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 Organizationfor Research and Treatment of Cancer 58881 Randomized Phase III Trial

Purpose: The European Organization for Research and Treatment of Cancer 588 81 study was designed to test in a prospective multicentric randomized tria l 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 relaps es in children with increased-risk acute lymphoblastic leukemia (ALL) or st age III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munst er (BFM)-based regimen. Patients and Methods: After completion of induction-consolidation phase, ch ildren with increased-risk (risk factor > 0.8 or T-lineage) ALL or stage II I and IV lymphoblastic lymphoma were randomized to receive four courses of I-ID MTX (5 g/m(2) over 24 hours every 2 weeks) and four intrathecal admini strations of MTX (Arm A) or the same treatment schedule with additional I-I D IV Ara-C (1 g/m(2) 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 o f 190 events (177 relapses and 13 deaths without relapse) were reported, an d 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% (S E = 1.9%) versus 76.3% (SE = 5.6%). Conclusion: Prevention of CNS relapse was satisfactorily achieved with HD I V MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based trea tment protocol in which cranial irradiation was omitted. Disappointingly, w ith the dose schedule used in this protocol, HD Ara-C added to HD MTX, alth ough well tolerated, failed to further decrease the incidence of CNS relaps e or to improve the overall DFS. (C) 2001 by American Society of Clinical O ncology.