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Value of High-Dose Cytarabine During Interval Therapy of a Berlin-Frankfurt-Munster–Based Protocol in Increased-Risk Children With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Results of the European Organization for Research and Treatment of Cancer 58881 Randomized Phase III Trial

From the Departments of Pediatrics, University Hospitals of Poitiers, Lyon, Lille, Strasbourg, Nantes, Paris (Hospital R. Debré), Toulouse, Caen, Montpellier, Besançon, Angers, Reims, and Grenoble, France, and Verviers, Gent, and Brussels (Hospital Reine Fabiola, Akademish Ziekenhuis Vreije Universitijt Brussel), Belgium; Department of Pediatrics, University Hospital of Porto, Portugal; Laboratory of Hematology-Cytology, University Hospital of Toulouse, France; and the European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium.

Address reprint requests to F. Millot, MD, Department of Hematology and Medical Oncology, University Hospital of Poitiers, 350 Ave Jacques Coeur, BP 557 – 86021 Poitiers Cedex, France; email: f.millot{at}chu- poitiers.fr.

PURPOSE: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)–based regimen.

PATIENTS AND METHODS: After completion of induction-consolidation phase, children with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m² over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m² in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B).

RESULTS: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P = .67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%).

CONCLUSION: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.

(HD)The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Cancer Institute.

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