Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis

Abstract

Background: Leukoencephalopathy is observed in some children undergoing chemotherapy for acute lymphoblastic leukaemia, although its effects on long-term outcomes is unknown. This study examines the associations between acute leukoencephalopathy and neurobehavioural, neurocognitive, and brain white matter imaging outcomes in long-term survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy without cranial radiation.

Methods: In this longitudinal analysis, we used data of children with acute lymphoblastic leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA) who had been treated between June 1, 2000, and Oct 31, 2010. Eligible patients were diagnosed with non-B-cell acute lymphoblastic leukaemia, aged at least 8 years, and survivors with at least 5 years since their initial diagnosis. Brain MRIs obtained during active therapy were systematically coded for leukoencephalopathy using Common Terminology Criteria for Adverse Event version 4. At least 5 years after their diagnosis, survivors completed neurocognitive testing, another brain MRI, and their parents completed neurobehavioural ratings of their child (Behavior Rating Inventory of Executive Function [BRIEF]). Follow-up MRI included diffusion tensor imaging to assess white matter integrity, with indices of fractional anisotropy, axial diffusivity, and radial diffusivity from frontal lobes, parietal lobes, and in the frontostriatal tract. The neuroradiologist, who assessed abnormal MRIs, was masked to both group assignment of survivors and the neurobehavioural and neurocognitive outcomes. The primary outcomes were neurobehavioural function, assessed from completed BRIEF, and neurocognitive performance, measured by direct neurocognitive tests (Delis-Kaplan Executive Function System, Wechsler Intelligence Scale for Children-IV/Wechsler Adult Intelligence Scale-III, Rey-Osterrieth Complex Figure Test, and Lafayette Grooved Pegboard Test). This study had completed enrolment in October, 2014, and is registered as an observational study at ClinicalTrials.gov, number NCT01014195.

Findings: Between Feb 18, 2010, and Oct 22, 2014, 210 (70%) of 301 eligible survivors participated in our study of whom 190 were evaluable, 162 had an MRI. 56 participants had quantitative brain imaging data and were included in evaluable population analyses. 51 (27%) of the 190 evaluable participants had acute leukoencephalopathy. Compared with population norms, survivors were reported to have more neurobehavioural problems with working memory, organisation, initiation, and planning (p<0·001 for all). Survivors had worse scores than the general population on direct measures of memory span, processing speed, and executive function (p<0·05 for all). Survivors with a history of acute leukoencephalopathy had more neurobehavioural problems than survivors with no history of leukoencephalopathy on organisation (adjusted T-score 56·2 [95% CI 53·3-59·1] vs 52·2 [50·4-53·9], p=0·020) and initiation (55·5 [52·7-58·3] vs 52·1 [50·4-53·8], p=0·045). Survivors with acute leukoencephalopathy also had reduced white matter integrity in the frontostriatal tract at follow-up: lower fractional anisotropy (p=0·069), higher axial diffusivity (p=0·020), and higher radial diffusivity (p=0·0077). A one-unit change in the radial diffusivity index corresponded with a 15·0 increase in raw score points on initiation, 30·3 on planning, and 28·0 on working memory (p<0·05 for all).

Interpretation: Acute leukoencephalopathy during chemotherapy treatment, without cranial radiation, for childhood acute lymphoblastic leukaemia predicted higher risk for long-term neurobehavioural problems and reduced white matter integrity in frontal brain regions. Survivors of childhood acute lymphoblastic leukaemia might benefit from preventive cognitive or behavioural interventions, particularly those who develop acute leukoencephalopathy.

Funding: National Institute of Mental Health, National Cancer Institute, American Lebanese Syrian Associated Charities.

Figure 1. Consort diagram

Consort Note: Potentially eligible survivors were treated according to the Total Therapy XV protocol and underwent on-therapy magnetic resonance imaging (MRI). Survivors were excluded from follow-up analyses if they had relapsed and were treated with cranial radiation therapy (CRT) or bone marrow transplantation (BMT), had a second malignant neoplasm (SMN) requiring additional treatment, had a neurodevelopmental disorder (e.g. prematurity with intra-ventricular hemorrhage), had a genetic disorder associated with neurocognitive impairment (e.g. Down Syndrome), had an unrelated brain injury (e.g. traumatic brain injury) or were non-fluent in English. Recruitment was not attempted for survivors who were discharged from pediatric follow-up care (i.e. >18 years old and >10 years from diagnosis), were in Foster care, or were in prison. Some survivors actively refused testing or brain imaging. Survivors were not assessable for brain imaging data if they had metallic objects in their body (e.g. braces). There are technical (program malfunction) or behavioral (participant movement during task performance) artifacts that prevented analysis of the imaging data. The subset of survivors with usable brain imaging data did not differ from the larger cohort on neurobehavioral or neurocognitive outcomes. Survivors with evaluable brain imaging data were older, due to behavioral limitations (eg. anxiety, unable to keep still during the brain scan) seen in survivors of younger age.

Figure 2. Acute Leukoencephalopathy and Neurobehavioral Outcomes

Figure 2 shows the association between acute leukoencephalopathy and neurobehavioral outcomes. Group P compares mean standardized T-scores (μ=50, σ=10), between survivors with versus without acute leukoencephalopathy for the specific BRIEF domains and overall scales, using general linear modeling, adjusted for age at diagnosis and parent’s education. A higher T-score is indicative of more neurobehavioral problems. Survivors who developed acute leukoencephalopathy demonstrated more parent-rated neurobehavioral problems than those who did not, on Initiation and Organization of Materials, and marginally significant for Planning and the overall Metacognition Index. Abbreviation: BRI, Behavioral Regulation Index; BRIEF, Behavior Rating Inventory of Executive Function; GEC, Global Executive Composite

Figure 3. Acute Leukoencephalopathy and Diffusion Tensor Imaging of White Matter Integrity at Follow-up

Figure 3 shows the association between acute leukoencephalopathy and white matter integrity at follow-up within the frontostriatal tract, frontal and parietal lobes. The P-values compare the DTI measures (FA, AD and RD) between survivors with and without acute leukoencephalopathy using general linear modeling, adjusted for current age. All models have been adjusted for false discovery rate. Survivors who developed acute leukoencephalopathy had reduced white matter integrity, demonstrated by lower FA and higher AD and RD indices. Abbreviation: AD, axial diffusivity; FA, fractional anisotropy; RD, radial diffusivity