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.

Abstract

PURPOSE:

To compare the efficacy and safety of two methotrexate doses and administration schedules in children with anaplastic large-cell lymphoma (ALCL).

PATIENTS AND 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).

CONCLUSION:

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.

• Authors: Laurence Brugières, Marie-Cécile Le Deley, Angelo Rosolen, Denise Williams, Keizo Horibe, Grazyna Wrobel, Georg Mann, Jozsef Zsiros, Anne Uyttebroeck, Ildiko Marky, Laurence Lamant, Alfred Reiter
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 27 Issue 6 Pg. 897-903 (Feb 20 2009) ISSN: 1527-7755 [Electronic] United States
• PMID: 19139435 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Methotrexate

Topics

• Adolescent
• Antimetabolites, Antineoplastic (administration & dosage)
• Child
• Child, Preschool
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Infant
• Injections, Spinal
• Lymphoma, Large B-Cell, Diffuse (drug therapy, pathology)
• Male
• Methotrexate (administration & dosage)
• Treatment Outcome
• Young Adult