PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

Biostatistics and Clinical Epidemiology Fondazione IRCCS San Gerardo dei Tintori Monza Italy

Department of Oncology Laboratory of Cancer Pharmacology IRCCS Istituto di Ricerche Farmacologiche Mario Negri Milano Italy

Department of Paediatric Hematology and Oncology University Hospital Muenster Muenster Germany

Department of Pediatric Haematology and Oncology 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Pediatric Hematology and Oncology IRCCS Ospedale Bambino Gesù Rome Catholic University of the Sacred Heart Rome Italy

Department of Pediatric Hematology and Oncology St Anna Children's Hospital Medical University of Vienna Vienna Austria

Department of Pediatric Hematology Oncology Hannover Medical School Hannover Germany

Department of Pediatric Hematology Oncology Schneider Children's Medical Center Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatric Oncology and Hematology Charité Universitätsmedizin Berlin Berlin Institute of Health at Charité Universitätsmedizin Berlin Berlin Germary

Department of Pediatrics 1 Pediatric Hematology Oncology ALL BFM Study Group Christian Albrechts University Kiel and University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Pediatrics Division of Hematology and Oncology Goethe University Frankfurt Frankfurt am Main Germany

Department of Pediatrics Jena University Hospital Jena Germany

Kids Cancer Centre Sydney Children's Hospital Randwick NSW Australia

Pediatric Hematology Oncology and Stem Cell Transplant Division Maternal and Child Health Department Padua University Padua Italy

Pediatrics Fondazione IRCCS San Gerardo dei Tintori Monza Italy

School of Medicine and Surgery University of Milano Bicocca Milan Italy

St Anna Children's Cancer Research Institute Vienna Austria

Tettamanti Center Fondazione IRCCS San Gerardo dei Tintori Monza Italy

The Cancer Centre for Children The Children's Hospital at Westmead Sydney NSW Australia

University Children Hospital Zurich Department of Oncology Zurich Switzerland

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ClinicalTrials.gov
NCT01117441