Originally published as JCO Early Release 10.1200/JCO.2008.18.1487 on January 12 2009

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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

From the Department of Pediatric Oncology and Biostatistics and Epidemiology Unit, Institut Gustave-Roussy, Villejuif; Univ Paris-Sud, Le Kremlin-Bicêtre; Department of Pathology, Centre Hospitalier Universitaire Toulouse, Hôpital Purpan; L'Institut National de la Santé et de la Recherche Médicale, U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France; Department of Pediatrics, University Hospital, Padova, Italy; Department of Pediatrics, Addenbrookes Hospital, Cambridge, United Kingdom; Clinical Research Center, National Hospital Organization Nagoya Medical Center, Aichi, Japan; Department of Bone Marrow Transplantation, Children Oncology and Hematology, Medical University, Wroclaw, Poland; Department of Paediatric Haematology and Oncology, St. Anna Children's Hospital, Vienna, Austria; Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Paediatric Haematology/Oncology, University Hospital, Leuven, Belgium; Department of Pediatrics, Göteborg University, Göteborg, Sweden; and Non-Hodgkin's Lymphoma–Berlin-Frankfurt-Muenster Study Centre, Department of Pediatric Hematology and Oncology, Justus-Liebig-University, Giessen, Germany.

Corresponding author: Laurence Brugieres, MD, Department of Pediatric Oncology, Institut Gustave-Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France; e-mail: brugiere{at}igr.fr.

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.

Supported by the Association Cent pour Sang la Vie and by the Institut Gustave-Roussy, France; the Forschungshilfe Station Peiper and the Berlin-Frankfurt-Muenster Study Centre, Giessen, Germany; the Associazione Italiana Contro le Leucemie and the Fondazione Città della Speranza, Padova, Italy; and the Ministry of Health, Labor and Welfare, Japan.

Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL, and the 39th Annual Meeting of the International Society of Pediatric Oncology, October 30-November 3, 2007, Mumbai, India.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

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