Longitudinal Assessment of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated on a Contemporary Chemotherapy Protocol

Abstract

Purpose: Survivors of childhood acute lymphoblastic leukemia (ALL) treated with CNS-directed chemotherapy are at risk for neurocognitive deficits. Prospective longitudinal studies are needed to clarify the neurodevelopmental trajectory in this vulnerable population.

Methods: Patients enrolled in the St. Jude Total Therapy Study XV, which omitted prophylactic cranial radiation therapy in all patients, completed comprehensive neuropsychological assessments at induction (n = 142), end of maintenance (n = 243), and 2 years after completion of therapy (n = 211). We report on longitudinal change in neurocognitive function and predictors of neurocognitive outcomes 2 years after completing therapy.

Results: Neurocognitive function was largely age appropriate 2 years after completing therapy; however, the overall group demonstrated significant attention deficits and a significantly greater frequency of learning problems as compared with national normative data (all P ≤ .005). Higher-intensity CNS-directed chemotherapy conferred elevated risk for difficulties in attention, processing speed, and academics (all P ≤ .01). The rate and direction of change in performance and caregiver-reported attention difficulties differed significantly by age at diagnosis and sex. End-of-therapy attention problems predicted lower academic scores 2 years later, with small to moderate effect sizes (│r│= 0.17 to 0.25, all P ≤ .05).

Conclusion: Two years after chemotherapy-only treatment, neurocognitive function is largely age appropriate. Nonetheless, survivors remain at elevated risk for attention problems that impact real-world functioning. Attention problems at the end of therapy predicted decreased academics 2 years later, suggesting an amplified functional impact of discrete neurocognitive difficulties. Age at diagnosis and patient sex may alter neurocognitive development in survivors of childhood ALL treated with chemotherapy-only protocols.

Fig 1.

(A) Univariate logistic regression comparing the frequency of below average performance by age at diagnosis (< 5 years old; ≥ 5 years old). Reference group: ≥ 5 years old at diagnosis. (B) Univariate logistic regression comparing the frequency of below average performance by treatment risk arm (low; standard/high). Reference group: low risk. (C) Frequency of below average performance by sex. Univariate logistic regression comparing the frequency of below average performance by sex. Reference group: male. Black bars indicate the expected frequency of performance outside the average range in the normative sample (16th percentile). *P ≤ .05, †P ≤ .01, ‡P ≤ .001. CPRS, Connors Parent Rating Scales; CPT, Continuous Performance Test; CVLT, California Verbal Learning Test; D′, discriminability; FFD, Freedom from Distractibility Index; LD, long delay; PSI, Processing Speed Index; SD, short delay; WIAT, Wechsler Individual Achievement Test.

Fig 2.

Change in sustained attention from End of Therapy to 2 Years Post by age at diagnosis. Group means from models with age at diagnosis predicting sustained attention scores (CPT): (A) omissions, (B) reaction time, (C) risk taking, and (D) attentiveness. Higher scores denote worse performance. CPT, Continuous Performance Test.

Fig 3.

Change in caregiver ratings from End of Therapy to 2 Years Post by sex. Group means from models with sex predicting caregiver-reported problems (CPRS): (A) hyperactivity and (B) impulsivity. Higher scores denote more problems. CPRS, Connors Parent Rating Scales.