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

Abstract

The objective of the study was to assess acute neurotoxicity associated with triple intrathecal therapy (TIT)7high-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 ¼ 182) were randomized to weekly low-dose MTX at 25 mg/m 2 /week (LD MTX, n ¼ 81) or HD MTX at 1.5 g/m 2 /2 weeks  6 (n ¼ 77). Intermediate-risk group (IR, n ¼ 672) were randomized to LD MTX (n ¼ 290) or HD MTX at 8 g/m 2 /2 weeks  4 (n ¼ 316). Higherrisk group (HR, n ¼ 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 ¼ 15 (1.1%), peripheral and spinal neuropathy: n ¼ 17 (1.2%) and encephalopathy: n ¼ 20 (1.4%). Age 410 years was significantly associated with neurotoxicity (P ¼ 0.01) and use of HD MTX is associated with encephalopathy (P ¼ 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.

Excellent prognosis of late relapses of ETV6/RUNX1-positive childhood acute lymphoblastic leukemia: lessons from the FRALLE 93 protocol

“…The FRALLE 93 study population was stratified into three groups (low-risk, intermediate-risk, and high-risk) based on the following risk factors: age, whitecell count at diagnosis, hemoglobin level, immunophenotype, karyotype, and response to steroids. The treatment, which has already been published, 22 is described in the Online Supplementary Data.…”

Neurotoxicity of chemotherapeutic and biologic agents in children with cancer

“…Winick et al [9] speculated that methotrexate was likely the causative agent, as the incidence dropped when patients were given folinic acid. Dufourg et al [6] found a significant increase of encephalopathy in patients treated with high-dose (10 of 20) versus lowdose (2 of 20) methotrexate (P = 0.03). They also found an increased incidence of encephalopathy and seizures in patients 10 years of age or older at onset of treatment.…”

“…Dufourg et al [6] published a paper stating that patients treated with high-dose methotrexate were more likely to develop encephalopathy. Patients were treated with triple intrathecal therapy (methylprednisolone, methotrexate, and cytarabine) and either high-dose or low-dose methotrexate for ALL in the French FRALLE 93 trial.…”

Posterior reversible encephalopathy syndrome after intrathecal methotrexate infusion: a case report and literature update

“…It can cause leukoencephalopathy, which ranges from acute and reversible to recurrent, chronic or irreversible and rarely fatal (5). The pathophysiology of leukoencephalopathy is not well understood.…”