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

Summary

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.

Introduction

Cranial radiation therapy (CRT) has been associated with serious adverse effects, including cognitive impairment and behavioural abnormalities, which can lead to poor educational attainment and unemployment in long-term survivors of childhood acute lymphoblastic leukaemia.¹ Contemporary protocols have now replaced CRT with systemic and intrathecal chemotherapy,2, 3 which has reduced the degree of survivors' cognitive impairment.⁴ In a large cohort of adults who underwent neurocognitive assessment at 26 years after their initial diagnosis of childhood acute lymphoblastic leukaemia, the risk for impaired executive function in survivors treated with chemotherapy only was six times less than those treated with CRT at 24 Gy.¹ Non-irradiated survivors also had better academic achievement than those who received CRT.

Research in context

Evidence before this study

We searched PubMed, Scopus, and PsycINFO databases on Dec 1, 2014, with the following combination of keywords: “acute lymphoblastic leukemia”, “childhood”, “pediatric”, “behavioral”, “psychological”, “neuropsychiatry”, “cognition”, “neurocognitive”, “memory”, “attention”, “learning”, “executive function”, “processing speed”, “leukoencephalopathy”, and “white matter”. We had no language restrictions and searched for articles published between Jan 1, 2000, and Dec 1, 2014, as clinicians from major international paediatric oncology groups started to adopt non-cranial radiation therapy (CRT) chemotherapy-based protocols for patients with childhood acute lymphoblastic leukaemia at both standard and high risk in the early 2000s. A review of the literature revealed that the effect of acute white matter changes on long-term functional outcomes is unknown. Our previous research showed that almost a quarter of children who developed leukoencephalopathy during chemotherapy treatment for acute lymphoblastic leukaemia. In another small cross-sectional study (n=66) of survivors treated with chemotherapy only and evaluated at more than 2 years after treatment, the rate of leukoencephalopathy at follow-up was 68% and these survivors presented with marginally more attention problems than those who did not have leukoencephalopathy. However, we found no studies that documented the effect of acute brain white matter pathology on neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukaemia who were treated with chemotherapy-only protocols.

Added value of the study

To our best knowledge, this study is one of the first that included prospective neuroimaging from active therapy to long-term follow-up, and comprehensive assessment of brain structural and functional outcomes in long-term survivors of acute lymphoblastic leukaemia who were treated on a contemporary, risk-adapted chemotherapy protocol without CRT. In one of the largest samples of long-term survivors of childhood acute lymphoblastic leukaemia reported in the literature, we showed that survivors who developed leukoencephalopathy during therapy displayed higher parent-rated neurobehavioural problems at more than 5 years after diagnosis than did survivors who did not have leukoencephalopathy. Moreover, these survivors also had reduced white matter integrity at follow-up, and these structural abnormalities were concurrently associated with neurobehavioural problems.

Implications of all the available evidence

These results provide evidence that leukoencephalopathy during chemotherapy treatment is associated with underlying persistent neuroanatomical changes in white matter integrity within the frontal brain regions, which is reflected in long-term neurobehavioural problems in organisation and initiation in survivors. Treatment-related leukoencephalopathy is predictive of abnormal neurodevelopment in the long term. Survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy may benefit from preventive cognitive rehabilitation. Children who develop acute neurotoxicity during the active treatment phase might have an even greater need for early behavioural intervention.

Despite lower prevalence of neurocognitive deficits with the omission of CRT, survivors of childhood acute lymphoblastic leukaemia who were treated with chemotherapy only are still at risk for neurotoxicity that can occur during the course of treatment and persist in the long term.4, 5, 6 Contemporary chemotherapy protocols now use high-dose intravenous methotrexate, intrathecal methotrexate, and corticosteroids. In the past 5 years, these neurotoxic drugs were shown to be associated with long-term problems in memory, attention, processing speed, and executive function.1, 6, 7, 8 These cognitive deficits might manifest as functional impairment in survivors' behavioural regulation and metacognitive abilities.7, 9 The criteria for early identification of those at risk for long-term problems have not been established.

Leukoencephalopathy, seizures, and cerebrovascular injury are additional neurological events that occur in patients with acute lymphoblastic leukaemia who were treated with chemotherapy protocols.5, 10 In 2014, we reported that 21% of children treated on an institutional protocol that eliminated CRT developed asymptomatic leukoencephalopathy while receiving therapy, and that 69% of these had abnormal findings on MRI at the end of therapy.⁵ In a small cross-sectional study⁸ of 66 survivors who were treated with chemotherapy only and evaluated at more than 2 years after treatment, 68% of patients developed leukoencephalopathy and these survivors presented with marginally more attention problems than those who did not have leukoencephalopathy. However, a paucity of literature is available that elucidates the effect of neurotoxicity during active treatment on brain function and integrity in long-term survivors of childhood acute lymphoblastic leukaemia. Although on-therapy radiological changes in brain structure might be transient, little is known about whether these acute white matter alterations could affect normal brain maturation and development during the survivorship phase, leading to long-term deficits.

In light of these research gaps, we examined the association between leukoencephalopathy during active treatment (referred to as “acute leukoencephalopathy” hereafter) with neurobehavioural and neurocognitive function, and white matter integrity during long-term follow-up in a large cohort of survivors of childhood acute lymphoblastic leukaemia who were treated with contemporary risk-adapted chemotherapy without CRT. We postulated that survivors who had acute leukoencephalopathy would be more likely to display neurocognitive and parent-reported neurobehavioural problems, and reduced white matter integrity at long-term follow-up compared with survivors of childhood acute lymphoblastic leukaemia with no previous acute leukoencephalopathy.