Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia.
To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol.



This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education.



Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue.



Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.
All authors: St Jude Children's Research Hospital, Memphis, TN kevin.krull@stjude.org.
Kevin R
KR
Krull
All authors: St Jude Children's Research Hospital, Memphis, TN.
Yin Ting
YT
Cheung
All authors: St Jude Children's Research Hospital, Memphis, TN.
Wei
W
Liu
All authors: St Jude Children's Research Hospital, Memphis, TN.
Slim
S
Fellah
All authors: St Jude Children's Research Hospital, Memphis, TN.
Wilburn E
WE
Reddick
All authors: St Jude Children's Research Hospital, Memphis, TN.
Tara M
TM
Brinkman
All authors: St Jude Children's Research Hospital, Memphis, TN.
Cara
C
Kimberg
All authors: St Jude Children's Research Hospital, Memphis, TN.
Robert
R
Ogg
All authors: St Jude Children's Research Hospital, Memphis, TN.
Deokumar
D
Srivastava
All authors: St Jude Children's Research Hospital, Memphis, TN.
Ching-Hon
CH
Pui
All authors: St Jude Children's Research Hospital, Memphis, TN.
Leslie L
LL
Robison
All authors: St Jude Children's Research Hospital, Memphis, TN.
Melissa M
MM
Hudson
D000293:Adolescent; D002648:Child; D056344:Executive Function; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects; D006801:Humans; D007360:Intelligence; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate / Q000097:blood; D059906:Neuroimaging; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology / Q000628:therapy; D017397:Prefrontal Cortex / Q000473:pathology; D016896:Treatment Outcome
D008727:Methotrexate