Late Effects After HCT in Children
Methodological Challenges Specific to HCT
Cardiovascular System Late Effects
Central Nervous System Late Effects
Digestive System Late Effects
Gastrointestinal, biliary, and pancreatic dysfunction
Endocrine System Late Effects
Abnormal body composition/metabolic syndrome
Musculoskeletal System Late Effects
Low bone mineral density
Reproductive System Late Effects
Respiratory System Late Effects
Chronic pulmonary dysfunction
Urinary System Late Effects
Quality of Life
Health-related quality of life (HRQL)
Published Guidelines for Long-Term Follow-Up
Data from studies of child and adult survivors of HCT have shown a significant impact from treatment-related exposures on survival and quality of life. Of those alive at 2 years after HCT, a 9.9-fold increased risk of premature death has been noted.Methodological Challenges Specific to HCT
Although the main cause of death in this cohort is from relapse of the primary disease, a sizeable number of these patients die from graft-versus-host disease (GVHD)-related infections, second malignancies, or cardiac or pulmonary issues.[2-5] In addition, other studies have revealed that up to 40% of HCT survivors experience either severe, disabling, and/or life-threatening events or die because of an adverse event associated with cancer treatment.[6,7]
Before initiating studies aimed at decreasing the incidence or severity of these effects, it is important to understand what leads to the development of these complications:
- Pretransplant therapy: Pretransplant therapy plays an important role, but the details of significant exposures associated with pre-HCT therapy are not included in many studies.
- Preparative regimen: The transplant preparative regimen itself (e.g., total-body irradiation [TBI], high-dose chemotherapy) has often been studied, but this intense therapy is only a small part of a long course of therapy filled with potential causes of late effects.
- Allogenicity: The effect of allogenicity—differences in major and minor human leukocyte antigens that lead to GVHD, autoimmunity, chronic inflammation, and sometimes, undetected organ damage—also contributes to these effects.
Individuals differ in their susceptibility to specific organ damage from chemotherapy or in their risk of GVHD based upon genetic differences in both the donor and recipient, which modifies the effect of these exposures.[8-10]Cardiovascular System Late Effects
Although cardiac dysfunction has been studied extensively in non-HCT settings, less is known about the incidence and predictors of congestive heart failure following HCT in childhood. Potentially cardiotoxic exposures unique to HCT include the following:
- Conditioning with high-dose chemotherapy, especially cyclophosphamide.
HCT survivors are at increased risk of developing cardiovascular risk factors such as hypertension and diabetes, likely due in part to exposure to TBI and prolonged immunosuppressive therapy following allogeneic HCT, or related to other health conditions (e.g., hypothyroidism or growth hormone deficiency).[7,11]
Rates of cardiovascular outcomes were examined among nearly 1,500 transplant survivors (surviving ≥2 years) treated in Seattle from 1985 to 2006. The survivors and a population-based comparison group were matched by age, year, and sex. Survivors experienced increased rates of cardiovascular death (adjusted incidence rate difference, 3.6 per 1,000 person-years [95% confidence interval, 1.7–5.5]) and had an increased cumulative incidence of ischemic heart disease, cardiomyopathy/heart failure, stroke, vascular diseases, and rhythm disorders. Survivors also had an increased cumulative incidence of related conditions that predispose towards more serious cardiovascular disease (i.e., hypertension, renal disease, dyslipidemia, and diabetes).
In addition, cardiac function and pre-HCT exposures to chemotherapy and irradiation have been shown to have significant impact on post-HCT cardiac function. In evaluating post-HCT patients for long-term issues, it is important to consider levels of pre-HCT anthracycline and chest irradiation. Although more specific work needs to be done to verify this, current evidence suggests that the risk of late-occurring cardiovascular complications following HCT may be largely due to pre-HCT therapeutic exposures, with little additional risk from conditioning-related exposures or GVHD.[14,15]Central Nervous System Late Effects
Researchers from St. Jude Children’s Research Hospital have reported on the largest longitudinal cohort to date, describing remarkable stability in global cognitive function and academic achievement during 5 years of posttransplant follow-up.[19-21] This group reported poorer outcome in patients undergoing unrelated donor transplant in those who received TBI, and in those who experienced GVHD, but these effects were small compared with the much larger effects seen based on differences in socioeconomic status. The majority of published studies report similar outcomes. Normal cognitive function and academic achievement was reported in a cohort of 47 patients followed prospectively through 2 years post-HCT. Stable cognitive function was also noted in a large cohort followed from pretransplant to 2 years post-HCT. A smaller study reported similar normal functioning and absence of declines over time in HCT survivors. HCT survivors did not differ from their siblings in cognitive and academic function, with the exception that survivors performed better than siblings on measures of perceptual organization. Based on the findings to date, it appears that HCT poses low to minimal risk for late cognitive and academic deficits in survivors.
A small number of studies, however, report some decline in cognitive function after HCT.[24-29] These studies tended to include samples with a high percentage of very young children. One study reported a significant decline in IQ in their cohort at 1 year post-HCT, and these deficits were maintained at 3 years post-HCT.[25,26] Similarly, studies from Sweden have reported deficits in visual-spatial domains and executive functioning in very young children who were transplanted with TBI.[28,29]Digestive System Late Effects
Gastrointestinal, biliary, and pancreatic dysfunction
Most gastrointestinal late effects are related to protracted acute GVHD and chronic GVHD (refer to Table 12).Table 12. Causes of Gastrointestinal (GI), Hepatobiliary, and Pancreatic Problems in Long-Term Transplant Survivorsa
|Problem Areas||Common Causes||Less Common Causes|
|Esophageal symptoms: heartburn, dysphagia, painful swallowing [31-36]||Oral chronic GVHD (mucosal changes, poor dentition, xerostomia)||Chronic GVHD of the esophagus (webs, rings, submucosal fibrosis and strictures, aperistalsis)|
|Reflux of gastric fluid||Hypopharyngeal dysmotility (myasthenia gravis, cricopharyngeal incoordination)|
|Squamous > adenocarcinoma|
|Infection (fungal, viral)|
|Upper gut symptoms: anorexia, nausea, vomiting [37-41]||Protracted acute GI GVHD||Secondary adrenal insufficiency|
|Activation of latent infection (CMV, HSV, VZV)||Acquisition of infection (enteric viruses, Giardia, cryptosporidia, Haemophilus pylori)|
|Medication adverse effects||Gut dysmotility|
|Mid gut and colonic symptoms: diarrhea and abdominal pain [42,43]||Protracted acute GI GVHD||Acquisition of infection (enteric viruses, bacteria, parasites)|
|Activation of latent CMV, VZV||Pancreatic insufficiency|
|Drugs (mycophenolate mofetil, Mg++, antibiotics)||Clostridium difficile colitis|
|Collagen-encased bowel (GVHD)|
|Rare: inflammatory bowel disease, sprue; bile salt malabsorption; disaccharide malabsorption|
|Liver problems [44-54]||Cholestatic GVHD||Hepatitic GVHD|
|Chronic viral hepatitis (B and C)||VZV or HSV hepatitis|
|Focal nodular hyperplasia||Nodular regenerative hyperplasia|
|Nonspecific elevation of liver enzymes in serum (AP, ALT, GGT)||Biliary obstruction|
|Drug-induced liver injury|
|Biliary and pancreatic problems [55-58]||Cholecystitis||Pancreatic atrophy/insufficiency|
|Common duct stones/sludge||Pancreatitis/edema, stone or sludge related|
|Gall bladder sludge (calcium bilirubinate)||Pancreatitis, tacrolimus related|
|ALT = alanine transaminase; AP = alkaline phosphatase; CMV = cytomegalovirus; GGT = gamma glutamyl transpeptidase; HSV = herpes simplex virus; Mg++ = magnesium; VZV = varicella zoster virus.|
|aReprinted from Biology of Blood and Marrow Transplantation, Volume 17 (Issue 11), Michael L. Nieder, George B. McDonald, Aiko Kida, Sangeeta Hingorani, Saro H. Armenian, Kenneth R. Cooke, Michael A. Pulsipher , K. Scott Baker, National Cancer Institute–National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on Late Effects After Pediatric Hematopoietic Cell Transplantation: Long-Term Organ Damage and Dysfunction, Pages 1573–1584, Copyright 2011, with permission from American Society for Blood and Marrow Transplantation and Elsevier.|
As GVHD is controlled and tolerance is developed, most symptoms resolve. Major hepatobiliary concerns include the consequences of viral hepatitis acquired before or during the transplant, biliary stone disease, and focal liver lesions. Viral serology and polymerase chain reaction should be performed to differentiate this from GVHD presenting with hepatocellular injury.Iron overload
Iron overload occurs in almost all patients who undergo HCT, especially if the procedure is for a condition associated with transfusion dependence before HCT (e.g., thalassemia, bone marrow failure syndromes) or pre-HCT treatments requiring transfusions after myelotoxic chemotherapy (e.g., acute leukemias). Inflammatory conditions such as GVHD also increase gastrointestinal iron absorption. The effects of iron overload on morbidity post-HCT have not been well studied; however, reducing iron levels after HCT for thalassemia has been shown to improve cardiac function. Non-HCT conditions leading to iron overload can lead to cardiac dysfunction, endocrine disorders (e.g., pituitary insufficiency, hypothyroidism), diabetes, neurocognitive effects, and second malignancies.
Although data supporting iron reduction therapies such as phlebotomy or chelation after HCT have not identified specific levels at which iron reduction should be performed, higher levels of ferritin and/or evidence of significant iron overload by liver biopsy or T2-weighted magnetic resonance imaging (MRI)  should be addressed by iron reduction therapy.Endocrine System Late Effects
Studies show that rates of thyroid dysfunction in children after myeloablative HCT vary, but larger series report an average incidence of about 30%.[62-71] A lower incidence in adults (on average, 15%) and a notable increase in incidence in children younger than 10 years undergoing HCT, suggest that a developing thyroid gland may be more susceptible to damage.[62,64,68] Pretransplant local thyroid radiation contributes to high rates of thyroid dysfunction in patients with Hodgkin lymphoma. Early studies showed very high rates of thyroid dysfunction after high single-dose fractions of TBI, but traditional fractionated TBI/cyclophosphamide compared with busulfan/cyclophosphamide shows similar rates of thyroid dysfunction, suggesting a role for high-dose chemotherapy in thyroid damage.[65-67] Rates of thyroid dysfunction associated with newer combinations of busulfan/fludarabine or reduced-intensity regimens have yet to be reported.
Of note, higher rates of thyroid dysfunction occur with single-drug versus three-drug GVHD prophylaxis, along with increased rates of thyroid dysfunction after unrelated versus related donor HCT (36% vs. 9%), suggesting a role for allo-immune damage in causing thyroid dysfunction.[67,74]Growth impairment
Growth impairment is generally multifactorial. Factors that play a role in failure to achieve expected adult height in young children who have undergone HCT include the following:
- Diminished growth hormone level.
- Thyroid dysfunction.
- Disruption of pubertal sex hormone production.
- Steroid therapy.
- Poor nutritional status.
The incidence of growth impairment varies from 20% to 80% depending on age, risk factors, and the definition of growth impairment used by reporting groups.[69,70,75-78] Risk factors include the following:[65,66,76,79]
- Cranial irradiation.
- Younger age.
- Undergoing HCT for acute lymphoblastic leukemia.
- HCT occurring during a pubertal growth spurt.
Patients younger than 10 years at the time of HCT are at highest risk of growth impairment, but also respond best to growth hormone replacement therapy. Early screening and referral of patients with signs of growth impairment to endocrinology specialists can result in significant restoration of height in younger children.Abnormal body composition/metabolic syndrome
Adult survivors after allogeneic HCT have a risk of premature cardiovascular-related death that is increased 2.3-fold compared with the general population.[81,82] The exact etiology of cardiovascular risk and subsequent death is largely unknown, although development of metabolic syndrome (a constellation of central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension), especially insulin resistance, as a consequence of HCT has been suggested.[83-85] In studies of conventionally treated leukemia survivors compared with those who underwent HCT, transplant survivors are significantly more likely to manifest metabolic syndrome or multiple adverse cardiac risk factors including central adiposity, hypertension, insulin resistance, and dyslipidemia.[30,86,87] The concern over time is that survivors who develop metabolic syndrome after HCT will be at higher risk for developing significant cardiovascular-related events and/or premature death from cardiovascular-related causes.Sarcopenic obesity
The association of obesity with diabetes and cardiovascular disease risk in the general population is well established, but obesity as determined by body mass index (BMI) is uncommon in long-term survivors after HCT. However, despite having a normal BMI, HCT survivors develop significantly altered body composition that results in both an increase in total percent fat mass and a reduction in lean body mass. This finding is termed sarcopenic obesity and results in a loss of myocyte insulin receptors and an increase in adipocyte insulin receptors; the latter are less efficient in binding insulin and clearing glucose, ultimately contributing to insulin resistance.[88-90] Preliminary data from 119 children and young adults and 81 healthy sibling controls found that HCT survivors had significantly lower weight but no differences in BMI or waist circumference when compared with siblings. HCT survivors had a significantly higher percent fat mass and lower lean body mass than the controls. HCT survivors were significantly more insulin resistant than controls, and they also had a higher incidence of other cardiovascular risk factors such as total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Of note, these differences were found only in patients who had received TBI as part of their transplant conditioning regimen.Musculoskeletal System Late Effects
Low bone mineral density
A limited number of studies have addressed low bone mineral density after HCT in children.[92-98] A significant portion of children experienced reduction in total-body bone mineral density or lumbar Z-scores showing osteopenia (18%–33%) or osteoporosis (6%–21%). Although general risk factors have been described (female gender, inactivity, poor nutritional status, white or Asian ethnicity, family history, TBI, craniospinal irradiation, corticosteroid therapy, GVHD, cyclosporine, and endocrine deficiencies [e.g., growth hormone deficiency, hypogonadism]), reported populations have been too small to perform multivariate analysis to test the relative importance of each of these factors.[99-109]
Treatment for children has generally included a multifactor approach, with vitamin D and calcium supplementation, minimization of corticosteroid therapy, weight-bearing exercise, and resolution of other endocrine problems. The role of bisphosphonate therapy in children with this condition is unclear.Osteonecrosis
Reported incidence of osteonecrosis in children after HCT was 1% to 14%; however, these studies were retrospective and underestimate actual incidence, as patients may be asymptomatic early in the course. Two prospective studies have shown an incidence of 30% to 44% with routine MRI screening of possible target joints.[96,112] Osteonecrosis generally occurs within 3 years after HCT, with a median onset of about 1 year. The most common locations include knees (30%–40%), hips (19%–24%), and shoulders (9%). Most patients experience osteonecrosis in two or more joints.[72,113-115]
In one prospective report, risk factors by multivariate analysis included age (markedly increased in children older than 10 years; odds ratio, 7.4) and presence of osteonecrosis at the time of transplant. It is important to note that pre-HCT factors such as corticosteroid exposure are very important in determining patient risk. In this study, 14 of 44 children who developed osteonecrosis had the disease before HCT.
Treatment has generally consisted of minimization of corticosteroid therapy and surgical joint replacement. Most patients are not diagnosed until they present with symptoms. Of note, in one study of 44 patients with osteonecrosis lesions in whom routine yearly MRI was performed, four resolved completely, and two had resolution of one of multiply involved joints. The observation that some lesions can heal over time suggests caution in the surgical management of asymptomatic lesions.Reproductive System Late Effects
Delayed, absent, or incomplete pubertal development occurs commonly after HCT. Two studies showed pubertal delay or failure in 16% of female children who received cyclophosphamide alone, 72% of those who received busulfan/cyclophosphamide, and 57% of those who underwent fractionated TBI. In males, incomplete pubertal development or failure was noted in 14% of those who received cyclophosphamide alone, 48% of those who received busulfan/cyclophosphamide, and 58% of those who underwent TBI.[71,116] Boys receiving more than 2,400 cGy of radiation to the testicles develop azoospermia and also experience failure of testosterone production, requiring supplementation to develop secondary sexual characteristics.Fertility
Pretransplant and transplant cyclophosphamide exposure is the best studied agent affecting fertility. Postpubertal women younger than 30 years can tolerate up to 20 g/m2 of cyclophosphamide and have preserved ovarian function; prepubertal females can tolerate as much as 25g/m2 to 30 g/m2. Although the additional effect added by pretransplant exposures to cyclophosphamide and other agents has not been specifically quantitated in studies, these exposures plus transplant-related chemotherapy and radiation therapy lead to ovarian failure in 65% to 84% of females undergoing myeloablative HCT.[118-121] The use of cyclophosphamide, busulfan, and TBI as part of the preparative regimen are associated with worse ovarian function. Younger age at the time of HCT is associated with a higher chance of menarche and ovulation.[122,123]
Studies of pregnancy are challenging because data are seldom collected that indicate whether individuals are trying to conceive. Nonetheless, a large study of pregnancy in pediatric and adult survivors of myeloablative transplantation demonstrated conception in 32 of 708 patients (4.5%). Of those trying to conceive, patients exposed to cyclophosphamide alone (total dose 6.7 g/m2 with no pretransplant exposure) had the best chance of conception (56 of 103, 54%), while those receiving myeloablative busulfan/cyclophosphamide (0 of 73, 0%) or TBI (7 of 532, 1.3%) had much lower rates of conception.Men
The ability of men to produce functional sperm decreases with exposure to higher doses and specific types of chemotherapy. Most men will become azoospermic at a cyclophosphamide dose of 300 mg/kg. After HCT, 48% to 85% will experience gonadal failure.[118,124,125] One study showed that men who received cyclophosphamide conceived only 24% of the time compared with 6.5% of men who received busulfan/cyclophosphamide and 1.3% of those who underwent TBI.Effect of reduced toxicity/reduced intensity/nonmyeloablative regimens
Based on clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, use of reduced intensity/toxicity and nonmyeloablative regimens will likely lead to a higher chance of preserved fertility after HCT. Because the use of these regimens is relatively new and mostly confined to older or sicker patients, most reports have consisted of single cases. Registry reports are beginning to describe pregnancies after these procedures, but large case-control studies have yet to show in detail the effect of less-toxic regimens on this complication.Respiratory System Late Effects
Chronic pulmonary dysfunction
- Obstructive lung disease.
- Restrictive lung disease.
The incidence of both forms of lung toxicity can range from 10% to 40% depending on donor source, the time interval after HCT, definition applied, and presence of chronic GVHD. In both conditions, collagen deposition and the development of fibrosis either in the interstitial space (restrictive lung disease) or peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.
The most common form of obstructive lung disease following allogeneic HCT is bronchiolitis obliterans.[128,132,133] This condition is an inflammatory process resulting in bronchiolar obliteration, fibrosis, and progressive obstructive lung disease. Historically, the term bronchiolitis obliterans has been used to describe chronic GVHD of the lung and begins 6 to 20 months after HCT. Pulmonary function tests show obstructive lung disease with general preservation of forced vital capacity (FVC), reductions in forced expiratory volume in one second (FEV1), and associated decreases in the FEV1/FVC ratio with or without significant declines in the diffusion capacity of the lung for carbon monoxide (DLCO). Risk factors for bronchiolitis obliterans include the following:[126,132]
- Lower pretransplant FEV1/FVC values.
- Concomitant pulmonary infections.
- Chronic aspiration.
- Acute and chronic GVHD.
- Older recipient age.
- Use of mismatched donors.
- High-dose (vs. reduced-intensity) conditioning.
The clinical course of bronchiolitis obliterans is variable, but patients frequently develop progressive and debilitating respiratory failure despite the initiation of enhanced immunosuppression.
Restrictive lung disease is defined by reductions in FVC, total lung capacity (TLC), and DLCO. In contrast to obstructive lung disease, the FEV1/FVC ratio is maintained near 100%. Restrictive lung disease is common after HCT and has been reported in 25% to 45% of patients by day 100. Importantly, declines in TLC or FVC occurring at 100 days and 1 year after HCT are associated with an increase in nonrelapse mortality. Early reports suggested that the incidence of restrictive lung disease increases with advancing recipient age, but more recent studies have revealed significant restrictive lung disease in children receiving HCT. The most recognizable form of restrictive lung disease is bronchiolitis obliterans organizing pneumonia. Clinical features include dry cough, shortness of breath, and fever. Radiographic findings show diffuse, peripheral, fluffy infiltrates consistent with airspace consolidation. Although reported in less than 10% of HCT recipients, the development of bronchiolitis obliterans organizing pneumonia is strongly associated with prior acute and chronic GVHD.
Standard treatment for obstructive lung disease combines enhanced immunosuppression with supportive care including antimicrobial prophylaxis, bronchodilator therapy, and supplemental oxygen when indicated. Unfortunately, the response in patients with restrictive lung disease to multiple agents including corticosteroids, cyclosporine, tacrolimus, and azathioprine is limited. The potential role for tumor necrosis factor-alpha in the pathogenesis of both obstructive and restrictive lung disease suggests that neutralizing agents such as etanercept may have promise.Urinary System Late Effects
Chronic kidney disease is frequently diagnosed after transplant. There are many clinical forms of chronic kidney disease, but the most commonly described ones include thrombotic microangiopathy, nephrotic syndrome, calcineurin inhibitor toxicity, acute kidney injury, and GVHD-related chronic kidney disease. Various risk factors associated with the development of chronic kidney disease have been described; however, recent studies suggest that acute and chronic GVHD may be a proximal cause of renal injury.
In a systematic review of 9,317 adults and children from 28 cohorts who underwent HCT, approximately 16.6% (range, 3.6% to 89%) of patients developed chronic kidney disease, defined as a decrease in estimated glomerular filtration rate of at least 24.5 mL/min/1.73 m2 within the first year after transplant. The cumulative incidence of chronic kidney disease developing approximately 5 years after transplant ranges from 4.4% to 44.3%, depending on the type of transplant and stage of chronic kidney disease.[138,139] Mortality rates among patients with chronic kidney disease in this setting are higher than in transplant recipients who retain normal renal function, even when controlled for comorbidities.
It is important to aggressively treat hypertension in patients post-HCT, especially in those treated with prolonged courses of calcineurin inhibitors. Whether post-HCT patients with albuminuria and hypertension benefit from treatment with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers requires further study, but careful control of hypertension with captopril, an ACE inhibitor, did show a benefit in a small study.Quality of Life
Health-related quality of life (HRQL)
HRQL is a multidimensional construct, incorporating a subjective appraisal of one’s functioning/well-being, with reference to the impact of the health issues on overall quality of life.[142,143]. Many studies have shown that HRQL varies according to the following:
- Time post-HCT: HRQL is worse with more recent HCT.
- Transplant type: Unrelated donor HCT has worse HRQL than autologous or allogeneic-related HCT.
- Presence or absence of HCT-related sequelae: HRQL is worse with chronic GVHD.
Pre-HCT factors, such as family cohesion and the child’s adaptive functioning, have been shown to affect HRQL. Several groups have also identified the importance of pre-HCT parenting stress on parental ratings of children’s HRQL post-HCT.[145-149] A report of the trajectories of HRQL over the 12 months following HCT noted that the poorest HRQL was seen at 3 months post-HCT, with steady improvement thereafter. Recipients of unrelated donor transplants had the steepest declines in HRQL from baseline to 3 months. Another study reported that compromised emotional functioning, high levels of worry, and reduced communication during the acute recovery period had a negative impact on HRQL at 1-year post-HCT. Longitudinal studies identified an association of additional baseline risk factors with the trajectory of HRQL following HCT that includes the following:
- Child's age (older children, worse HRQL).[145,151,152]
- Child's gender (females, worse HRQL).
- Rater (mothers report lower HRQL than fathers; parents report lower HRQL than children).[153,154]
- Concordance by primary language or by gender of the raters (concordant pairs, higher HRQL).
- Parental emotional distress (greater parental distress, worse HRQL).
- Child's race (African American children, better HRQL).
A report on the impact of specific HCT complications on children’s HRQL indicated that HRQL was worse among children with severe end-organ toxicity, systemic infection, or GVHD. Cross-sectional studies report that the HRQL among pediatric HCT survivors of 5 years or more is reasonably good, although psychological, cognitive, or physical problems appear to negatively influence HRQL. Female gender, causal diagnosis for HCT (acute myelogenous leukemia, worse HRQL), and intensity of pre-HCT therapy were all identified as affecting HRQL post-HCT.[156,157] Finally, another cross-sectional study of children 5 to 10 years post-HCT cautioned that parental concerns about the child’s vulnerability may induce overprotective parenting.Functional outcomes
Physician reported physical performance
Clinician reports of long-term disability among childhood HCT survivors suggest that the prevalence and severity of functional loss is low. A study from the European Group for Blood and Marrow Transplantation used the Karnofsky performance scale to report outcomes among 647 HCT survivors (surviving ≥5 years). In this cohort, 40% of survivors were younger than 18 years when transplanted; only 19% had Karnofsky scores of less than 100. Seven percent had scores less than 80, defined as the inability to work. Similar low rates of clinician-graded poor functional outcome were reported by two other groups.[156,159] Among 50 survivors of childhood allogeneic HCT treated at the City of Hope National Medical Center and Stanford University Hospital, all had Karnofsky scores of 90 or 100. Among 73 young adults (mean age, 26 years) treated at the Karolinska University Hospital, the median Karnofsky score at 10 years post-HCT was 90.Self-reported physical performance
Self-reported and proxy data among survivors of childhood HCT indicate similar low rates of functional loss. One study evaluated 22 survivors of childhood allogeneic HCT (mean age at HCT, 11 years; mean age at questionnaire, 25 years) and reported no differences between survivors’ scores and population-expected values on standardized physical performance scales. Another study compared a group of survivors transplanted for childhood leukemia (n = 142) with a group of childhood leukemia survivors treated with chemotherapy alone (n = 288). There were no differences between the groups on the physical function and leisure scales using multiple standardized measures
Conversely, in the Bone Marrow Transplant Survivors Study (BMTSS), among 235 survivors of childhood HCT, 17% reported long-term physical performance limitations compared with 8.7% of a sibling comparison group. Additionally, a Seattle study evaluated physical function in 214 young adults (median age at questionnaire, 28.7 years; 118 males) who were transplanted at a median age of 11.9 years. When compared with age- and sex-matched controls, the HCT survivors in this cohort scored one-half standard deviation lower on the physical function, role physical, and physical component summary subscales of the SF-36, a quality-of-life measure. Finally, a Swedish study also identified lower self-reported physical health among 73 young adult (median age, 26 years) HCT survivors who were a median of 10 years from transplant. HCT survivors scored significantly below population normative values on physical functioning (90.2 for HCT survivors vs. 95.3 for population), satisfaction with physical health (66.0 for HCT survivors vs. 78.7 for population), and role limitation due to physical health (72.7 for HCT survivors vs. 84.9 for population).Measured physical performance
Objective measurements of function in the pediatric HCT patient and survivor population hints that loss of physical capacity may be a bigger problem than revealed in studies that rely on either clinician or self-report data. Most of these data are from objective measures of cardiopulmonary fitness. One study used exercise capacity with cycle ergometry in a group of 20 children and young adults before HCT, 31 patients 1-year post-HCT, and 70 healthy controls. Average peak oxygen consumption was 21 ml/kg/min in the pre-HCT group, 24 ml/kg/min in the post-HCT group, and 34 ml/kg/min in the healthy controls. Among the HCT survivors, 62% of those with cancer diagnoses scored in the lowest fifth percentile for peak oxygen consumption compared with healthy controls. Another study examined exercise capacity with a Bruce treadmill protocol in 31 survivors of pediatric HCT. In this cohort, 25.8% of HCT survivors had exercise capacities in the 70% to 79% of predicted category, and 41.9% had exercise capacities in the less than 70% of predicted category. In a third study of exercise capacity among 33 HCT survivors transplanted at a mean age of 11.3 years, at the 5-year post-HCT time point, only 4 of 33 survivors scored above the 75th percentile on a serial cycle ergometry test.Predictors of poor physical performance
In the BMTSS, associations were found between chronic GVHD, cardiac conditions, immune suppression, or treatment for a second malignant neoplasm and poor physical performance outcomes. In the a study from the Fred Hutchison Cancer Research Center, poor performance was associated with myeloid disease.Published Guidelines for Long-Term Follow-Up
A number of organizations have put forward consensus guidelines for follow up for late effects after HCT. The Center for International Blood and Marrow Transplant Research (CIBMTR) along with the American Society of Blood and Marrow Transplant (ASBMT) in cooperation with five other international transplant groups published consensus recommendations for screening and preventive practices for long-term survivors of HCT. Although some pediatric-specific challenges are addressed in these guidelines, many important pediatric issues are not. Some of these issues have been partially covered by general guidelines published by the Children’s Oncology Group (COG) and other children’s cancer groups (UK, Scotland, and Netherlands). To address the lack of detailed pediatric-specific late effects data and guidelines for long-term follow-up after HCT, the Pediatric Blood and Marrow Transplant Consortium (PBMTC) published six detailed papers outlining existing data and summarizing recommendations from key groups (CIBMTR/ASBMT, COG, and the UK), along with expert recommendations for pediatric specific issues.[8,30,61,168-170] Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are underway, the PBMTC summary and guideline recommendations provide the most current outline for following children for late effects after HCT.References
- Sun CL, Francisco L, Kawashima T, et al.: Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 116 (17): 3129-39; quiz 3377, 2010. [PUBMED Abstract]
- Bhatia S, Francisco L, Carter A, et al.: Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood 110 (10): 3784-92, 2007. [PUBMED Abstract]
- Bhatia S, Robison LL, Francisco L, et al.: Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood 105 (11): 4215-22, 2005. [PUBMED Abstract]
- Gooley TA, Chien JW, Pergam SA, et al.: Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 363 (22): 2091-101, 2010. [PUBMED Abstract]
- Martin PJ, Counts GW Jr, Appelbaum FR, et al.: Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. J Clin Oncol 28 (6): 1011-6, 2010. [PUBMED Abstract]
- Geenen MM, Cardous-Ubbink MC, Kremer LC, et al.: Medical assessment of adverse health outcomes in long-term survivors of childhood cancer. JAMA 297 (24): 2705-15, 2007. [PUBMED Abstract]
- Oeffinger KC, Mertens AC, Sklar CA, et al.: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355 (15): 1572-82, 2006. [PUBMED Abstract]
- Bhatia S, Davies SM, Scott Baker K, et al.: NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges. Biol Blood Marrow Transplant 17 (10): 1428-35, 2011. [PUBMED Abstract]
- Behar E, Chao NJ, Hiraki DD, et al.: Polymorphism of adhesion molecule CD31 and its role in acute graft-versus-host disease. N Engl J Med 334 (5): 286-91, 1996. [PUBMED Abstract]
- Goodman RS, Ewing J, Evans PC, et al.: Donor CD31 genotype and its association with acute graft-versus-host disease in HLA identical sibling stem cell transplantation. Bone Marrow Transplant 36 (2): 151-6, 2005. [PUBMED Abstract]
- van Dalen EC, van der Pal HJ, Kok WE, et al.: Clinical heart failure in a cohort of children treated with anthracyclines: a long-term follow-up study. Eur J Cancer 42 (18): 3191-8, 2006. [PUBMED Abstract]
- Chow EJ, Mueller BA, Baker KS, et al.: Cardiovascular hospitalizations and mortality among recipients of hematopoietic stem cell transplantation. Ann Intern Med 155 (1): 21-32, 2011. [PUBMED Abstract]
- Armenian SH, Sun CL, Francisco L, et al.: Late congestive heart failure after hematopoietic cell transplantation. J Clin Oncol 26 (34): 5537-43, 2008. [PUBMED Abstract]
- Armenian SH, Sun CL, Mills G, et al.: Predictors of late cardiovascular complications in survivors of hematopoietic cell transplantation. Biol Blood Marrow Transplant 16 (8): 1138-44, 2010. [PUBMED Abstract]
- Armenian SH, Sun CL, Kawashima T, et al.: Long-term health-related outcomes in survivors of childhood cancer treated with HSCT versus conventional therapy: a report from the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS). Blood 118 (5): 1413-20, 2011. [PUBMED Abstract]
- Arvidson J, Kihlgren M, Hall C, et al.: Neuropsychological functioning after treatment for hematological malignancies in childhood, including autologous bone marrow transplantation. Pediatr Hematol Oncol 16 (1): 9-21, 1999 Jan-Feb. [PUBMED Abstract]
- Barrera M, Atenafu E: Cognitive, educational, psychosocial adjustment and quality of life of children who survive hematopoietic SCT and their siblings. Bone Marrow Transplant 42 (1): 15-21, 2008. [PUBMED Abstract]
- Kupst MJ, Penati B, Debban B, et al.: Cognitive and psychosocial functioning of pediatric hematopoietic stem cell transplant patients: a prospective longitudinal study. Bone Marrow Transplant 30 (9): 609-17, 2002. [PUBMED Abstract]
- Phipps S, Brenner M, Heslop H, et al.: Psychological effects of bone marrow transplantation on children and adolescents: preliminary report of a longitudinal study. Bone Marrow Transplant 15 (6): 829-35, 1995. [PUBMED Abstract]
- Phipps S, Rai SN, Leung WH, et al.: Cognitive and academic consequences of stem-cell transplantation in children. J Clin Oncol 26 (12): 2027-33, 2008. [PUBMED Abstract]
- Phipps S, Dunavant M, Srivastava DK, et al.: Cognitive and academic functioning in survivors of pediatric bone marrow transplantation. J Clin Oncol 18 (5): 1004-11, 2000. [PUBMED Abstract]
- Cognitive functioning after BMT. In: Pot-Mees CC: The Psychological Effects of Bone Marrow Transplantation in Children. The Netherlands: Eburon Delft, 1989, pp 96–103.
- Simms S, Kazak AE, Golomb V, et al.: Cognitive, behavioral, and social outcome in survivors of childhood stem cell transplantation. J Pediatr Hematol Oncol 24 (2): 115-9, 2002. [PUBMED Abstract]
- Cool VA: Long-term neuropsychological risks in pediatric bone marrow transplant: what do we know? Bone Marrow Transplant 18 (Suppl 3): S45-9, 1996. [PUBMED Abstract]
- Kramer JH, Crittenden MR, DeSantes K, et al.: Cognitive and adaptive behavior 1 and 3 years following bone marrow transplantation. Bone Marrow Transplant 19 (6): 607-13, 1997. [PUBMED Abstract]
- Kramer JH, Crittenden MR, Halberg FE, et al.: A prospective study of cognitive functioning following low-dose cranial radiation for bone marrow transplantation. Pediatrics 90 (3): 447-50, 1992. [PUBMED Abstract]
- Shah AJ, Epport K, Azen C, et al.: Progressive declines in neurocognitive function among survivors of hematopoietic stem cell transplantation for pediatric hematologic malignancies. J Pediatr Hematol Oncol 30 (6): 411-8, 2008. [PUBMED Abstract]
- Smedler AC, Bolme P: Neuropsychological deficits in very young bone marrow transplant recipients. Acta Paediatr 84 (4): 429-33, 1995. [PUBMED Abstract]
- Smedler AC, Winiarski J: Neuropsychological outcome in very young hematopoietic SCT recipients in relation to pretransplant conditioning. Bone Marrow Transplant 42 (8): 515-22, 2008. [PUBMED Abstract]
- Nieder ML, McDonald GB, Kida A, et al.: National Cancer Institute-National Heart, Lung and Blood Institute/pediatric Blood and Marrow Transplant Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: long-term organ damage and dysfunction. Biol Blood Marrow Transplant 17 (11): 1573-84, 2011. [PUBMED Abstract]
- Mackey JR, Desai S, Larratt L, et al.: Myasthenia gravis in association with allogeneic bone marrow transplantation: clinical observations, therapeutic implications and review of literature. Bone Marrow Transplant 19 (9): 939-42, 1997. [PUBMED Abstract]
- Shimada K, Yokozawa T, Atsuta Y, et al.: Solid tumors after hematopoietic stem cell transplantation in Japan: incidence, risk factors and prognosis. Bone Marrow Transplant 36 (2): 115-21, 2005. [PUBMED Abstract]
- McDonald GB, Sullivan KM, Schuffler MD, et al.: Esophageal abnormalities in chronic graft-versus-host disease in humans. Gastroenterology 80 (5 pt 1): 914-21, 1981. [PUBMED Abstract]
- McDonald GB, Sullivan KM, Plumley TF: Radiographic features of esophageal involvement in chronic graft-vs.-host disease. AJR Am J Roentgenol 142 (3): 501-6, 1984. [PUBMED Abstract]
- Schima W, Pokieser P, Forstinger C, et al.: Videofluoroscopy of the pharynx and esophagus in chronic graft-versus-host disease. Abdom Imaging 19 (3): 191-4, 1994 May-Jun. [PUBMED Abstract]
- Minocha A, Mandanas RA, Kida M, et al.: Bullous esophagitis due to chronic graft-versus-host disease. Am J Gastroenterol 92 (3): 529-30, 1997. [PUBMED Abstract]
- Patey-Mariaud de Serre N, Reijasse D, Verkarre V, et al.: Chronic intestinal graft-versus-host disease: clinical, histological and immunohistochemical analysis of 17 children. Bone Marrow Transplant 29 (3): 223-30, 2002. [PUBMED Abstract]
- Akpek G, Chinratanalab W, Lee LA, et al.: Gastrointestinal involvement in chronic graft-versus-host disease: a clinicopathologic study. Biol Blood Marrow Transplant 9 (1): 46-51, 2003. [PUBMED Abstract]
- Filipovich AH, Weisdorf D, Pavletic S, et al.: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11 (12): 945-56, 2005. [PUBMED Abstract]
- McDonald GB, Bouvier M, Hockenbery DM, et al.: Oral beclomethasone dipropionate for treatment of intestinal graft-versus-host disease: a randomized, controlled trial. Gastroenterology 115 (1): 28-35, 1998. [PUBMED Abstract]
- Hockenbery DM, Cruickshank S, Rodell TC, et al.: A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. Blood 109 (10): 4557-63, 2007. [PUBMED Abstract]
- Iyer RV, Hahn T, Roy HN, et al.: Long-term use of oral beclomethasone dipropionate for the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant 11 (8): 587-92, 2005. [PUBMED Abstract]
- Borgaonkar MR, Duggan PR, Adams G: Differing clinical manifestations of celiac disease transmitted by bone marrow transplantation. Dig Dis Sci 51 (1): 210-2, 2006. [PUBMED Abstract]
- McDonald GB: Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology 51 (4): 1450-60, 2010. [PUBMED Abstract]
- Sullivan KM, Shulman HM, Storb R, et al.: Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 57 (2): 267-76, 1981. [PUBMED Abstract]
- Tomás JF, Pinilla I, García-Buey ML, et al.: Long-term liver dysfunction after allogeneic bone marrow transplantation: clinical features and course in 61 patients. Bone Marrow Transplant 26 (6): 649-55, 2000. [PUBMED Abstract]
- Strasser SI, Shulman HM, Flowers ME, et al.: Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis. Hepatology 32 (6): 1265-71, 2000. [PUBMED Abstract]
- Malik AH, Collins RH Jr, Saboorian MH, et al.: Chronic graft-versus-host disease after hematopoietic cell transplantation presenting as an acute hepatitis. Am J Gastroenterol 96 (2): 588-90, 2001. [PUBMED Abstract]
- Akpek G, Boitnott JK, Lee LA, et al.: Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion. Blood 100 (12): 3903-7, 2002. [PUBMED Abstract]
- Shulman HM, Sharma P, Amos D, et al.: A coded histologic study of hepatic graft-versus-host disease after human bone marrow transplantation. Hepatology 8 (3): 463-70, 1988 May-Jun. [PUBMED Abstract]
- Strasser SI, Myerson D, Spurgeon CL, et al.: Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up. Hepatology 29 (6): 1893-9, 1999. [PUBMED Abstract]
- Ljungman P, Johansson N, Aschan J, et al.: Long-term effects of hepatitis C virus infection in allogeneic bone marrow transplant recipients. Blood 86 (4): 1614-8, 1995. [PUBMED Abstract]
- Strasser SI, Sullivan KM, Myerson D, et al.: Cirrhosis of the liver in long-term marrow transplant survivors. Blood 93 (10): 3259-66, 1999. [PUBMED Abstract]
- Peffault de Latour R, Lévy V, Asselah T, et al.: Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103 (5): 1618-24, 2004. [PUBMED Abstract]
- Ko CW, Murakami C, Sekijima JH, et al.: Chemical composition of gallbladder sludge in patients after marrow transplantation. Am J Gastroenterol 91 (6): 1207-10, 1996. [PUBMED Abstract]
- Akpek G, Valladares JL, Lee L, et al.: Pancreatic insufficiency in patients with chronic graft-versus-host disease. Bone Marrow Transplant 27 (2): 163-6, 2001. [PUBMED Abstract]
- Maringhini A, Gertz MA, DiMagno EP: Exocrine pancreatic insufficiency after allogeneic bone marrow transplantation. Int J Pancreatol 17 (3): 243-7, 1995. [PUBMED Abstract]
- Radu B, Allez M, Gornet JM, et al.: Chronic diarrhoea after allogenic bone marrow transplantation. Gut 54 (1): 161, 174, 2005. [PUBMED Abstract]
- Mariotti E, Angelucci E, Agostini A, et al.: Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden. Br J Haematol 103 (4): 916-21, 1998. [PUBMED Abstract]
- Angelucci E, Muretto P, Lucarelli G, et al.: Treatment of iron overload in the "ex-thalassemic". Report from the phlebotomy program. Ann N Y Acad Sci 850: 288-93, 1998. [PUBMED Abstract]
- Pulsipher MA, Skinner R, McDonald GB, et al.: National Cancer Institute, National Heart, Lung and Blood Institute/Pediatric Blood and Marrow Transplantation Consortium First International Consensus Conference on late effects after pediatric hematopoietic cell transplantation: the need for pediatric-specific long-term follow-up guidelines. Biol Blood Marrow Transplant 18 (3): 334-47, 2012. [PUBMED Abstract]
- Sanders JE, Hoffmeister PA, Woolfrey AE, et al.: Thyroid function following hematopoietic cell transplantation in children: 30 years' experience. Blood 113 (2): 306-8, 2009. [PUBMED Abstract]
- Bailey HK, Kappy MS, Giller RH, et al.: Time-course and risk factors of hypothyroidism following allogeneic hematopoietic stem cell transplantation (HSCT) in children conditioned with fractionated total body irradiation. Pediatr Blood Cancer 51 (3): 405-9, 2008. [PUBMED Abstract]
- Ishiguro H, Yasuda Y, Tomita Y, et al.: Long-term follow-up of thyroid function in patients who received bone marrow transplantation during childhood and adolescence. J Clin Endocrinol Metab 89 (12): 5981-6, 2004. [PUBMED Abstract]
- Michel G, Socié G, Gebhard F, et al.: Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle. J Clin Oncol 15 (6): 2238-46, 1997. [PUBMED Abstract]
- Afify Z, Shaw PJ, Clavano-Harding A, et al.: Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. Bone Marrow Transplant 25 (10): 1087-92, 2000. [PUBMED Abstract]
- Slatter MA, Gennery AR, Cheetham TD, et al.: Thyroid dysfunction after bone marrow transplantation for primary immunodeficiency without the use of total body irradiation in conditioning. Bone Marrow Transplant 33 (9): 949-53, 2004. [PUBMED Abstract]
- Berger C, Le-Gallo B, Donadieu J, et al.: Late thyroid toxicity in 153 long-term survivors of allogeneic bone marrow transplantation for acute lymphoblastic leukaemia. Bone Marrow Transplant 35 (10): 991-5, 2005. [PUBMED Abstract]
- Leung W, Ahn H, Rose SR, et al.: A prospective cohort study of late sequelae of pediatric allogeneic hematopoietic stem cell transplantation. Medicine (Baltimore) 86 (4): 215-24, 2007. [PUBMED Abstract]
- Dvorak CC, Wright NB, Wong WB, et al.: Safety of hematopoietic stem cell transplantation in children less than three years of age. Pediatr Hematol Oncol 25 (8): 705-22, 2008. [PUBMED Abstract]
- Sanders JE, Woolfrey AE, Carpenter PA, et al.: Late effects among pediatric patients followed for nearly 4 decades after transplantation for severe aplastic anemia. Blood 118 (5): 1421-8, 2011. [PUBMED Abstract]
- Socié G, Salooja N, Cohen A, et al.: Nonmalignant late effects after allogeneic stem cell transplantation. Blood 101 (9): 3373-85, 2003. [PUBMED Abstract]
- Katsanis E, Shapiro RS, Robison LL, et al.: Thyroid dysfunction following bone marrow transplantation: long-term follow-up of 80 pediatric patients. Bone Marrow Transplant 5 (5): 335-40, 1990. [PUBMED Abstract]
- Savani BN, Koklanaris EK, Le Q, et al.: Prolonged chronic graft-versus-host disease is a risk factor for thyroid failure in long-term survivors after matched sibling donor stem cell transplantation for hematologic malignancies. Biol Blood Marrow Transplant 15 (3): 377-81, 2009. [PUBMED Abstract]
- Huma Z, Boulad F, Black P, et al.: Growth in children after bone marrow transplantation for acute leukemia. Blood 86 (2): 819-24, 1995. [PUBMED Abstract]
- Giorgiani G, Bozzola M, Locatelli F, et al.: Role of busulfan and total body irradiation on growth of prepubertal children receiving bone marrow transplantation and results of treatment with recombinant human growth hormone. Blood 86 (2): 825-31, 1995. [PUBMED Abstract]
- Cohen A, Rovelli A, Van-Lint MT, et al.: Final height of patients who underwent bone marrow transplantation during childhood. Arch Dis Child 74 (5): 437-40, 1996. [PUBMED Abstract]
- Sanders JE, Guthrie KA, Hoffmeister PA, et al.: Final adult height of patients who received hematopoietic cell transplantation in childhood. Blood 105 (3): 1348-54, 2005. [PUBMED Abstract]
- Cohen A, Rovelli A, Bakker B, et al.: Final height of patients who underwent bone marrow transplantation for hematological disorders during childhood: a study by the Working Party for Late Effects-EBMT. Blood 93 (12): 4109-15, 1999. [PUBMED Abstract]
- Eggleston B, Patience M, Edwards S, et al.: Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia. Br J Haematol 136 (4): 673-6, 2007. [PUBMED Abstract]
- Reusch JE: Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol 90 (5A): 19G-26G, 2002. [PUBMED Abstract]
- Trevisan M, Liu J, Bahsas FB, et al.: Syndrome X and mortality: a population-based study. Risk Factor and Life Expectancy Research Group. Am J Epidemiol 148 (10): 958-66, 1998. [PUBMED Abstract]
- Lakka HM, Laaksonen DE, Lakka TA, et al.: The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288 (21): 2709-16, 2002. [PUBMED Abstract]
- Taskinen M, Saarinen-Pihkala UM, Hovi L, et al.: Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet 356 (9234): 993-7, 2000. [PUBMED Abstract]
- Baker KS, Ness KK, Steinberger J, et al.: Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 109 (4): 1765-72, 2007. [PUBMED Abstract]
- Eaton SB, Cordain L, Sparling PB: Evolution, body composition, insulin receptor competition, and insulin resistance. Prev Med 49 (4): 283-5, 2009. [PUBMED Abstract]
- Boirie Y: Physiopathological mechanism of sarcopenia. J Nutr Health Aging 13 (8): 717-23, 2009. [PUBMED Abstract]
- Baker KS, Chow E, Goodman P, et al.: Adverse Impact of hematopoietic cell transplantation (HCT) on body composition and insulin resistance (IR) is associated with increased cardiovascular risk. [Abstract] Biol Blood Marrow Transplant 17 (2 Suppl): A-61, S174, 2011.
- Cook S, Weitzman M, Auinger P, et al.: Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 157 (8): 821-7, 2003. [PUBMED Abstract]
- Genuth S, Alberti KG, Bennett P, et al.: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26 (11): 3160-7, 2003. [PUBMED Abstract]
- Grundy SM, Brewer HB Jr, Cleeman JI, et al.: Definition of metabolic syndrome: Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 109 (3): 433-8, 2004. [PUBMED Abstract]
- Petryk A, Bergemann TL, Polga KM, et al.: Prospective study of changes in bone mineral density and turnover in children after hematopoietic cell transplantation. J Clin Endocrinol Metab 91 (3): 899-905, 2006. [PUBMED Abstract]
- Bhatia S, Ramsay NK, Weisdorf D, et al.: Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies. Bone Marrow Transplant 22 (1): 87-90, 1998. [PUBMED Abstract]
- Nysom K, Holm K, Michaelsen KF, et al.: Bone mass after allogeneic BMT for childhood leukaemia or lymphoma. Bone Marrow Transplant 25 (2): 191-6, 2000. [PUBMED Abstract]
- Daniels MW, Wilson DM, Paguntalan HG, et al.: Bone mineral density in pediatric transplant recipients. Transplantation 76 (4): 673-8, 2003. [PUBMED Abstract]
- Kaste SC, Shidler TJ, Tong X, et al.: Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation. Bone Marrow Transplant 33 (4): 435-41, 2004. [PUBMED Abstract]
- Perkins JL, Kunin-Batson AS, Youngren NM, et al.: Long-term follow-up of children who underwent hematopoeitic cell transplant (HCT) for AML or ALL at less than 3 years of age. Pediatr Blood Cancer 49 (7): 958-63, 2007. [PUBMED Abstract]
- Carpenter PA, Hoffmeister P, Chesnut CH 3rd, et al.: Bisphosphonate therapy for reduced bone mineral density in children with chronic graft-versus-host disease. Biol Blood Marrow Transplant 13 (6): 683-90, 2007. [PUBMED Abstract]
- Weilbaecher KN: Mechanisms of osteoporosis after hematopoietic cell transplantation. Biol Blood Marrow Transplant 6 (2A): 165-74, 2000. [PUBMED Abstract]
- Rodgers C, Monroe R: Osteopenia and osteoporosis in pediatric patients after stem cell transplant. J Pediatr Oncol Nurs 24 (4): 184-9, 2007 Jul-Aug. [PUBMED Abstract]
- McClune BL, Polgreen LE, Burmeister LA, et al.: Screening, prevention and management of osteoporosis and bone loss in adult and pediatric hematopoietic cell transplant recipients. Bone Marrow Transplant 46 (1): 1-9, 2011. [PUBMED Abstract]
- Schulte CM, Beelen DW: Bone loss following hematopoietic stem cell transplantation: a long-term follow-up. Blood 103 (10): 3635-43, 2004. [PUBMED Abstract]
- Schimmer AD, Minden MD, Keating A: Osteoporosis after blood and marrow transplantation: clinical aspects. Biol Blood Marrow Transplant 6 (2A): 175-81, 2000. [PUBMED Abstract]
- Banfi A, Podestà M, Fazzuoli L, et al.: High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer 92 (9): 2419-28, 2001. [PUBMED Abstract]
- Castañeda S, Carmona L, Carvajal I, et al.: Reduction of bone mass in women after bone marrow transplantation. Calcif Tissue Int 60 (4): 343-7, 1997. [PUBMED Abstract]
- Lee WY, Baek KH, Rhee EJ, et al.: Impact of circulating bone-resorbing cytokines on the subsequent bone loss following bone marrow transplantation. Bone Marrow Transplant 34 (1): 89-94, 2004. [PUBMED Abstract]
- Baker KS, Gurney JG, Ness KK, et al.: Late effects in survivors of chronic myeloid leukemia treated with hematopoietic cell transplantation: results from the Bone Marrow Transplant Survivor Study. Blood 104 (6): 1898-906, 2004. [PUBMED Abstract]
- Stern JM, Sullivan KM, Ott SM, et al.: Bone density loss after allogeneic hematopoietic stem cell transplantation: a prospective study. Biol Blood Marrow Transplant 7 (5): 257-64, 2001. [PUBMED Abstract]
- Ebeling PR, Thomas DM, Erbas B, et al.: Mechanisms of bone loss following allogeneic and autologous hemopoietic stem cell transplantation. J Bone Miner Res 14 (3): 342-50, 1999. [PUBMED Abstract]
- Tauchmanovà L, De Rosa G, Serio B, et al.: Avascular necrosis in long-term survivors after allogeneic or autologous stem cell transplantation: a single center experience and a review. Cancer 97 (10): 2453-61, 2003. [PUBMED Abstract]
- Kananen K, Volin L, Tähtelä R, et al.: Recovery of bone mass and normalization of bone turnover in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 29 (1): 33-9, 2002. [PUBMED Abstract]
- Sharma S, Yang S, Rochester R, et al.: Prevalence of osteonecrosis and associated risk factors in children before allogeneic BMT. Bone Marrow Transplant 46 (6): 813-9, 2011. [PUBMED Abstract]
- Socié G, Cahn JY, Carmelo J, et al.: Avascular necrosis of bone after allogeneic bone marrow transplantation: analysis of risk factors for 4388 patients by the Société Française de Greffe de Moëlle (SFGM). Br J Haematol 97 (4): 865-70, 1997. [PUBMED Abstract]
- Bürger B, Beier R, Zimmermann M, et al.: Osteonecrosis: a treatment related toxicity in childhood acute lymphoblastic leukemia (ALL)--experiences from trial ALL-BFM 95. Pediatr Blood Cancer 44 (3): 220-5, 2005. [PUBMED Abstract]
- Mattano LA Jr, Sather HN, Trigg ME, et al.: Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children's Cancer Group. J Clin Oncol 18 (18): 3262-72, 2000. [PUBMED Abstract]
- Sanders J: Growth and development after hematopoietic cell transplantation . In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1608-19.
- Sanders JE, Flournoy N, Thomas ED, et al.: Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graft-versus-host disease. Med Pediatr Oncol 13 (4): 165-72, 1985. [PUBMED Abstract]
- Sanders JE, Hawley J, Levy W, et al.: Pregnancies following high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 87 (7): 3045-52, 1996. [PUBMED Abstract]
- Carter A, Robison LL, Francisco L, et al.: Prevalence of conception and pregnancy outcomes after hematopoietic cell transplantation: report from the Bone Marrow Transplant Survivor Study. Bone Marrow Transplant 37 (11): 1023-9, 2006. [PUBMED Abstract]
- Salooja N, Szydlo RM, Socie G, et al.: Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 358 (9278): 271-6, 2001. [PUBMED Abstract]
- Loren AW, Chow E, Jacobsohn DA, et al.: Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant 17 (2): 157-66, 2011. [PUBMED Abstract]
- Shalet SM, Didi M, Ogilvy-Stuart AL, et al.: Growth and endocrine function after bone marrow transplantation. Clin Endocrinol (Oxf) 42 (4): 333-9, 1995. [PUBMED Abstract]
- Schubert MA, Sullivan KM, Schubert MM, et al.: Gynecological abnormalities following allogeneic bone marrow transplantation. Bone Marrow Transplant 5 (6): 425-30, 1990. [PUBMED Abstract]
- Howell SJ, Shalet SM: Spermatogenesis after cancer treatment: damage and recovery. J Natl Cancer Inst Monogr (34): 12-7, 2005. [PUBMED Abstract]
- Anserini P, Chiodi S, Spinelli S, et al.: Semen analysis following allogeneic bone marrow transplantation. Additional data for evidence-based counselling. Bone Marrow Transplant 30 (7): 447-51, 2002. [PUBMED Abstract]
- Yoshihara S, Yanik G, Cooke KR, et al.: Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13 (7): 749-59, 2007. [PUBMED Abstract]
- Chien JW, Duncan S, Williams KM, et al.: Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft-versus-host disease. Biol Blood Marrow Transplant 16 (1 Suppl): S106-14, 2010. [PUBMED Abstract]
- Hildebrandt GC, Fazekas T, Lawitschka A, et al.: Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD. Bone Marrow Transplant 46 (10): 1283-95, 2011. [PUBMED Abstract]
- Chien JW, Martin PJ, Gooley TA, et al.: Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 168 (2): 208-14, 2003. [PUBMED Abstract]
- Cerveri I, Zoia MC, Fulgoni P, et al.: Late pulmonary sequelae after childhood bone marrow transplantation. Thorax 54 (2): 131-5, 1999. [PUBMED Abstract]
- Freudenberger TD, Madtes DK, Curtis JR, et al.: Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants. Blood 102 (10): 3822-8, 2003. [PUBMED Abstract]
- Chien JW, Zhao LP, Hansen JA, et al.: Genetic variation in bactericidal/permeability-increasing protein influences the risk of developing rapid airflow decline after hematopoietic cell transplantation. Blood 107 (5): 2200-7, 2006. [PUBMED Abstract]
- Hildebrandt GC, Granell M, Urbano-Ispizua A, et al.: Recipient NOD2/CARD15 variants: a novel independent risk factor for the development of bronchiolitis obliterans after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 14 (1): 67-74, 2008. [PUBMED Abstract]
- Norman BC, Jacobsohn DA, Williams KM, et al.: Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 46 (10): 1369-73, 2011. [PUBMED Abstract]
- Cooke KR, Yanik G: Lung injury following hematopoietic stem cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1456-72.
- Yanik GA, Mineishi S, Levine JE, et al.: Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 18 (7): 1044-54, 2012. [PUBMED Abstract]
- Ellis MJ, Parikh CR, Inrig JK, et al.: Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant 8 (11): 2378-90, 2008. [PUBMED Abstract]
- Choi M, Sun CL, Kurian S, et al.: Incidence and predictors of delayed chronic kidney disease in long-term survivors of hematopoietic cell transplantation. Cancer 113 (7): 1580-7, 2008. [PUBMED Abstract]
- Ando M, Ohashi K, Akiyama H, et al.: Chronic kidney disease in long-term survivors of myeloablative allogeneic haematopoietic cell transplantation: prevalence and risk factors. Nephrol Dial Transplant 25 (1): 278-82, 2010. [PUBMED Abstract]
- Cohen EP, Piering WF, Kabler-Babbitt C, et al.: End-stage renal disease (ESRD)after bone marrow transplantation: poor survival compar ed to other causes of ESRD. Nephron 79 (4): 408-12, 1998. [PUBMED Abstract]
- Cohen EP, Irving AA, Drobyski WR, et al.: Captopril to mitigate chronic renal failure after hematopoietic stem cell transplantation: a randomized controlled trial. Int J Radiat Oncol Biol Phys 70 (5): 1546-51, 2008. [PUBMED Abstract]
- Wilson IB, Cleary PD: Linking clinical variables with health-related quality of life. A conceptual model of patient outcomes. JAMA 273 (1): 59-65, 1995. [PUBMED Abstract]
- Eisen M, Donald CA, Ware JE, et al.: Conceptualization and Measurement of Health for Children in the Health Insurance Study. Santa Monica, Calif: Rand Corporation, 1980.
- Parsons SK, Barlow SE, Levy SL, et al.: Health-related quality of life in pediatric bone marrow transplant survivors: according to whom? Int J Cancer Suppl 12: 46-51, 1999. [PUBMED Abstract]
- Barrera M, Atenafu E, Hancock K: Longitudinal health-related quality of life outcomes and related factors after pediatric SCT. Bone Marrow Transplant 44 (4): 249-56, 2009. [PUBMED Abstract]
- Parsons SK, Shih MC, Duhamel KN, et al.: Maternal perspectives on children's health-related quality of life during the first year after pediatric hematopoietic stem cell transplant. J Pediatr Psychol 31 (10): 1100-15, 2006 Nov-Dec. [PUBMED Abstract]
- Barrera M, Boyd-Pringle LA, Sumbler K, et al.: Quality of life and behavioral adjustment after pediatric bone marrow transplantation. Bone Marrow Transplant 26 (4): 427-35, 2000. [PUBMED Abstract]
- Jobe-Shields L, Alderfer MA, Barrera M, et al.: Parental depression and family environment predict distress in children before stem cell transplantation. J Dev Behav Pediatr 30 (2): 140-6, 2009. [PUBMED Abstract]
- Vrijmoet-Wiersma CM, Kolk AM, Grootenhuis MA, et al.: Child and parental adaptation to pediatric stem cell transplantation. Support Care Cancer 17 (6): 707-14, 2009. [PUBMED Abstract]
- Felder-Puig R, di Gallo A, Waldenmair M, et al.: Health-related quality of life of pediatric patients receiving allogeneic stem cell or bone marrow transplantation: results of a longitudinal, multi-center study. Bone Marrow Transplant 38 (2): 119-26, 2006. [PUBMED Abstract]
- Parsons SK, Ratichek SJ, Rodday AM: Caring for the caregiver: eHealth interventions for parents of pediatric hematopoietic stem cell transplant recipients. [Abstract] Pediatr Blood Cancer 56 (7): 1157, 2011.
- Brice L, Weiss R, Wei Y, et al.: Health-related quality of life (HRQoL): the impact of medical and demographic variables upon pediatric recipients of hematopoietic stem cell transplantation. Pediatr Blood Cancer 57 (7): 1179-85, 2011. [PUBMED Abstract]
- Kaplan SH, Barlow S, Spetter D: Assessing functional status and health-related quality of life among school-aged children: reliability and validity of a new self-reported measure. [Abstract] Qual Life Res 4 (5): 444-45, 1995.
- Barrera M, Atenafu E, Doyle J, et al.: Differences in mothers' and fathers' health-related quality of life after pediatric SCT: a longitudinal study. Bone Marrow Transplant 47 (6): 855-9, 2012. [PUBMED Abstract]
- Feichtl RE, Rosenfeld B, Tallamy B, et al.: Concordance of quality of life assessments following pediatric hematopoietic stem cell transplantation. Psychooncology 19 (7): 710-7, 2010. [PUBMED Abstract]
- Löf CM, Winiarski J, Giesecke A, et al.: Health-related quality of life in adult survivors after paediatric allo-SCT. Bone Marrow Transplant 43 (6): 461-8, 2009. [PUBMED Abstract]
- Sanders JE, Hoffmeister PA, Storer BE, et al.: The quality of life of adult survivors of childhood hematopoietic cell transplant. Bone Marrow Transplant 45 (4): 746-54, 2010. [PUBMED Abstract]
- Duell T, van Lint MT, Ljungman P, et al.: Health and functional status of long-term survivors of bone marrow transplantation. EBMT Working Party on Late Effects and EULEP Study Group on Late Effects. European Group for Blood and Marrow Transplantation. Ann Intern Med 126 (3): 184-92, 1997. [PUBMED Abstract]
- Schmidt GM, Niland JC, Forman SJ, et al.: Extended follow-up in 212 long-term allogeneic bone marrow transplant survivors. Issues of quality of life. Transplantation 55 (3): 551-7, 1993. [PUBMED Abstract]
- Helder DI, Bakker B, de Heer P, et al.: Quality of life in adults following bone marrow transplantation during childhood. Bone Marrow Transplant 33 (3): 329-36, 2004. [PUBMED Abstract]
- Michel G, Bordigoni P, Simeoni MC, et al.: Health status and quality of life in long-term survivors of childhood leukaemia: the impact of haematopoietic stem cell transplantation. Bone Marrow Transplant 40 (9): 897-904, 2007. [PUBMED Abstract]
- Ness KK, Bhatia S, Baker KS, et al.: Performance limitations and participation restrictions among childhood cancer survivors treated with hematopoietic stem cell transplantation: the bone marrow transplant survivor study. Arch Pediatr Adolesc Med 159 (8): 706-13, 2005. [PUBMED Abstract]
- Larsen RL, Barber G, Heise CT, et al.: Exercise assessment of cardiac function in children and young adults before and after bone marrow transplantation. Pediatrics 89 (4 Pt 2): 722-9, 1992. [PUBMED Abstract]
- Eames GM, Crosson J, Steinberger J, et al.: Cardiovascular function in children following bone marrow transplant: a cross-sectional study. Bone Marrow Transplant 19 (1): 61-6, 1997. [PUBMED Abstract]
- Hogarty AN, Leahey A, Zhao H, et al.: Longitudinal evaluation of cardiopulmonary performance during exercise after bone marrow transplantation in children. J Pediatr 136 (3): 311-7, 2000. [PUBMED Abstract]
- Fraser CJ, Bhatia S, Ness K, et al.: Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 108 (8): 2867-73, 2006. [PUBMED Abstract]
- Rizzo JD, Wingard JR, Tichelli A, et al.: Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant 37 (3): 249-61, 2006. [PUBMED Abstract]
- Bunin N, Small T, Szabolcs P, et al.: NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: persistent immune deficiency in pediatric transplant survivors. Biol Blood Marrow Transplant 18 (1): 6-15, 2012. [PUBMED Abstract]
- Dvorak CC, Gracia CR, Sanders JE, et al.: NCI, NHLBI/PBMTC first international conference on late effects after pediatric hematopoietic cell transplantation: endocrine challenges-thyroid dysfunction, growth impairment, bone health, & reproductive risks. Biol Blood Marrow Transplant 17 (12): 1725-38, 2011. [PUBMED Abstract]
- Parsons SK, Phipps S, Sung L, et al.: NCI, NHLBI/PBMTC First International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: health-related quality of life, functional, and neurocognitive outcomes. Biol Blood Marrow Transplant 18 (2): 162-71, 2012. [PUBMED Abstract]