CNS-Directed Therapy and Neurocognitive Outcomes in Survivors of Childhood ALL Receiving No Cranial Irradiation

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In a single-institution study reported in the Journal of Clinical Oncology, Jacola et al found that survivors of childhood acute lymphoblastic leukemia (ALL) who received central nervous system (CNS)-directed therapy excluding cranial irradiation had poorer outcomes in numerous neurocognitive domains compared with age-based norms. For patients treated with vs without intensified CNS-directed therapy, no differences in domains were observed among low-risk patients, whereas several deficits were observed among standard-risk and high-risk patients.

As stated by the investigators, “Findings from St. Jude Total Therapy Study 16 (Total 16) showed early intensification of triple intrathecal therapy (ITT) improved CNS disease control for children with newly diagnosed ALL at the greatest risk of CNS relapse. We examined the impact of this treatment on end-of-therapy neurocognitive outcomes.”

Study Details

The study included 400 patients (83.5% of 470 eligible patients) treated with Total 16 risk-directed chemotherapy including ITT at St. Jude Children’s Research Hospital who completed neurocognitive testing at the end of therapy between 2007 and 2017. Intensified ITT was defined as 21 cumulative doses for patients with low-risk ALL and ≥ 27 doses for those with standard/high-risk ALL; intensified ITT was received by 70 of 194 low-risk patients and 81 of 206 standard/high-risk patients.

Key Findings

Compared with age-based norms, the entire cohort had significantly lower estimated intelligence quotient (P < .0001), attention (P = .0051), working memory (P = .0001), processing speed (P = .0002), fine motor speed (P = .0001), and math performance (P = .0087). Caregiver ratings of patient functioning indicated elevated risk for problems with attention (P = .0173), executive function (P = .0001), and adaptive skills (P =.0001).

Compared with low-risk patients, standard/high risk patients had worse working memory (P = .0070), processing speed (P = .0040), and math performance (P = .0465).

In the low-risk group, there were no significant differences between patients treated with vs without intensified ITT in any neurocognitive domains (P > .10 for all). Among patients not receiving intensified ITT, males had poorer working memory vs females (P = .0015).

In the standard/high- risk group, patients treated with vs without intensified ITT had poorer working memory (P = .0328), fine motor speed (P = .0403), attention (P = .0189), and executive function (P = .0245). Female patients treated with vs without intensified ITT had poorer working memory (P = .0053).  

Insurance status was associated with outcomes in both groups: among low-risk patients, public or no insurance vs private insurance was associated with significantly poorer estimated intelligence quotient, processing speed, math performance, attention, and executive function; among high-risk patients, public or no insurance was associated with significantly poorer processing speed and math performance.

The investigators concluded, “Standard-to-high risk patients treated with intensified ITT are at moderately increased risk for neurocognitive problems. The findings suggest a threshold effect for ITT exposure, which can inform the design of future clinical trials and approaches to neurocognitive monitoring and intervention.”

Lisa M. Jacola, PhD, of the Department of Psychology, St. Jude Children’s Research Hospital, Memphis, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.