title: Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia.
abstract: OBJECTIVE
  Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity.
  
  
  METHODS
  Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities.
  
  
  RESULTS
  Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity.
  
  
  CONCLUSIONS
  MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
authors.affiliation: All authors: St Jude Children's Research Hospital; and Deepa Bhojwani, Jun J. Yang, Hiroto Inaba, Jeffrey E. Rubnitz, Monika L. Metzger, Scott C. Howard, Raul C. Ribeiro, Sima Jeha, John T. Sandlund, and Ching-Hon Pui, University of Tennessee Health Sciences Center, College of Medicine, Memphis, TN.
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: Noah D
authors.initials: ND
authors.lastname: Sabin
authors.forename: Deqing
authors.initials: D
authors.lastname: Pei
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Raja B
authors.initials: RB
authors.lastname: Khan
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Krull
authors.forename: Hiroto
authors.initials: H
authors.lastname: Inaba
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Monika L
authors.initials: ML
authors.lastname: Metzger
authors.forename: Scott C
authors.initials: SC
authors.lastname: Howard
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Wilburn E
authors.initials: WE
authors.lastname: Reddick
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: John T
authors.initials: JT
authors.lastname: Sandlund
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D056784:Leukoencephalopathies / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D016015:Logistic Models; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D008727:Methotrexate