Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal therapy, leukovorin rescue and frequency of systemic MTX administration in children with acute lymphoblastic leukemia. In this study, neurocognitive outcomes and neuroradiologic evidence of leukoencephalopathy were compared in children treated with intense central nervous system directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). 66 children from 16 Pediatric Oncology Group (POG) institutions with “standard risk” ALL, 1.00 to 9.99 years at diagnosis, without evidence of CNS leukemia at diagnosis were enrolled on ACCL0131: 28 from P9201 and 38 from P9605. MRI scans and standard neuropsychologic tests were performed > 2.6 years following end of treatment. Significantly more P9605 patients developed leukoencephalopathy than P9201 (68%, 95% CI 49%-83% vs. 22%, 95% CI 5%-44%; p=0.001) identified as late as 7.7 years following end of treatment. Overall 40% of patients scored <85 on either VIQ or PIQ. Children on both studies had significant attention problems but P9605 children scored below average on more neurocognitive measures than those treated on P9201 (82%, 14/17 measures vs. 24%, 4/17 measures). This supports ongoing concerns about intensive methotrexate exposure as a major contributor to CNS late effects.
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