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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2027-2033 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.6135 Cognitive and Academic Consequences of Stem-Cell Transplantation in Children
From the Division of Behavioral Medicine; Department of Biostatistics; and the Division of Stem Cell Transplant, Department of Oncology, St Jude Children's Research Hospital, Memphis, TN Corresponding author: Sean Phipps, PhD, Division of Behavioral Medicine, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: sean.phipps{at}stjude.org
Purpose To describe cognitive and academic outcomes in survivors after pediatric stem-cell transplantation (SCT) through 5-years post-SCT. Patients and Methods A battery of neurocognitive measures were administered before admission and at 1, 3, and 5 years post-SCT for 268 patients who underwent SCT; the study sample is comprised of 158 patients who survived and were evaluated at 1-year post-SCT. Random coefficient models were generated to depict change over time, and to test differences in slope and intercept for medical and demographic predictor variables. Results In the cohort as a whole, no significant changes were seen in global intelligence quotient and academic achievement. Despite the overall stability, some significant differences in slopes were found based on diagnosis, type of transplantation, use of total-body irradiation (TBI), and presence of graft-versus-host disease (GVHD). However, these differences were small, and of limited clinical significance. In comparison, differences as a function of socioeconomic status (SES) were much larger. SES was a significant determinant of all cognitive and academic outcomes, and the effect size generally dwarfed that of other significant predictor variables. Age, which had previously been identified as an important determinant of outcome, was not significantly predictive of outcome in this cohort. Conclusion The procedure of SCT entails minimal risk of late cognitive and academic sequelae. Subgroups of patients are at relatively higher risk: patients undergoing unrelated donor transplantation, receiving TBI, and those who experience GVHD. However, these differences are small relative to differences in premorbid functioning, particularly those associated with SES.
Survivors of pediatric hematopoietic stem-cell transplantation (SCT) are thought to be at risk for late neurocognitive deficits as a result of their exposure to a number of potentially neurotoxic agents.1-2 Among the agents used in pretransplant conditioning, total-body irradiation (TBI) has been a primary focus, but other cytotoxic conditioning agents are potentially neurotoxic as well.3,4 CNS toxicities also are associated with agents commonly used for the prophylaxis and/or treatment of graft-versus-host disease (GVHD).5 More speculative is the possibility of direct effects of GVHD on the CNS.6,7 Extant studies of neurocognitive outcomes have been hindered by small sample sizes, retrospective designs, or limited prospective follow-up.8 The findings reported have been contradictory, with a few studies indicating declines in cognitive function after SCT,9-11 but a larger number of studies reported normal neurodevelopment, with no evidence of decline.12-17 Kramer et al10 reported a significant decline in intelligence quotient (IQ) at 1-year post-SCT, and these deficits were maintained at 3-year post-SCT.10 In contrast, our group found no significant declines in IQ or academic achievement in 102 survivors assessed at 1-year post-SCT, nor in a subset of 54 survivors observed through 3-year post-SCT.13 The discrepancies between these studies may be explained by the differential age of the two cohorts. Within our cohort, the subset of children younger than 6 years showed declines comparable with those reported by Kramer's group. Our youngest patients (< 3 years) showed a greater cognitive decline that continued through 3 years. In neither the Kramer et al10 nor the Phipps et al13 studies was there any adverse effect of TBI. These findings led us to conclude that SCT, even with TBI, poses low to minimal risk for late cognitive and academic deficits in patients who are at least 6 years old at the time of transplantation. For younger patients, the risk of cognitive impairment may be increased. The results of recently reported studies continue to support these conclusions. Simms et al16 reported normal cognitive function and academic achievement in a cohort of 47 patients observed prospectively through 2-year post-SCT. However, the children in their cohort who were younger than 3 years at SCT showed declines in developmental indices post-SCT.16 Kupst et al17 noted stable cognitive function in a large cohort observed from pretransplantation to 2-years post-SCT, with no evidence of decline in children younger than 3 years. Likewise, in smaller studies, Arvidson et al14 and Daniel-Llach et al,15 have reported similar normal functioning and absence of declines over time in SCT survivors. Despite substantial exposure to potentially neurotoxic agents, studies have generally shown survivors of pediatric SCT to be within normal limits in cognitive and academic functioning, and with stable performance over time, although children who are younger at the time of transplantation may be at increased risk for cognitive impairment. These are tentative conclusions given the methodologic limitations, and particularly since no study has yet reported data beyond 3-years post-SCT. This article addresses these issues by reporting prospective follow-up of a larger cohort assessed at 5 years or more after SCT. Prior reports from this cohort described outcomes at 1 and 3 years post-SCT.13,18 The size of the cohort now allows for analysis using growth curve modeling treating time as a continuous variable. This report focuses on the global indices of intelligence and academic achievement.
Patients Patients undergoing SCT at St Jude Children's Research Hospital (Memphis, TN) were eligible for the study, except for those with brain tumors or those for whom English was not their primary language. Over an 8-year period ending January, 1999, 268 patients were enrolled onto study and underwent neurocognitive assessment before admission for SCT. Of these, 158 who were alive at 1 year after SCT and completed at least one post-transplant assessment comprise the study cohort. Follow-up evaluations were scheduled for 1, 3, and 5 years post-transplantation. A total of 80 patients participated in a 5-year post-transplant assessment, with the remainder missing due to late mortality, excessive morbidity, study noncompliance, or lost to follow-up. Comparison of patients who did and did not provide follow-up observations at 3 and 5 years show no differences on any cognitive measures (ie, there is no evidence of selective attrition). Multiple SCT treatment protocols were represented over the study period, but the conditioning regimens were similar across studies and have been described elsewhere.13,19 The demographic and medical characteristics of the baseline cohort and study cohort are presented in Table 1.
Measures This article focuses on global intelligence and academic achievement, for which the following instruments were used: Bayley Scales of Infant Development (BSID, BSID-II) and Wechsler Intelligence Scales (WPPSI-R, WISC-R, WISC-III, WAIS-R) for global intelligence, and the Wide Range Achievement Test (WRAT-R, WRAT-III) for academic achievement. Bayley Scales of Infant Development (BSID, BSID-II). This instrument provides for assessment of children from 1 to 42 months.20,21 All patients requiring a Bayley at 1- and 3-year evaluations were tested with the same version that was used in their evaluation before bone marrow transplantation. Wechsler Intelligence Scales (WPPSI-R, WISC-R, WISC-III, WAIS-R).22-25 The Wechsler Pre-School and Primary Scale of Intelligence (WPPSI-R)22 was used for patients age 3 to 6 years. The Wechsler Intelligence Scale for Children was used for patients age 6 to 16. To maintain consistency, the same version of the scale used at the baseline assessment was used for follow-up. Patients older than 16 years were assessed with the Wechsler Adult Intelligence Scales (WAIS-R).25 Patients were assessed at baseline with an abbreviated form of the instrument based on three subtests (information, similarities, block design), and survivors underwent standard administration for all subsequent assessments. This short form was found to correlate highly (.94) with full scale IQ in the standardization sample,26 and comparable correlations have been found in studies of pediatric brain tumor survivors.27 Wide Range Achievement Test (WRAT-R, WRAT-III).28,29 This instrument provides age and grade normed standard scores in the domains of reading, spelling, and arithmetic for children age 6 and older (Table 2).
Statistical Approach Longitudinal change in IQ and academic achievement was investigated using random coefficient models.30,31 This provides an estimate of the average rate of change in function (slope) over time, as well as differences in slopes between subgroups. To examine the effects of demographic and medical variables, a random coefficients model was fitted that had a different intercept (mean score) and slope (rate of change) for each level of the independent variable, which allows testing of differences between groups in intercept or slope, as well as testing whether the slope of a subgroup differs significantly from 0. In a longitudinal study across this age range, testing patients with more than one version of IQ measure is unavoidable. Some investigators have dealt with this by removing observations that involved a change in versions, while maintaining the most observations possible for each patient.32 However, with this data set, a large percentage of patients (38%) had a change of scales, and this approach would have involved removing 84 of 418 observations, including all of those who were younger than 3 years at transplantation. Thus, we compared slopes and intercepts for the subset with no change in IQ scales to the entire cohort including both those who did and did not have a change in scales, and no significant differences were detected. Therefore, all data and statistical tests presented here include the full cohort.
Changes in Neurocognitive Function Across Entire Cohort The intercept of estimated IQ for the entire cohort was low (93.7) and differed significantly from the expected population average of 100 (P < .01). However, the slope estimate of –0.35 (interpreted as loss of 0.35 IQ points per year) did not differ significantly from zero (P > .10). Thus, for the entire cohort the estimated change through 5-years post-transplant was a nonsignificant decline of less than 2 points. Similarly, verbal IQ (VIQ) showed a slope estimate of –0.10 (P > .5), while performance IQ (PIQ) showed a slope of 0.80, which actually represents a significant improvement (P < .05). The estimated slopes for WRAT reading, spelling, and math were –0.03, –0.12, and 0.08, respectively, none of which differed significantly from 0 (all P values > .5; Table 2). The observed stability is illustrated in Figure 1 for estimated IQ.
Neurocognitive Outcomes by Subgroup Outcomes were examined by demographic and medical variables, including age group, sex, socioeconomic status (SES), diagnosis, type of transplantation, use of TBI, and presence of GVHD, and history of prior CNS therapy. There were no significant differences observed in intercept or slope on any neurocognitive outcome as a function of age group. In regards to IQ, the slope was positive for the age group  12 years, and negative for all the others. The age group younger than 3 years, thought to be at highest risk, showed a slope estimate of –0.85, but this did not differ significantly from 0 (P > .10). The discrepancy of this finding with our prior report from this cohort may be explained by a leveling off in the younger than 3-years age group from the year 3 to year 5 observation (Fig 2). By sex, there were no differences in slope on any outcome, but there were significant differences in intercept for academic achievement in reading (P < .05), spelling (P < .001), and math (P < .05), indicating that females obtained higher scores on all outcomes. The largest differences were seen as a function of SES, where significant differences in intercept were seen on all neurocognitive outcomes. For IQ, intercept estimates differed significantly (P < .001), with a 20-point difference between those in the highest (Hollingshead33 classes I & II, estimate = 100.8) and lowest SES groups (Hollinghead33 classes IV & V, estimate = 80.8). Similar outcomes were observed on all IQ subscales and academic achievement measures. In contrast, there were no significant differences in slope as a function of SES (Figs 3A to 3C).
Significant differences in slope were seen as a function of diagnosis, type of transplant, TBI, GVHD, and history of prior CNS therapy. By diagnosis, significant differences in slope were found for VIQ, PIQ, reading, and spelling (all P values < .05). Examination of subgroups reveals that, for VIQ, patients with acute lymphoblastic leukemia (ALL; –0.91 points/year) and other leukemia (–1.11 points/year) showed negative slopes, while those with nonmalignancy (1.24 points/year) showed a significantly positive slope. Similar breakdowns were seen on the other variables, with the subset of patients with nonmalignant disease showing a positive slope on all outcomes. Type of transplantation was a significant predictor of slope only for VIQ (P < .01), where patients who had an unrelated donor transplantation showed a significant decline (slope = –0.84; P < .05), while those who had a matched sibling or autologous transplant showed a nonsignificant improvement. Regarding TBI, significant differences in slope were seen on VIQ (P < .01), PIQ (P < .01), reading (P < .05), spelling (P < .05), and a marginal difference on math (P = .06). For VIQ, those patients who received TBI showed a significant decline (slope = –0.65; P < .05), while those without TBI showed a significant improvement (slope = 0.81; P < .05). On PIQ, those with TBI showed no change, in comparison to the significant improvement in the no TBI group (slope = 1.87; P < .001). On the achievement outcomes, those who received TBI showed a nonsignificant decline in comparison to a nonsignificant improvement in the no TBI group. The effects of TBI, while significant, are small, reflecting a between group difference of approximately 3 points over a 5-year period, compared with the 20-point difference observed between high and low SES groups (Figs 3D to 3F). Because the number of patients with significant chronic GVHD was small, we focused on acute GVHD, and dichotomized into those with and without GVHD. Substantial differences in slopes were observed on estimated, full scale, and VIQ (all P values < .01), and in all outcomes, those with acute GVHD showed significant declines over time, while those with no GVHD showed improvement. A significant difference was also seen on PIQ (P < .05), but the GVHD group showed no change over time, while the no GVHD group showed a significant improvement (slope = 1.40; P < .01). Again, these effects, while statistically significant, are relatively small (Fig 4).
Regarding prior CNS therapy, 17 patients, all ALL survivors, were exposed to both intrathecal (IT) chemotherapy and high-dose methotrexate. Only six patients were exposed to cranial radiation therapy, all of whom received IT therapy and high-dose methotrexate. When we examined this group of 17 separately, significant differences in slope were found for full scale IQ, PIQ, and reading (all P values < .05), with the CNS group showing significant declines and the no CNS group nonsignificant improvement.
These findings demonstrate general stability in global cognitive and academic functioning in pediatric SCT survivors in the 5-year period after transplantation. To our knowledge, this sample represents the largest cohort and longest period of follow-up of pediatric SCT survivors yet reported in a prospective, longitudinal study of cognitive functioning, and our models were sufficient to detect a change of 0.6 to 0.8 points/year with 80% power. While for global IQ the slope was negative, suggesting a trend towards a decline over time, the degree of change was small, accounting for a loss of fewer than 2 IQ points over 5 years, a magnitude within the margin of error of the test instrument, therefore lacking in both clinical as well as statistical significance. For academic achievement, the stability was even more striking, with slopes close to 0. Young age at transplantation, previously thought to be a prominent risk factor, no longer emerged as a significant determinant of outcome. Although some subgroups of patients demonstrated a higher risk of cognitive decline, including those who received TBI or experienced GVHD, these differences were small and of limited clinical significance, particularly in comparison to the large differences in premorbid function associated with SES. The finding that age was not a significant determinant of outcome contradicts an earlier report from this same cohort.13 While examination of the predicted trajectories suggests a declining trend through 3 years post-SCT for the younger than 3 years age group, there is some leveling off by year 5. These results are complicated by the necessity of a change in test instruments for this group over the course of the study. Although change in test instruments across observations was not predictive of outcome in the cohort as a whole, the youngest subset of patients all required at least one change in IQ measure over the 5-year period. Thus, an artifactual influence of changes in test instrumentation cannot be ruled out. Consequently, we cannot conclude with confidence that younger age at SCT is not a risk factor, and would hesitate to do so given the well documented age effects associated with cognitive outcomes in survivors of ALL and brain tumors.34,35 We would continue to recommend closer monitoring of cognitive development in those children who receive transplantation at a young age, particularly since their young age at follow-up precludes conclusions regarding some higher executive functions. However, parents can be counseled that age effects, even if present, are likely to be small. Also in contrast to the earlier report from this cohort,13 these findings suggest that TBI is a significant determinant of cognitive outcome. However, the effect sizes were small, and generally accounted for more by improvement in the no TBI group than decline in the TBI group. The decline in the TBI group was generally nonsignificant and so small as to suggest that the 14 Gy dosage falls below a threshold where neurotoxicty may be largely reduced or eliminated. The differences observed as a function of TBI, type of transplantation, GVHD, or prior CNS therapy were all in the expected direction, indicating that patients who receive TBI, unrelated donor transplants, who experience GVHD, or had prior CNS therapy will be at slightly higher risk for neurocognitive sequelae. But these risks should be considered in the context of the observed effects of SES. When comparing higher and lower SES groups, differences were generally larger than one standard deviation, exceeding 20 points for full scale IQ, and dwarfing those of any medical or treatment factors. This is understandable given that the best predictor of post-transplantation cognitive functioning is pretransplant cognitive functioning,17 and SES is well documented as the most important determinant of cognitive and academic functioning in children.36 This factor is often overlooked in the oncology literature, despite evidence that SES has also been shown to be a strong predictor of cognitive outcomes in ALL,37 as well as in other chronic illnesses and childhood conditions.38-40 In this context, the effects of TBI and other medical factors, while significant, represent relatively minor perturbations superimposed on the much larger effect of SES. There are a number of limitations to this study. One of the major issues relates to the changes in test instruments over time, which has been previously discussed. Another concern is the substantial attrition over time. Although attrition due to death was reduced by restricting our sample to those that survived to 1-year after SCT, there continued to be some late mortality, with an additional 34 patients lost to death (21.5% of the original sample). However, the majority of attrition at the 3-year and 5-year assessments was due to other factors, predominantly refusal or noncompliance. We cannot assume this data is missing completely at random, but posthoc comparisons at years 1 and 3 of those who did and did not provide subsequent assessments indicated no significant differences. Finally, this report focused only on global outcomes of IQ and academic achievement, and did not examine more specific neuropsychological functions. These data are available and will be addressed in subsequent reports. In summary, this study reveals stability in global cognitive and academic functioning through 5 years post-SCT. Although subgroups appear to be at higher risk including those who received transplantation with TBI, those receiving a MUD transplant, and those who experienced GVHD, SES is far and away the strongest predictor of outcome in the SCT setting. The major clinical implication is for clinicians counseling prospective SCT candidates, who can provide good news and offer reassurance regarding the minimal risk of cognitive late effects. Comprehensive ongoing cognitive surveillance of all SCT patients appears unnecessary, although closer monitoring of younger patients is still recommended. Surveillance might be reduced to readily obtained parent-report measures, with comprehensive follow-up when there is suggestion of a problem. Beyond that, identification of patients at highest risk should be based primarily on their premorbid cognitive and academic history and SES.
The author(s) indicated no potential conflicts of interest.
Conception and design: Sean Phipps, Shelly Lensing Provision of study materials or patients: Wing-Hang Leung, Maggi Dunavant Collection and assembly of data: Sean Phipps, Maggi Dunavant Data analysis and interpretation: Sean Phipps, Shesh N. Rai, Wing-Hang Leung, Shelly Lensing Manuscript writing: Sean Phipps, Shesh N. Rai, Wing-Hang Leung Final approval of manuscript: Sean Phipps, Shesh N. Rai, Wing-Hang Leung, Shelly Lensing, Maggi Dunavant
Supported in part by a Grant No. CA60616 from the National Cancer Institute, and by the American Lebanese-Syrian Associated Charities. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
