Pediatric acute lymphoblastic leukemia (ALL) patients treated with chemotherapy alone remain at risk for attention and learning problems that persist after treatment ends, according to investigators at St. Jude Children’s Research Hospital. The findings were published in the Journal of Clinical Oncology.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the most curable. This study represents the largest and most comprehensive prospective evaluation to date of neurocognitive outcomes in children treated with modern, intensive chemotherapy without prophylactic cranial irradiation.
Contemporary chemotherapy strategies have reduced many treatment-related cognitive deficits while maintaining high cure rates. Still, although roughly 90 percent of children with ALL survive a decade or more, survivors continue to face elevated risks for attention problems and slowed processing speed that can affect learning and school success.
Study participants underwent detailed neurocognitive testing at three time points: at diagnosis (induction), at the end of maintenance therapy, and again two years after completing treatment. The primary focus was on neurocognitive functioning two years off therapy and on changes that emerged since the end of treatment.
Two years after finishing therapy, survivors generally scored within age-expected ranges for overall intelligence, learning, and memory. However, they showed a statistically higher incidence of attention difficulties, and caregivers reported increased learning challenges compared with normative expectations. The highest risks were observed among children diagnosed before age five and among those who received more intensive CNS-directed chemotherapy. Notably, attention problems identified at the end of therapy predicted lower academic performance two years later.
“These results add to evidence that replacing cranial irradiation with intensified chemotherapy has improved overall neurocognitive outcomes for childhood ALL survivors,” said Lisa Jacola, Ph.D., of the St. Jude Department of Psychology, first and corresponding author on the paper. “At the same time, our data show that attention deficits persist for a subset of survivors and that these deficits have real-world consequences for learning and school achievement.”
“Attention is a foundational skill for learning, and in this study early attention difficulties were associated with later academic problems,” Jacola added. “Identifying attention problems at the end of therapy creates an opportunity to intervene earlier to reduce or prevent long-term educational impacts.”
The participants were enrolled on the St. Jude Total XV protocol (2000–2007), a study that omitted prophylactic cranial irradiation for all patients. Survivors completed standardized assessments of intelligence, attention, learning, and academic achievement, and parents and caregivers completed ratings of attention, learning, and behavior.
Of 339 patients who were eligible for the serial assessments, 167 completed evaluations at both the end of therapy and two years later. Investigators found no meaningful differences between those who completed both assessments and those who did not, indicating that the results likely generalize to the broader study cohort.
“Prior studies were smaller or used study designs that limited assessment of treatment impact,” Jacola noted. “This larger, longitudinal sample improves our ability to detect clinically relevant changes and highlights the importance of routine neurocognitive and academic screening as part of survivorship care for all pediatric ALL survivors.”
Ongoing research is examining how ALL therapy alters brain structure and function, particularly in the majority of patients diagnosed between ages three and five. While stimulant medications can improve attention in some survivors, they are not always appropriate or acceptable. Computer-based interventions—often presented as game-like training—have shown promise for improving working memory in survivors with memory deficits and are more acceptable to many families. Additional research is needed to determine optimal timing and types of interventions to prevent or reduce long-term cognitive and academic difficulties.
Other contributing authors include Kevin Krull, Ching-Hon Pui, Deqing Pei, Cheng Cheng, Wilburn Reddick, and senior author Heather Conklin, all affiliated with St. Jude Children’s Research Hospital.
Funding: The research was supported by the National Institutes of Health/National Cancer Institute and ALSAC.
Source: Frannie Marmorstein, St. Jude Children’s Research Hospital
Image credit: Public domain image
Original research: Abstract for “Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol” by Lisa M. Jacola et al., Journal of Clinical Oncology. Published online February 8, 2016. doi:10.1200/JCO.2015.64.3205
Abstract
Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol
Purpose Survivors of childhood ALL treated with CNS-directed chemotherapy remain at risk for neurocognitive deficits. Prospective, longitudinal data are needed to clarify neurodevelopmental trajectories in this population.
Methods Patients enrolled in the St. Jude Total Therapy Study XV, which omitted prophylactic cranial irradiation, underwent comprehensive neuropsychological testing at induction (n = 142), at the end of maintenance therapy (n = 243), and two years after therapy completion (n = 211). The study evaluated longitudinal changes in neurocognitive functioning and identified predictors of outcomes two years after therapy.
Results Overall neurocognitive performance was largely age appropriate two years after completing chemotherapy-only treatment. Nevertheless, the cohort demonstrated significant attention deficits and a higher frequency of learning problems compared with national norms (all P ≤ .005). Higher-intensity CNS-directed chemotherapy increased the risk for impaired attention, slower processing speed, and poorer academic performance (all P ≤ .01). The trajectory and direction of change in both performance-based and caregiver-reported attention measures varied by age at diagnosis and by sex. Attention problems present at the end of therapy predicted lower academic scores two years later, with small to moderate effect sizes (│r│ = 0.17 to 0.25, all P ≤ .05).
Conclusion Two years after chemotherapy-only treatment, most survivors demonstrate age-appropriate neurocognitive function. However, a subgroup remains at elevated risk for attention problems that influence real-world functioning and academic outcomes. Early attention difficulties at the end of therapy predicted diminished academic achievement two years later, highlighting the functional impact of specific neurocognitive deficits. Age at diagnosis and patient sex appear to modify neurocognitive development in these survivors.