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Original Investigation
March 2, 2021

Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial

Author Affiliations
  • 1IRCCS Ospedale Pediatrico Bambino Gesù and Sapienza University of Rome, Rome, Italy
  • 2Amgen Research (Munich GmbH), Munich, Germany
  • 3University of Milano–Bicocca, MBBM Foundation, Monza, Italy
  • 4Amgen Inc, Thousand Oaks, California
  • 5Jena University Hospital, Jena, Germany
  • 6Universitätsklinikum Frankfurt am Main, Frankfurt, Germany
  • 7Azienda Ospedaliera di Rilievo Nazionale Santobono Pausilipon, Naples, Italy
  • 8Medizinische Hochschule Hannover, Hannover, Germany
  • 9Universitätsklinikum Freiburg, Freiburg, Germany
  • 10Sorbonne Université, Hôpital Armand Trousseau, AP-HP, Paris, France
  • 11IRCCS Istituto Giannina Gaslini, Genova, Italy
  • 12Amgen Ltd, Uxbridge, United Kingdom
  • 13Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 14Universitätsklinikum Schleswig–Holstein, Kiel, Germany
  • 15Westmead Hospital, Sydney, New South Wales, Australia
  • 16Charles University, Motol University Hospital, Prague, Czech Republic
  • 17St Anna Children’s Hospital, Vienna, Austria
  • 18The University of Manchester, Manchester, United Kingdom
  • 19Tata Translational Cancer Research Center, Tata Medical Center, Kolkata, West Bengal, India
JAMA. 2021;325(9):843-854. doi:10.1001/jama.2021.0987
Visual Abstract. Blinatumomab vs Chemotherapy and Event-Free Survival in B-Cell Acute Lymphoblastic Leukemia
Blinatumomab vs Chemotherapy and Event-Free Survival in B-Cell Acute Lymphoblastic Leukemia
Key Points

Question  After induction therapy and 2 blocks of consolidation chemotherapy, does 1 cycle of blinatumomab compared with a third course of consolidation chemotherapy before allogeneic hematopoietic stem cell transplant improve event-free survival in high-risk first-relapse B-cell acute lymphoblastic leukemia (B-ALL) in children?

Findings  In this randomized clinical trial that included 108 children with high-risk first-relapse B-ALL, treatment with blinatumomab compared with chemotherapy for consolidation treatment resulted in a statistically significant hazard ratio for event-free survival of 0.33 after a median of 22.4 months of follow-up.

Meaning  Blinatumomab compared with chemotherapy for consolidation treatment improved event-free survival in children with relapsed B-ALL.

Abstract

Importance  Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Objective  To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant.

Design, Setting, and Participants  In this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts ≥5% and <25%) at randomization.

Intervention  Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m2/d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation.

Main Outcomes and Measures  The primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.

Results  A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.

Conclusions and Relevance  Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up.

Trial Registration  ClinicalTrials.gov Identifier: NCT02393859

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