-term survivors. Interestingly, their prospective cohort of patients who received a HSCT from 1998 to 2000 showed a lower prevalence of chronic renal failure (10%), reflecting the improvements in supportive care along with the less frequent use of nephrotoxic medications including amphotericin, aminoglycosides, and tighter control of cyclosporine A trough level targets. However, only 4–5% had GFR <70 ml/min/1.73 m2 [44]. High serum creatinine pre-HSCT is a strong predictor of CRF, and acute renal failure in the first 3 months post-HSCT shows a trend toward predicting CRF. The previously believed contributing role of TBI toward CRF has not been confirmed in recent studies. This observation is most likely due to the use of high-dose fractionated TBI nowadays. 3–12% of children have been found to have proximal tubular dysfunction 5 years after HSCT, and approximately 9–13% of patients have mild distal tubular dysfunction. However, neither of them is clinically significant.

Renal function normally stabilizes about 1-year post-HSCT, but yearly serum creatinine monitoring in long-term survivors is essential as a screening test of renal function. Serum creatinine, blood urea nitrogen, and serum chemistry should be checked at baseline. Urinalysis and blood pressure measurements should be performed at baseline and then annually thereafter.

Ocular Late Effects

The development of cataracts is a common complication in survivors of childhood HSCT (see Chap. 24). A study of HSCT survivors who were transplanted during childhood or adolescence showed that the cumulative incidence of cataracts was 36% at 15-year posttransplant [45]. The use of TBI for conditioning, cranial radiation, and GvHD is the greatest risk factor for cataract development. The cataracts from TBI are posterior and subcapsular which are different from the ones that occur with old age (nuclear cataracts). Hyperfractionated TBI has a lower incidence of cataract development than single-dose TBI (13% vs 21% p < 0.01) [46]. Other risk factors include age at the time of HSCT, steroid administration, and pre-HSCT cranial radiation.

Ocular surface disease such as dry eye syndrome (DES) , blepharitis, infection, conjunctivitis, corneal ulceration, keratitis, and keratoconjunctivitis sicca syndrome (KCS) has been seen post-HSCT of which DES is the most common in children, likely due to the fast regeneration of conjunctival epithelial cells in children. Severe ocular GvHD can lead to vision-threatening lesions such as uveitis, corneal ulceration, and severe KCS. Supportive care strategies, including the use of preservative-free artificial tears, long-acting lubricants, and close follow-up with an ophthalmologist, are essential. Severe KCS not responsive to supportive therapy can be treated with custom-fitted, fluid-ventilated, and gas permeable scleral lenses.

Patients with exposure to TBI, cranial radiation, and corticosteroids need annual ophthalmologic evaluations.

Dental and Oral Complications

Teeth: Many of the oral and dental sequelae of chemotherapy and radiation are irreversible and have long-term implications. Structural anomalies like enamel hypoplasia, microdontia, tooth agenesis, root malformation, increased risk of dental carries, as well as abnormal salivary function and secondary oral malignancies are increasingly recognized after allogeneic HSCT [47]. HSCT conditioning regimens, specifically those containing TBI, may cause tooth agenesis and root anomalies [47, 48]. A study of long-term childhood cancer survivors who were treated before the age of 10 years found that children who underwent HSCT with a TBI-containing conditioning regimen had smaller tooth roots as compared to children treated with other conditioning modalities [49].

Salivary gland: Salivary gland dysfunction in HSCT recipients occurs as a secondary effect of the conditioning regimens or as an early symptom of chronic GvHD. 60% of the HSCT survivors exposed to a conditioning regimen with cyclophosphamide and a 10-Gy single dose of TBI have decreased salivary secretion rates as compared to 26% in those who received cyclophosphamide and busulfan [50]. Chronic GvHD-associated salivary dysfunction is seen in 75–85% of patients with chronic GvHD and is secondary to the lymphocyte-mediated attack on the salivary duct and acinar tissue. Decreased and thickened saliva predisposes patients to increased and recurrent infections, dental decay, and periodontitis.

Others: Squamous cell carcinoma and parotid gland cancers are frequent secondary solid tumors following HSCT. Leukoplakia that occurs more than 2–3 years after HSCT may be misdiagnosed as chronic GvHD, and, thus, suspicious lesions need to be monitored closely and biopsied periodically to exclude malignant transformation.

Early identification of oral and dental morbidity and early interventions can optimize health and quality of life. Patients should be encouraged to maintain good oral hygiene and should be counseled to avoid carcinogenic exposures like tobacco use and excessive sun exposure.

Neurocognitive Complications

TBI and prolonged immune suppression post-HSCT increase the HSCT survivor’s risk for long-term neurocognitive complications (also see Chap. 24). The actual incidence of neurocognitive disabilities varies and is related to previous chemotherapeutic exposure (systemic and intrathecal), cranial radiation and age at the time of HSCT [51]. Several studies using neuropsychological testing have identified memory and attention deficits as the most prevalent and long-lasting neurocognitive impairments affecting adult HSCT survivors. Although some survivors have acute deficits in neurocognitive function that appear to improve over time, other patients have progressive declines that are chronic. Phipps et al. found that children less than three years of age at the time of HSCT and those who received cranial radiation as part of prior therapy were at increased risk, especially those who received extra CNS radiation dose from TBI [52].

Patients and families should be counseled about possible cognitive impairment that may occur during and immediately after HSCT. Neurocognitive testing should ideally be performed prior to HSCT, and then as the child progresses through school, an individualized education plan should be generated for the patient as needed to help set the survivor up for success by allowing the patient’s educational strengths to overcome any noted deficits.

Conclusion

The high burden of late effects resulting from the intensive regimens used for attaining cure highlight the need for alternative strategies to help decrease a child’s cumulative exposure to chemotherapy and radiation. Pre-HSCT therapeutic exposure, conditioning regimens, immune suppression post-HSCT, and GvHD all contribute toward the development of chronic and sometimes debilitating health conditions. New advances with targeted therapies and promising results with chimeric antigen receptor T cells (CAR-T cells) [53, 54] (which are genetically modified, tumor directed T cells) offer novel approaches other than HSCT for attaining remission for relapsed and refractory disease. Research efforts are ongoing to explore reduced intensity conditioning regimens for various diseases which would significantly decrease the morbidity from these therapy-related late effects. Chronic GvHD remains a significant contributor to the chronic health conditions resulting from a HSCT, not only from the direct effects it has on multiple organ systems but also the toxic therapies that are needed to treat it. Determined attempts to find novel approaches to prevent and treat GvHD are of utmost importance and being actively investigated.

In addition, the timely and appropriate screening of patients for therapy-related late effects in long-term follow-up clinics dedicated to HSCT patients is critical due to the direct impact of these long-term effects on the morbidity and mortality of the survivors. It is essential to educate patients about their past therapy and possible late effects resulting from it to so that they are aware of the signs and symptoms and will be proactive about seeking out medical attention early on. Innovative therapies as well as risk-adapted and patient-specific timely screening for treatment-related effects will help decrease the burden of late effects in this unique pediatric population.

Key Points

  • Hematopoietic stem cell transplant (HSCT) is gaining increasing prominence as a curative therapeutic option for patients with malignancies and many nonmalignant conditions.

  • Two-thirds of HSCT survivors will develop at least one chronic condition.

  • Mortality rates among 15-year survivors of HSCT remain twice as high as the general population.

  • Alkylators and topoisomerase II inhibitors are major culprits for the development of treatment-related myelodysplastic syndrome (t-MDS).

  • HSCT survivors are at a 2.3- to 4.0-fold increased risk of death due to cardiac-related causes compared to the general population.

  • Hypothyroidism, metabolic syndrome, and growth impairment are common endocrine problems in patients who received a total body irradiation (TBI)-containing conditioning regimen.

  • Gonadal failure is directly related to the age at HSCT and the conditioning regimen.

  • Radiation therapy (especially TBI), high-dose steroids, and low estrogen secondary to gonadal failure are key factors for the development of decreased bone mineral density and avascular necrosis in HSCT patients.

  • Risk-based and exposure-related screening for therapy-related late effects is critical in order to avoid long-term morbidity in this unique population.