The Impact of Intensified CNS-Directed Therapy on Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation

Abstract

PURPOSE 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 acute lymphoblastic leukemia (ALL) at the greatest risk of CNS relapse. We examined the impact of this treatment on end-of-therapy neurocognitive outcomes. METHODS Between 2007 and 2017, 400 (83.5%) of 479 eligible patients treated with Total 16 risk-directed chemotherapy completed protocol-directed neurocognitive testing at the end of therapy. Intensified ITT was defined as ≥ 21 cumulative doses for patients with low-risk ALL (n = 70/194) and ≥ 27 doses for those with standard-to-high risk ALL (n = 81/206). RESULTS Compared with age-normative expectations, the overall group 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 ( P = .0087). Caregiver ratings of patient functioning showed elevated risk for problems in attention ( P = .0173), executive function ( P = .0001), and adaptive skills ( P = .0001). Among the low-risk treatment group, there were no significant differences between patients treated with or without intensified ITT (all P's >.10). Among patients with standard-to-high risk ALL, those treated with intensified ITT had poorer working memory ( P = .0328) and fine motor speed ( P = .0403), and elevated ratings of inattention ( P = .0189) and executive dysfunction ( P = .0245). In the standard-to-high risk group, females treated with intensified ITT had lower working memory scores. Public insurance status was associated with worse neurocognitive outcomes in both treatment groups. CONCLUSION 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.