Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group.
OBJECTIVE
To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL).


METHODS
This randomized trial for children with ALCL was based on the Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Muenster 90 (NHL-BFM90) study protocol and compared six courses of methotrexate 1 g/m2 over 24 hours and an intrathecal injection (IT) followed by folinic acid rescue at 42 hours (MTX1 arm) with six courses of methotrexate 3 g/m2 over 3 hours followed by folinic acid rescue at 24 hours without IT (MTX3 arm). This trial involved most European pediatric/lymphoma study groups and a Japanese group.


RESULTS
Overall, 352 patients (96% ALK positive) were recruited between 1999 and 2005; 175 were randomly assigned to the MTX1 arm, and 177 were assigned to the MTX3 arm. Ninety-two percent of patients received protocol treatment. Median follow-up time is 3.7 years. Event-free survival (EFS) curves were superimposed with 2-year EFS rates (73.6% and 74.5% in the MTX1 and MTX3 arms, respectively; hazard ratio = 0.98; 91.76% CI, 0.69 to 1.38). Two-year overall survival rates were 90.1% and 94.9% in MTX1 and MTX3, respectively. Only two CNS relapses occurred (both in the MTX1 arm). Toxicity was assessed after 2,050 courses and included grade 4 hematologic toxicity after 79% and 64% of MTX1 and MTX3 courses, respectively (P < .0001); infection after 50% and 32% of courses, respectively (P < .0001); and grade 3 to 4 stomatitis after 21% and 6% of courses, respectively (P < .0001).


CONCLUSIONS
The results of the NHL-BFM90 study were reproduced in this large international trial. The methotrexate schedule of the NHL-BFM90 protocol including IT therapy can be safely replaced by a less toxic schedule of methotrexate 3 g/m2 in a 3-hour infusion without IT therapy.
Brugières
Laurence
L
Department of Pediatric Oncology and Biostatistics and Epidemiology Unit, Institut Gustave-Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France. brugiere@igr.fr
Le Deley
Marie-Cécile
MC
Rosolen
Angelo
A
Williams
Denise
D
Horibe
Keizo
K
Wrobel
Grazyna
G
Mann
Georg
G
Zsiros
Jozsef
J
Uyttebroeck
Anne
A
Marky
Ildiko
I
Lamant
Laurence
L
Reiter
Alfred
A
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate