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Neurocognitive and Neuroradiologic Central Nervous System Late Effects in Children Treated on Pediatric Oncology Group (POG) P9605 (Standard Risk) and P9201 (Lesser Risk) Acute Lymphoblastic Leukemia Protocols (ACCL0131): A Methotrexate Consequence? A Report From the Children’s Oncology Group

Duffner, Patricia K. MD; Armstrong, Floyd Daniel PhD; Chen, Lu PhD; Helton, Kathleen J. MD; Brecher, Martin L. MD; Bell, Beverly MD; Chauvenet, Allen R. MD, PhD

Journal of Pediatric Hematology/Oncology: January 2014 - Volume 36 - Issue 1 - p 8–15
doi: 10.1097/MPH.0000000000000000
Original Articles

Concerns about long-term methotrexate (MTX) neurotoxicity in the 1990s led to modifications in intrathecal (IT) therapy, leucovorin 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 (CNS)-directed therapy (P9605) versus those receiving fewer CNS-directed treatment days during intensive consolidation (P9201). A total of 66 children from 16 Pediatric Oncology Group institutions with “standard-risk” acute lymphoblastic leukemia, 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. Magnetic resonance imaging scans and standard neuropsychological tests were performed ≥2.6 years after the end of treatment. Significantly more P9605 patients developed leukoencephalopathy compared with P9201 patients (68%, 95% confidence interval 49%-83% vs. 22%, 95% confidence interval 5%-44%; P=0.001) identified as late as 7.7 years after the end of treatment. Overall, 40% of patients scored <85 on either Verbal or Performance IQ. 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 MTX exposure as a major contributor to CNS late effects.

*Department of Neurology, University at Buffalo School of Medicine

Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY

Department of Pediatrics, University of Miami Miller School of Medicine and Holtz Children’s Hospital, Miami, FL

Statistics and Data Center, Children’s Oncology Group, Monrovia, CA

§Department of Radiological Sciences, St Jude Children’s Research Hospital, Memphis, TN

Department of Pediatrics, Georgia Health Science Center, Augusta, GA

#Department of Pediatrics, West Virginia University Health Science Center, Charleston, WV

Research is supported by the Chair’s Grant CA98543-08 of the Children’s Oncology Group from the National Cancer Institute, National Institutes of Health, Bethesda, MD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the NIH. A complete listing of grant support for research conducted by CCG and POG before initiation of the COG grant in 2003 is available online at:

The authors declare no conflict of interest.

Reprints: Patricia K. Duffner, MD, Department of Neurology, University at Buffalo School of Medicine, 39 Saybrook Place, Buffalo, NY 14209 (e-mail:

Received February 28, 2013

Accepted August 20, 2013

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