Vincristine (VCR) - Dexamethasone (DEXA) Pulses for Intermediate Risk (IR) Childhood Acute Lymphoblastic Leukemia (ALL) Treated with BFM Based Protocols: Results of the I-BFM-SG ALL IR 95 Study.

Abstract

Abstract Introduction: Various studies conducted in the 70ies and 80ies suggested that the intensification of the continuation therapy phase with VCR + steroids pulses improved the outcome of childhood ALL. Aim: Aim of this study was to investigate the efficacy and toxicity of the addition of VCR-DEXA pulses to conventional continuation therapy in a large cohort of children with IR ALL treated with BFM therapy. Patients and Methods: The following pediatric oncology groups participated to this study: BFM (Germany + Switzerland), BFM (Austria), AIEOP (Italy), PINDA (Chile), GATLA (Argentina), the pediatric oncology group of Hungary, CPH (Czech Republic), and EORTC (France + Belgium + Portugal). All these groups belonged to the International BFM Study Group (I-BFM-SG) and used very similar BFM-oriented frontline ALL protocols, which included the Induction (protocol I), Consolidation (protocol M), Reinduction (protocol II) and continuation therapy phases; the definition of IR (age <1y or > 6y or WBC count ≥ 20,000/cmm, with < 1,000 blasts/cmm in peripheral blood after 7 days of steroid therapy and one dose of i.t. MTX on day 1, CR after 5 or 6 weeks of chemotherapy and absence of t(9;22) or t(4;11) translocations) was the same in every group; at the beginning of the continuation therapy phase every group randomized between administering (Arm P) or not (Arm NoP) VCR (1.5 mg/sqm weekly x2) and DEXA (6 mg/sqm daily x 7 days) pulses q 10 weeks x 6, on top of conventional 6-MP and Methotrexate therapy. Analysis of treatment effect (DFS: time from randomization to relapse or death in CR) was performed according to intention to treat. Results: In the period April 1995 – December 2000 a total of 3109 newly diagnosed patients entered the IR ALL study. One hundred and seventy four patients (5.6%) relapsed or died in CR before randomization (start of the continuation phase). Out of this cohort, 2935 patients were eligible for randomization and 2618 were randomized: 1325 in Arm P and 1293 in Arm NoP. With a median follow-up of 4.7 yrs, 481 relapses occurred (240 in Arm P and 241 in Arm NoP); other events were 29 (15 in Arm P and 14 in Arm NoP). The 5 and 7-year percent estimates were 79.8 (SE 1.2) and 77.5 (SE 1.5) in the yes pulses arm and 79.2 (SE 1.2) and 78.4 (SE 1.3) for the Arm NoP, respectively. The addition of pulses was associated to a non significant 3% relative risk reduction, as indicated by the estimated HR of 0.96 (95% confidence intervals: 0.81–1.14, p-value=0.63). Conclusion: In the prospective randomized intergroup I-BFM-SG IR ALL 95 study the addition of VCR - DEXA pulses during maintenance phase in patients with IR ALL was not related to any long term difference in DFS, relapse rate or treatment related mortality. According to this study, there is no evidence that children with IR ALL who received intensive BFM-based initial therapy may benefit from the intensification with pulses of the continuation therapy phase.