Children who survive hematopoietic stem cell transplantation (HSCT) are at risk for an inordinate number of long-term side effects. Late effects can be secondary to the underlying diagnosis for which the transplant is performed, prior treatment of the disease, the transplant preparative regimen, treatment of the complications of transplant, and immunologic interactions between the graft and the host. This article describes the risks and manifestations of the most commonly reported late effects in survivors of pediatric HSCT.
In the last several decades, hematopoietic stem cell transplantation (HSCT) has become accepted as a standard-of-care treatment modality for an increasing number of malignant and nonmalignant diseases of children. Advances in patient and donor selection, preparative regimen design and delivery, and supportive care have led to improved patient survival. As more children survive HSCT, however, the price of survival has become increasingly apparent in the protean manifestations of the late effects of treatment.
Late effects following treatment of childhood cancer are increasingly well studied; less is known about late effects specifically attributable to HSCT, although several studies document more complications in transplant survivors than in those treated with chemotherapy alone for similar diseases. Very little is known about late complications following reduced-intensity conditioning regimens, or HSCT for nonmalignant disorders.
This article reviews recent literature on the study of childhood HSCT survivors through a systems-based approach and provides current references for topics of interest.
Systems-based review
Cardiovascular
The risks for late cardiovascular (CV) disease or events in survivors after HSCT have not yet been studied in detail. For the HSCT patient, the risk is cumulative, and in addition to pretransplant conditioning therapy, pre-HSCT treatment exposures including cumulative doses of anthracyclines and exposure to radiation therapy that may have included the heart or mediastinum, have to be accounted for. For anthracyclines the risk is dose and age dependent, with the highest risk for cardiomyopathy seen at doses of 550 mg/m 2 or higher in patients older than 18 years, and at doses of 300 mg/m 2 or higher in patients less than 18 years at the time of treatment. However, higher risks are associated with the combined exposure to radiation therapy. In HSCT patients there is frequently the additional exposure to high-dose cyclophosphamide (CY), which has been described as a cause of acute cardiotoxicity, and to total body irradiation (TBI). In practice the CY/TBI regimen is a commonly used transplant regimen, and there does not seem to be a great deal of clinical evidence on the long-term risk of cardiomyopathy in HSCT patients who do not have significant pre-HSCT exposure to cardiotoxic therapies.
A higher risk of CV mortality has been described in childhood cancer survivors; the standardized mortality ratio for cardiac-related deaths was 8.2 (95% confidence interval [CI] 6.4–10.4) among 5-year or longer survivors of childhood cancer, and 3.8 (95% CI 1.5–7.6) for leukemia survivors. Although CV mortality has not been specifically evaluated in a population of pediatric survivors after HSCT, large studies of late mortality after HSCT that have included children have shown a higher risk of mortality from CV events compared with the general population. The Bone Marrow Transplant Survivor Study has evaluated selected CV risk factors, and survivors of allogeneic HSCT were found to be 3.65 times (95% CI 1.82–7.32) more likely to report diabetes mellitus than siblings and 2.06 times (95% CI 1.39–3.04) more likely to report hypertension compared with siblings. Allogeneic HSCT survivors were also more likely to develop hypertension (OR = 2.31, 95% CI1.45–3.67) than autologous recipients and TBI exposure was associated with an increased risk of diabetes mellitus (OR = 3.42, 95% CI 1.55–7.52). The patients in this cohort were relatively young (mean age at survey completion was 39.3 years); thus, the concern is that the higher risk of these outcomes at a relatively young age will lead to a higher than expected risk of CV events as these individuals grow older. Long-term screening for the development of hypertension and diabetes mellitus and screening for other CV risk factors such as lipid abnormalities and obesity are certainly indicated in HSCT survivors.
Metabolic Syndrome
The metabolic syndrome (central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension) is associated with a substantially increased risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD). Although limited, there is evidence to suggest that long-term childhood cancer survivors may be at high risk for premature development of characteristics associated with the metabolic syndrome. In 1 study, 23 long-term survivors (median age 20 years), who were 3–18 years post HSCT for leukemia, 13 patients in remission from leukemia without HSCT, and 23 healthy age- and sex-matched controls were evaluated for metabolic syndrome parameters. Hyperinsulinemia, impaired glucose tolerance, hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol, and abdominal obesity were more common among the HSCT survivors than among the non-HSCT group of leukemia patients or the healthy controls. Core signs of the metabolic syndrome were found in 39% of HSCT survivors versus 8% of leukemia controls and 0% of healthy controls. Fifty-two percent of HSCT patients were found to have hyperinsulinemia and 43% had abnormal glucose metabolism, compared with none of the healthy controls ( P = .0002 and 0.001 respectively). Variables associated with hyperinsulinemia in the HSCT patients were time from transplantation ( P = .01), presence of chronic graft-versus-host disease (GVHD) ( P = .01), and hypogonadism ( P = .04). Another study in 34 children and adolescents after either autologous or allogeneic HSCT compared with 21 age- and sex-matched controls found that the 18 patients who received TBI had a significantly higher first phase insulin response and insulinemia/glycemia ratio on glucose tolerance testing compared with patients who received only lymphoid radiation, no radiation, or controls. These results suggest that TBI may play a role in the development of insulin resistance.
In ongoing studies of CV risk in survivors of HSCT for hematologic malignancy, measures of insulin resistance, fasting glucose, insulin, lipids, anthropometry, blood pressure, and carotid artery compliance and distensibility were determined in 106 children and young adults (current age 26.6 years) who had received HSCT for hematologic malignancy during childhood (mean age at HSCT 9.9 years) and 72 healthy sibling controls. Sixty-two patients received TBI, 20 received cranial radiation before TBI (TBI + cranial radiation), and 24 received no TBI or cranial radiation (noXRT) before or during HSCT. Metabolic syndrome was present in 15/106 (14.2%) HSCT survivors and 4/72 (5.6%) controls (odds ratio [OR] 2.3, 95% CI 0.7–7.7, P = .16). However, 2 or more components of metabolic syndrome were present in 39/106 (37%) survivors and only 10/72 (13.9%) controls (OR, 2.7, 95% CI 1.2–5.9, P = .015). Compared with siblings, there were no differences between groups for glucose, body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), waist circumference, percent body fat, or blood pressure. However, HSCT survivors who had TBI or TBI + cranial radiation all had significantly higher total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and insulin. Those who received TBI + cranial radiation had significantly lower HDL-cholesterol and were also more insulin resistant. However, for the patients who did not receive any radiation before or during HSCT, there were no differences in any of the CV risk factors compared with controls. These findings are of concern and suggest that even at a relatively young age, and independent of obesity, survivors of HSCT for childhood hematologic malignancies have increased CV risk factors that are associated with exposure to TBI and/or cranial radiation. These abnormalities may ultimately contribute to a higher risk of early CV morbidity and mortality; thus early screening and management of modifiable CV and metabolic risk factors should be considered in HSCT survivors.
Pulmonary Late Effects
Pulmonary toxicity of HSCT is a major cause of morbidity and mortality in the first year after transplant and impaired pulmonary function (PF) after transplant is a common late effect. Obstructive pattern PF is present in bronchiolitis obliterans within the context of chronic GVHD, typically in the first year after transplant. Obstructive PF is only found in up to 10% of childhood HSCT survivors, but has a high morbidity and mortality. Restrictive and impaired diffusion pattern PF have been shown to be much more common long-term after HSCT. Restrictive PF and/or impaired diffusion capacity have been found in 20% to 40% and 35% to 80% of childhood HSCT survivors, respectively. It has been shown that PF may be abnormal even before HSCT, likely as a result of previous treatment, such as chemotherapy or radiation for malignant disease. After HSCT, PF may deteriorate in the first 1 to 2 years, with some improvement in the years thereafter. However, PF does not normalize or return to pretransplant values and 5 to 10 years after HSCT, restrictive PF abnormality and impaired diffusion persist. Currently, the course of the PF abnormalities more than 10 years after HSCT in childhood is unknown. Only 1 cross-sectional study analyzed PF in pediatric HSCT survivors more than 10 years after HSCT. Fortunately, most children have only mild to moderate impairment of PF and are asymptomatic, with impaired function detected by PF tests only. Analysis of risk factors for impaired PF after HSCT has been hampered by small patient numbers in most studies; some patients received pulmotoxic treatment of their underlying malignant disease pre-HSCT and most conditioning regimens include at least 1 pulmotoxic modality. Busulfan and TBI in the conditioning regimen have been determined to be risk factors for impaired PF.
Although childhood cancer survivors are noted to have an increased risk of recurrent infection and chronic cough, no such data exist for children who have undergone HSCT. Additional information is required with regard to long-term PF in children who have undergone transplantation.
Endocrine
There is a high prevalence of endocrine dysfunction in children who survive HSCT. This is attributed to the conditioning regimens used, whether or not they contain radiation or high-dose chemotherapy only. Disturbances in thyroid function, onset of puberty, fertility, bone health, and growth and development, all are commonly reported.
Thyroid dysfunction
Thyroid dysfunction is common post HSCT and is reported in up to 50% of survivors. The wide variation in incidence may be attributed to time post transplant, with those surviving longest at highest risk.
Abnormalities described include sick euthyroid syndrome, especially occurring early post HSCT, overt hypothyroidism, compensated hypothyroidism, thyrotoxicosis (rarely), and secondary thyroid carcinomas. The use of radiation was initially felt to be the primary cause of thyroid dysfunction. However, recent data have also implicated chemotherapy-only regimens, particularly those using busulfan.
Puberty and fertility
Normal pubertal development is a result of complex interactions between the hypothalamus (gonadotropin-releasing hormone), the pituitary (luteinizing hormone (LH) and follicle-stimulating hormone (FSH) production), sex steroid hormone production and secretion, and target organ responsiveness. For most individuals studied post HSCT, the hypothalamic-pituitary axis appears intact, with increased production of LH and FSH in the setting of delayed puberty, amenorrhea, and/or azoospermia. In general, for women, hormonal function correlates with fertility. Prepubertal females can tolerate higher doses of alkylating agents than pubertal females due to decreasing ovarian follicle reserves with age, but high doses of radiation and busulfan can lead to premature ovarian failure. For males, endocrine function is retained at higher doses of radiation or alkylating agents than females, but spermatogenesis is much more vulnerable. High-dose chemotherapy and radiation result in damage to the germinal epithelium, with increased LH levels but usually normal testosterone levels, reflecting the Leydig cells’ resistance to cytotoxic agents relative to Sertoli cells. Puberty is often delayed for these boys. Girls receiving chemotherapy and fractionated radiation before puberty may enter and progress through puberty normally; postpubertal girls often experience amenorrhea, with few experiencing ovarian function recovery over time. Preparative regimens that include busulfan and radiation are strongly associated with ovarian failure and azoospermia. In contrast, children receiving cyclophosphamide alone usually enter and progress through puberty normally, although ovarian failure has been observed in these patients.
There have been several reports of successful pregnancies in women who have undergone HSCT or are married to men who underwent HSCT. Congenital anomalies are not increased more than that of the general population; however, there is a higher incidence of cesarean section, preterm delivery, and low birthweight in babies born to transplant survivors compared with the general population.
Growth
Like puberty, growth is dependent on the complex interplay of several factors. Several studies have demonstrated significant growth delay in children undergoing HSCT. Radiation, especially craniospinal radiation, is implicated as the primary cause of growth failure post HSCT. The hypothalamic-pituitary axis can be damaged by cranial radiation, resulting in decreased growth hormone (GH) production. Radiation can also damage the epiphyseal growth plates of bone, leading to premature fusion. In addition, the pubertal growth spurt, which is dependent on the interaction between sex steroids and GH, will not occur in the setting of poor gonadal function. Growth deficiency has been documented in children receiving TBI, TBI plus craniospinal irradiation, and in children who received TBI who also were treated for chronic GVHD. Fractionated TBI seems to have less effect than single-dose radiation, but still produces overall reduced final height (although still within population norms). In documented GH deficiency, GH replacement has been helpful in minimizing the growth loss associated with HSCT-related therapies, but it does not seem to result in catch-up growth.
Bone health
There are several retrospective and cross-sectional studies of bone mineral density (BMD) in pediatric HSCT survivors, and 1 prospective study. Whether decreased BMD is related to transplant or caused by pretransplant conditions is unclear. Childhood cancer survivors, for example, are known to be at high risk for osteopenia and osteoporosis, conditions that predispose to or are associated with decreased BMD. Recently, however, studies have shown that children with nonmalignant diseases may also have decreased BMD before undergoing transplantation. BMD loss for children undergoing HSCT has been shown to be more profound than that of adults. This is highly significant, as BMD loss in childhood may result in relatively decreased peak bone mass and increased risk or early onset osteoporosis and fractures later in life. A prospective study from the University of Minnesota showed the most profound loss of BMD within the first 6 months following HSCT, similar to what is reported in adults. Some children recovered; however, 33% remained osteopenic and 19% osteoporotic at 1 year following HSCT.
Risk factors for BMD loss during HSCT include chemo- and radiotherapy, glucocorticoid use, prolonged physical inactivity, transient estrogen insufficiency in females, and use of total parenteral nutrition. A retrospective study from Seattle suggests that the use of bisphosphonates in addition to supplemental vitamin D and calcium may reverse osteopenia and osteoporosis post HSCT. This intervention requires further study.
Renal
Acute and chronic renal dysfunction have long been associated with HSCT. Multiple factors contribute to acute renal insufficiency in the immediate posttransplant setting, including chemotherapy and radiation, medications used during HSCT (particularly calcineurin inhibitors), extreme fluid shifts, venoocclusive disease of the liver, hepatorenal syndrome, sepsis, and the antimicrobial agents used to treat infections. Chronic renal insufficiency following HSCT has often been attributed to radiation-induced renal injury but has also been associated with chronic GVHD. There are 3 prospective studies reporting on renal function in children post HSCT. Kist-van Holthe and colleagues found acute renal insufficiency post HSCT to be associated with venoocclusive disease of the liver, high serum cyclosporine levels, and foscarnet therapy, but not with radiation. In addition, they found that acute renal insufficiency was the only risk factor for development of chronic renal disease. Patzer and colleagues 59 found glomerular filtration rates to be normal post HSCT, but significantly lower than pre-HSCT testing. Unlike Kist-van Holthe and colleagues these investigators found no correlation between renal insufficiency early after transplant and chronic renal insufficiency. Frisk and colleagues was the only study to find a correlation between renal insufficiency and radiation. These investigators found that TBI was associated with chronic renal insufficiency.
Gastrointestinal/Hepatic Late Effects
Most HSCT procedures are complicated by gastrointestinal mucosal injury. The gastrointestinal tract is also commonly involved in acute GVHD. However, late luminal gastrointestinal problems after HSCT have not been reported to date and acute gastrointestinal problems seem to be reversible in most children.
By contrast, elevated liver enzymes are a common occurrence in the acute phase after HSCT and long-term, with studies in children and adults showing a prevalence of recurrent or persistently abnormal liver enzymes 1 to 10 years after transplant that varies from 10% to 57%. Only 3 studies have focused on late (1–6 years post HSCT) hepatic effects after transplant in childhood. These studies showed a prevalence of abnormal liver enzymes in childhood allogeneic HSCT survivors of 25% and 53%, respectively. In the study by Locasciulli and colleagues this was explained in more than half of the patients by hepatitis C virus (HCV) and/or hepatitis B virus (HBV) infection in children who had received blood transfusion before HCV screening was implemented. Abnormal liver enzymes late after HSCT have been found to be caused by chronic viral hepatitis B or C, iron overload, chronic GVHD, and autoimmune hepatitis. As a result of the implementation of screening of blood products for HBV and HCV, transfusion-acquired viral hepatitis is less common in survivors of HSCT transplanted more recently. Chronic GVHD as a cause of abnormal liver enzymes is more prevalent in adults compared with children after HSCT. In a proportion of HSCT survivors with elevated liver enzymes, no apparent cause is found.
In most HSCT survivors with elevated liver enzymes, synthetic and metabolic liver function is normal and no signs or symptoms of liver disease are found. Pediatricians are obviously reluctant to perform liver biopsies in these children, and histopathologic correlates are thus unknown. It is uncertain, especially in cases of unknown cause, how liver function may evolve in these patients over time and if survivors are at risk for cirrhosis.
Another reported late hepatic effect of chemotherapy and/or HSCT is the development of focal nodular hyperplasia (FNH). FNH is the second most common benign tumor of the liver and may mimic metastases and secondary malignant tumors. Magnetic resonance images are diagnostic and no further investigations are needed, but long-term imaging surveys are recommended. Neither complications nor malignant transformation of FNH have been reported to date.
Oral/Dental Late Effects
Reported oral and dental problems after cancer treatment and/or HSCT include xerostomia, gingivitis, abnormal development of teeth (tooth agenesis, hypodontia, microdontia, enamel hypoplasia, malformed roots, taurodontia), delayed eruption, over-retention of primary teeth, and increased caries index. Disturbances in craniofacial growth may be seen and a higher risk of developing secondary oral tumors exists. Adverse effects on mineralized dental tissues are typically irreversible and may affect the quality of life (QoL) of survivors permanently. Some studies have indicated that xerostomia is a significant problem in childhood HSCT survivors, even in those who did not receive TBI. Fibrosis of the salivary gland ducts may occur in the context of chronic GVHD.
Chemotherapy and radiotherapy have been described as risk factors for dental late effects. Children less than 5 years old at the time of HSCT have been shown to have the highest risk for dental late effects, especially involving developmental problems but also including caries and gingival problems. Dental late effects are less common in children aged 12 years or older at the time of transplant. The development of permanent teeth and their roots starts at about 3 years of age and may last up to the age of 7.5 years. Chemotherapy and radiotherapy given at this time will therefore likely interfere with dental development.
Regular dental care by a dentist familiar with HSCT-related oral and dental late effects is important in children and adults after HSCT in childhood.
Ocular Late Effects
Cataracts are the most commonly reported ocular late effect of pediatric HSCT, with cumulative incidence rates ranging from 28% to 78% in various studies. The development of cataracts is strongly associated with the use of TBI in conditioning regimens, but in some studies is also influenced by steroid administration and the presence of chronic GVHD. Ocular sicca syndrome (associated with chronic GVHD) and microvascular retinopathy have also been reported.
Neurocognitive Late Effects
As more and more children survive HSCT, progress through school, and enter adulthood, more attention is being focused on neurocognitive and psychosocial outcomes. Several recent prospective studies have evaluated neurocognitive function before and after HSCT, with patients evaluated from 1 to 5 years post transplant. All studies suffer from high attrition rates. In addition, measurement scales are not consistent across ages and developmental stages, which makes longitudinal comparison of outcomes problematic.
Kupst and colleagues found virtually no decline in neurocognitive function in 74 survivors followed up to 2 years post HSCT. Socioeconomic status and pre-HSCT full scale intelligence quotient (IQ) measures correlated strongly with post-HSCT outcomes. Phipps and colleagues, who followed children prospectively for 5 years post HSCT, found a very slight global decline in IQ (2 IQ points, within the margin of error for the testing performed). There were small but significant declines in IQ in children transplanted for malignant disorders, those who received TBI or craniospinal radiation, and those who developed acute GVHD. Again, socioeconomic status was the most important determinant of cognitive and academic function. Kramer and colleagues found a modest but significant decline in mean IQ 1 year post HSCT, with no significant further decline at 3-year follow-up. However, more than 40% of children in this study experienced declines in IQ of greater than 2 standard deviations from baseline measures. Again, pre-HSCT IQ was the most significant predictor of post-BMT functioning; there was no association with age at HSCT, the use of TBI and/or busulfan-containing regimens, or any other factors related to treatment or diagnosis. Most of these patients were less than 6 years of age when transplanted, so may have been more susceptible to deleterious effects. Barrera and colleagues found normal to higher than average verbal, performance, and full IQ scores 2 years post transplant; however, these children had mean arithmetical scores significantly less than normal. This is consistent with data from survivors of childhood leukemia and central nervous system tumors, and requires further investigation.
In the studies referred to earlier, patients with multiple pretransplant diagnoses were pooled. In a recent study including only children with hematologic malignancies, the Stanford group found significant declines in verbal skills 3 years post HSCT. When evaluated 5 years following transplantation, this group showed continued declines in verbal skills, performance skills, and long-term and overall memory. All declines were significant compared with sibling controls. When children who underwent HSCT that included a conditioning regimen with craniospinal radiation were compared with those who had not received craniospinal radiation, the former group was found to have significantly worse scores in cognitive function, performance skills, and short- and long-term memory.
Immune Reconstitution
Immune reconstitution following HSCT is extremely complex and dependent on various factors. Recipient factors include age, the underlying disease for which the transplant is being performed, prior treatment, and general physical condition. Stem cell source (autologous, allogeneic matched related or unrelated, umbilical cord blood, bone marrow or peripheral stem cells, manipulated (ie, T-cell depleted) or unmanipulated) also affects immune reconstitution, as do the conditioning and GVHD prophylaxis regimens used. The occurrence of GVHD has a profound effect on immune reconstitution. A thorough review of immune reconstitution is beyond the scope of this article, but several excellent review articles are available.
Children commonly require revaccination following recovery from HSCT. The United States Centers for Disease Control (CDC) and the European Blood and Marrow Transplant Group (EBMT) have established somewhat arbitrary timetables for the initiation of revaccination following HSCT; the CDC recommends beginning killed vaccines at 1 year post HSCT and live viral vaccines at 2 years, whereas the EBMT recommends initiation of vaccination as early as 6 months post HSCT. It is by no means clear that all children will be sufficiently immune-replete to mount a protective response to vaccines at these time points. Many individual centers, therefore, have developed their own approaches for revaccination, including the evaluation of surrogate markers (ie, CD4+ counts, IgG levels, and so forth.) of immune reconstitution before initiating vaccines. This is an area requiring further study and careful standardization of practice.
Chronic GCHD (cGVHD) and Multisystem Effects
cGVHD in children can result in significant long-term morbidity and mortality. cGVHD, reviewed elsewhere in this issue, can certainly lead to multiple long-term complications for patients after HSCT. The manifestations from skin and joint involvement, with sclerodermatous features and joint contractures, can lead to impairment in mobility and function with subsequent difficulties with activities of daily living, school, and work. Liver involvement can result in abnormalities of liver function, persistent jaundice, and in severe cases, liver failure. Pulmonary involvement with significant obstructive pulmonary disease is one of the most devastating consequences of cGVHD. Pulmonary involvement can be very difficult to treat and can lead to significant disability. cGVHD and the ongoing immunosuppressive therapies required for its treatment can result in significant suppression of immune function and the risk for secondary bacterial, viral, or fungal infections.
Other common features of cGVHD that can result in long-term problems include xerostomia and keratoconjunctivitis sicca. Both can be medically managed, but these conditions do have an adverse effect on a patient’s QoL. When prolonged therapy for cGVHD is required, steroids are a necessary part of the management. Thus, children with cGVHD receiving months to years of steroid therapy are also at high risk for the long-term complications of steroid therapy such as avascular necrosis, growth failure, glucose intolerance, hypertension, and others.
Special situations
Sequelae for Infants
Infants requiring HSCT are one of the most significant challenges for pediatric transplant centers. The long-term complications that can occur after HSCT in infants result from exposures to pretransplant chemotherapy (and possibly central nervous system (CNS)-directed radiation therapy [CRT]), and the high-dose chemotherapy with or without TBI associated with the transplant preparative regimen. There are only a handful of studies on the long-term complications after HSCT for infants. One from the University of Minnesota examined the long-term follow-up of 17 children who underwent HSCT for acute myeloblastic leukemia or acute lymphoblastic leukemia (ALL) at less than 3 years of age. Eleven patients (65%) received TBI (none received CRT) and 7 received preparative regimens with busulfan and cyclophosphamide. Median follow-up was 11.5 years after HSCT. Medical outcomes and complications of HSCT that occurred in survivors included GH deficiency (58.8%), hypothyroidism (35.3%), abnormal pubertal development (11.8%), osteopenia/osteoporosis (23.5%), short stature (47.1%), dental abnormalities (47.1%), and cataracts (47.1%). Dyslipidemias were present in 58.8% of patients, hyperinsulinemia in 17.6%, and hypertension in 11.8%, all characteristics associated with the metabolic syndrome. All patients underwent neuropsychological testing. Survivors were found to perform more poorly on measures of sustained attention, inhibition, response speed, and consistency of attentional effort ( P <.001). They also performed more poorly on measures of fine motor speed/dexterity ( P <.001) and visual-motor integration skills ( P <.006). However, performance on measures of general intellectual ability and academic achievement were within expectations based on population norms. In addition, measures of QoL in survivors were not different compared with population norms. Although two-thirds of patients in this study received TBI and showed a range of neuropsychological deficits, most were actually functioning at an average academic level or higher. This study was unable to make any definitive comparisons between preparative regimens with and without TBI.
A similar study from St Jude Children’s Research Hospital reported on the late sequelae of 34 children diagnosed with acute leukemia at age 12 months or younger. These patients were divided into 3 groups based on treatment exposures: group A, chemotherapy alone (n = 10); group B, chemotherapy and CRT (n = 17); and group C, chemotherapy, HSCT, and CRT (n = 7, [cranial only n = 2, craniospinal n = 1, TBI n = 4]). From a growth standpoint, compared with patients in group A, patients in group B had a greater decrease in height Z scores, and patients in group C had the greatest decrease in height Z scores with 71% of them decreasing by more than 2 standard deviations. Other endocrine abnormalities included hypothyroidism (21%, from groups B and C only). Three patients had precocious puberty (from groups B and C) and 1 patient from group B had delayed puberty after testicular radiation. Two patients developed mild cardiac dysfunction and 2 exposed to TBI developed cataracts. Neuropsychological evaluations found that 50% did not have any academic difficulties that required special tutoring or special education classes, whereas the other 50% did require these services. Patients in groups B and C had higher incidences of academic difficulties (59% and 86%, respectively) compared with 10% in group A. The odds of academic difficulties were inversely related to age, and increased by 18% for each month of age younger at the time of CRT.
More data are needed to better define the impact of non-TBI conditioning regimens in infants undergoing HSCT and to account for the additive effect of pretransplant treatment exposures on the ultimate development of chronic medical conditions. In addition, the factors associated with HSCT that influence the success rate of the HSCT itself, such as TBI for children with ALL, and whether the same holds true for infants, must be taken into account.
Transplant for Nonmalignant Disease
There are a wide variety of nonmalignant disorders for which HSCT is a common therapeutic option, including immune deficiency disorders, metabolic storage disorders, nonmalignant hematologic diseases such as thalassemia and sickle cell disease, congenital bone marrow failure syndromes, and others. Late complications in these patients can be associated with the transplant conditioning regimen but also to issues specific to the underlying disease, including iron overload with cardiac, growth, hepatic, and endocrine consequences for thalassemia, sickle cell disease, and other bone marrow failure diseases for which large numbers of transfusions have been administered. Patients with mucopolysaccharide storage diseases may have cardiac, musculoskeletal, and neurologic complications that become more problematic as they age, because their life expectancy is prolonged after successful HSCT. Patients with Fanconi anemia and other diseases with underlying genetic instability have an inherent risk of certain types of malignancies and these risks may be further amplified by the exposure to certain chemotherapeutic agents or to TBI. Thus, children transplanted for these types of disorders require not only standard posttransplant long-term follow-up but also surveillance for additional complications that may be related to their underlying disease.
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