1. ¹Service d'hématologie et d'oncologie pédiatrique Hôpital d'Enfant Armand Trousseau, AP-HP, Paris, France
2. ²Service d'hématologie pédiatrique Hôpital St Louis, AP-HP, Paris, France
3. ³Service de pédiatrie II hospital d'Enfant Vandoeuvre les Nancy, Paris, France
4. ⁴Département de pédiatrie CHU Pellerin Bordeaux, Paris, France
5. ⁵Service d'hématologie pédiatrique CHU La Timone, Marseille, Paris, France
6. ⁶Département d'informatique médicale Hôpital Tenon, AP-HP, Paris, France
7. ⁷Service de pédiatrie CHR de Limoges
8. ⁸Service de pédiatrie CHR Rennes
9. ⁹Service d'hématologie CHR Clermont Ferrand
10. ¹⁰Département de pédiatrie CHR Rouen, for the French cooperative group FRALLE

Correspondence: Professor J Landman-Parker, Service d'hématologie et d'oncologie pédiatrique, AP-HP hôpital Armand Trousseau, 26 avenue Arnold Netter, 75012 Paris, France. E-mail: judith.landman-parker@trs.ap-hop-paris.fr

Received 11 September 2006; Revised 16 October 2006; Accepted 20 October 2006; Published online 14 December 2006.

Abstract

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/m²/week (LD MTX, n=81) or HD MTX at 1.5 g/m²/2 weeks 6 (n=77). Intermediate-risk group (IR, n=672) were randomized to LD MTX (n=290) or HD MTX at 8 g/m²/2 weeks 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.