Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children

Leukemia. 2007 Feb;21(2):238-47. doi: 10.1038/sj.leu.2404495. Epub 2006 Dec 14.


The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)+/-high-dose methotrexate (HD MTX) in children with acute lymphoblastic leukemia (ALL). 1395 children were enrolled on FRALLE 93 protocol from 1993 to 1999. Lower-risk group (LR, n=182) were randomized to weekly low-dose MTX at 25 mg/m(2)/week (LD MTX, n=81) or HD MTX at 1.5 g/m(2)/2 weeks x 6 (n=77). Intermediate-risk group (IR, n=672) were randomized to LD MTX (n=290) or HD MTX at 8 g/m(2)/2 weeks x 4 (n=316). Higher-risk group (HR, n=541) prednisone-responder patients received LD MTX and cranial radiotherapy. HR group steroid resistant cases were grafted (autologous or allogenic). TIT (MTX, cytarabine and methylprednisolone) was given every 2 weeks during 16-18 weeks and every 3 months during maintenance therapy in LR and IR patients. 52 patients (3.7%) developed neurotoxicity. Isolated seizures: n=15 (1.1%), peripheral and spinal neuropathy: n=17 (1.2%) and encephalopathy: n=20 (1.4%). Age >10 years was significantly associated with neurotoxicity (P=0.01) and use of HD MTX is associated with encephalopathy (P=0.03). Sequels are reported respectively in 60 and 33% of spinal neuropathy and encephalopathy cases. Current strategies tailoring risk of neurological sequels has to be defined.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Age Factors
  • Antimetabolites, Antineoplastic / adverse effects*
  • Brain Diseases, Metabolic / chemically induced*
  • Brain Diseases, Metabolic / epidemiology
  • Brain Diseases, Metabolic / prevention & control
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Infant
  • Male
  • Methotrexate / adverse effects*
  • Neurotoxins
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / radiotherapy
  • Risk Assessment


  • Antimetabolites, Antineoplastic
  • Neurotoxins
  • Methotrexate