Martin Schrappe, Franco Locatelli, Maria Grazia Valsecchi, Gerhard Zugmaier, Michaela Vossen-Gajcy, Jan Starý, Andishe Attarbaschi, Anja Möricke, Jean-Pierre Bourquin, Draga Barbaric, Sarah Elitzur, Daniela Silvestri, Alexandra Kolenova, Luciano Dalla-Pozza, Nicole Bodmer, Martin Stanulla, Julia Alten, Faraz Zaman, Anke Bergmann, Giovanni Cazzaniga, Monika Brüggemann, Barbara Buldini, Rolf Köhler, Grazia Fazio, Claudia Rössig, Lucie Sramkova, Rosanna Parasole, Patrick Hundsdörfer, Maria Caterina Putti, Arndt Borkhardt, Franca Fagioli, Laura Rachele Bettini, Fiona Poyer, Arend von Stackelberg, Luciana Vinti, Valentino Conter, Martin Zimmermann, Carmelo Rizzari, Gunnar Cario, Andrea Biondi, AIEOP-BFM ALL 2017 Consortium
In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival at 4 years. (Funded by Deutsche Krebshilfe and others; AIEOP-BFM ALL 2017 EudraCT number, 2016-001935-12; EU Clinical Trials number, 2023-509856-32-00; and ClinicalTrials.gov number, NCT03643276.).
BACKGROUND: Blinatumomab, a bispecific T-cell engager targeting the CD19 antigen on B cells, may offer an option to safely replace cycles of traditional chemotherapy in pediatric patients with newly diagnosed high-risk B-cell acute lymphoblastic leukemia (ALL).
METHODS: We randomly assigned, in a 1:1 ratio, children with high-risk B-cell ALL to receive two cycles of blinatumomab (blinatumomab group) or two cycles of chemotherapy (control group) after consolidation. The primary end point was event-free survival as evaluated in a time-to-event analysis; the duration of event-free survival was defined as the time from randomization to the first event among resistance to protocol treatment, relapse, second cancer, or death from any cause. Our primary objective was to evaluate whether the 4-year event-free survival would be 10 percentage points higher in the blinatumomab group than in the control group.
RESULTS: Overall, 709 of 768 eligible patients (92.3%) underwent randomization; 358 were assigned to the blinatumomab group and 351 to the control group. A planned interim analysis at a median follow-up of 2.9 years showed an estimated 4-year event-free survival of 83.0% (95% confidence interval [CI], 77.4 to 87.4) in the blinatumomab group and 70.3% (95% CI, 63.8 to 75.9) in the control group (P = 0.0002 in an intention-to-treat analysis). The estimated hazard ratio for a primary end-point event (blinatumomab vs. control) was 0.51 (95% CI, 0.35 to 0.73) as assessed with a Cox model. Infection related to the trial treatment occurred in 23.9% of patients in the blinatumomab group and in 69.4% of those in the control group (P<0.001). Life-threatening adverse events occurred in 2 patients (0.5%) in the blinatumomab group, including one (in 0.3%) that was fatal, and in 16 patients (4.7%) in the control group. Neurotoxic events were reported in 12.0% and 3.2%, respectively (P<0.001). Cytokine release syndrome of grade 2 or higher occurred in 1.1% of patients in the blinatumomab group.
CONCLUSIONS: In children with newly diagnosed high-risk B-cell ALL, replacement of two cycles of highly toxic conventional chemotherapy with blinatumomab resulted in a significantly greater percentage of patients with event-free survival at 4 years. (Funded by Deutsche Krebshilfe and others; AIEOP-BFM ALL 2017 EudraCT number, 2016-001935-12; EU Clinical Trials number, 2023-509856-32-00; and ClinicalTrials.gov number, NCT03643276.).