Late Effects After HCT in Children
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 severe, disabling, and/or life-threatening events or die because of an adverse event associated with cancer treatment.[6,7]
Before studies aimed at decreasing the incidence or severity of these effects are initiated, 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 HLA 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 on the basis of 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, partly as a result of 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 radiation 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 after 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 on the basis of differences in socioeconomic status. Most published studies report similar outcomes. Normal cognitive function and academic achievement were reported in a cohort of 47 patients monitored prospectively through 2 years post-HCT. Stable cognitive function was also noted in a large cohort monitored 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. On the basis of the findings to date, it appears that HCT poses low to minimal risk of late cognitive and academic deficits in survivors.
A number of studies, however, have reported some decline in cognitive function after HCT.[24-30] 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 underwent transplantation with TBI.[28,29] Another study from St. Jude Children's Research Hospital reported that while all children younger than 3 years had a decline in IQ at 1 year after transplant, patients who did not receive TBI during conditioning recovered later. However, patients who received TBI had a significantly lower IQ at 5 years (P = .05) than did those who did not receive TBI.
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 13).
|Problem Areas||Common Causes||Less Common Causes|
|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.|
|Esophageal symptoms: heartburn, dysphagia, painful swallowing [32-37]||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 [38-42]||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 [43,44]||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 [45-55]||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 [56-59]||Cholecystitis||Pancreatic atrophy/insufficiency|
|Common duct stones/sludge||Pancreatitis/edema, stone or sludge related|
|Gall bladder sludge (calcium bilirubinate)||Pancreatitis, tacrolimus related|
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 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%.[63-72] 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.[63,65,69]
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.[66-68] 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 alloimmune damage in causing thyroid dysfunction.[68,75]
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.[70,71,76-79] Risk factors include the following:[66,67,77,80]
- 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.[82,83] 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.[84-86]
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.[31,87,88] The concern over time is that survivors who develop metabolic syndrome after HCT will be at higher risk of developing significant cardiovascular-related events and/or premature death from cardiovascular-related causes.
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.[89-91]
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 did controls. HCT survivors were significantly more insulin resistant than were 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.[93-99] 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]), most reported populations have been too small to perform multivariate analysis to test the relative importance of each of these factors.[100-110]
Treatment for children has generally included a multifactorial 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.
Reported incidence of osteonecrosis in children after HCT was 1% to 14%; however, these studies were retrospective and underestimated actual incidence because 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.[97,113] 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.[73,114-116]
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. A Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective nested control study of 160 cases and 478 control children suggested older age (>5 years), female gender, and the presence of chronic GVHD as risk factors for osteonecrosis.
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.[72,118] Boys receiving more than 24 Gy of radiation to the testicles developed azoospermia and also experienced failure of testosterone production, requiring supplementation to develop secondary sexual characteristics.
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.[120-123] 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.[124,125]
Studies of pregnancy are challenging because data seldom 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.
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.[120,126,127] 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
On the basis of clear evidence of dose effect and the lowered gonadotoxicity of some reduced-toxicity chemotherapy regimens, the 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 in either the interstitial space (restrictive lung disease) or the peribronchiolar space (obstructive lung disease) are believed to underlie the pathology.
The most common form of obstructive lung disease post–allogeneic HCT is bronchiolitis obliterans.[130,133,135,136] 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 1 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).
- 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 subsequent 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 fewer than 10% of HCT recipients, the development of bronchiolitis obliterans organizing pneumonia is strongly associated with previous 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 such as 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.[141,142] Mortality rates among patients with chronic kidney disease in this setting are higher than those in transplant recipients who retain normal renal function, even when studies have 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.[145,146]. Many studies have shown that HRQL varies according to the following:
- Time after HCT: HRQL is worse with more recent HCT.
- Transplant type: Unrelated donor HCT has worse HRQL than does 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.[148-152] A report of the trajectories of HRQL over the 12 months after 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 the following additional baseline risk factors with the trajectory of HRQL following HCT:
- Child's age (older children, worse HRQL).[148,154,155]
- Child's gender (females, worse HRQL).
- Rater (mothers report lower HRQL than do fathers; parents report lower HRQL than do children).[156,157]
- 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.[159,160] 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.
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 lower than 100. Seven percent had scores lower than 80, defined as the inability to work. Similar low rates of clinician-graded poor functional outcome were reported by two other groups.[159,162] 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. Studies measuring cardiopulmonary fitness have observed the following:
- One study used exercise capacity with cycle ergometry in a group of 20 children and young adults before HCT, 31 patients at 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 lower than 70% of predicted category.
- In a third study of exercise capacity among 33 HCT survivors who underwent transplantation 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 CIBMTR along with the American Society of Blood and Marrow Transplant (ASBMT) and 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 (United Kingdom, 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 United Kingdom), along with expert recommendations for pediatric-specific issues.[8,31,62,171-173] Although international efforts at further standardization and harmonization of pediatric-specific follow-up guidelines are under way, the PBMTC summary and guideline recommendations provide the most current outline for monitoring children for late effects after HCT.
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