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Pediatric Cancer

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

Educational Objective
To learn the effect of blinatumomab vs standard consolidation chemotherapy in the treatment of children with high-risk first-relapse B-cell precursor acute lymphoblastic leukemia (B-ALL).

1 Credit CME

JAMA

Published Online: March 2, 2021

Original Investigation

Article Information and Disclosures

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

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Original Investigation

Consolidation With Blinatumomab vs Chemotherapy in First Relapse of B-Cell Acute Lymphoblastic Leukemia

Patrick A. Brown, MD; Lingyun Ji, PhD; Xinxin Xu, MS; Meenakshi Devidas, PhD; Laura E. Hogan, MD; Michael J. Borowitz, MD, PhD; Elizabeth A. Raetz, MD; Gerhard Zugmaier, MD; Elad Sharon, MD, MPH; Melanie B. Bernhardt, PharmD; Stephanie A. Terezakis, MD; Lia Gore, MD; James A. Whitlock, MD; Michael A. Pulsipher, MD; Stephen P. Hunger, MD; Mignon L. Loh, MD

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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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Article Information

Corresponding Author: Franco Locatelli, MD, PhD, Sapienza, University of Rome, Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Piazza Sant'Onofrio, 4, 00165 Rome, Italy (franco.locatelli@opbg.net).

Accepted for Publication: January 22, 2021.

Author Contributions: Dr Locatelli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Locatelli, Zugmaier, Morris, Parasole, Micalizzi, Mergen, Peters, Saha, von Stackelberg.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Locatelli, Zugmaier, Morris, Parasole, Mergen, Peters, Saha, von Stackelberg.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Zugmaier, Mohammad.

Administrative, technical, or material support: Morris, Gruhn, Klingebiel, Petit, Eckert, Möricke, Sartor, Saha, von Stackelberg.

Supervision: Locatelli, Zugmaier, Morris, Parasole, Mergen, Eckert, Saha, von Stackelberg.

Contribution to statistical sections of manuscript and revisions/suggestions: Mohammad.

Recruitment of cases, collecting data and information, discussing management of patients, evaluating results: Rizzari.

Conflict of Interest Disclosures: Dr Locatelli reports receiving personal fees from Amgen Speakers' Bureau and advisory board membership, Novartis Speakers' Bureau and advisory board membership, Bellicum Pharmaceuticals advisory board membership, Miltenyi Speakers' Bureau, Jazz Pharmaceutical Speakers' Bureau, Takeda Speakers' Bureau, Neovii advisory board membership, and Medac Speakers' Bureau outside the submitted work. Dr Zugmaier reports receiving personal fees from Amgen outside the submitted work, receiving issue of patents (20190300609, 20130323247, and 20110262440), and having patents pending (10696744, 10662243, 20190142846, 20190142846, 20170327581, 10130638, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140228316, 20140227272, 20130287778, and 20130287774). Dr Rizzari reports receiving personal fees from SOBI Advisory Board during the conduct of the study. Dr Morris reports receiving personal fees from Amgen employee during the conduct of the study and personal fees from and employment at Amgen. Dr Klingebiel reports receiving grants from Amgen GmbH during the conduct of the study. Dr Mergen reports employment by Amgen Research (Munich) GmbH. Ms Mohammad reports being an employee and shareholder of Amgen Ltd. Dr Eckert reports receiving other from Amgen Service for central minimal residual disease quantification during the conduct of the study. Dr Möricke reports receiving other from Amgen Payments to the institution for laboratory work during the conduct of the study. Dr Sartor reports receiving grants from Amgen during the conduct of the study. Dr Hrusak reports receiving grants from Amgen covering costs of minimal residual disease monitoring by cytometry during the conduct of the study. Dr Peters reports receiving personal fees from Amgen during the conduct of the study; grants from Amgen, Medac, Neovii, and Riemser outside the submitted work; and personal fees from Novartis, Amgen, and Jazz outside the submitted work. Dr Saha reports receiving personal fees from Amgen during the conduct of the study. Dr von Stackelberg reports receiving personal fees from Amgen Advisory Board during the conduct of the study and personal fees from Novartis Advisory Board, MorphoSys Advisory Board, Jazz Pharmaceuticals Advisory Board, and Shire Advisory Board outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by Amgen Inc.

Role of the Funder/Sponsor: Amgen Inc participated in the conception, design, and conduct of the trial and the analysis and interpretation of data; managed patient data collected at the study sites; and supported the external authors in submitting the results of this clinical trial for publication in JAMA in parallel with the publication of Study AALL1331 from the Children’s Oncology Group. Amgen did not control the decision. Amgen did not have the right to veto publication or to control the decision regarding to which journal the manuscript was submitted.

Group Information: A complete list of principal investigators is provided in the eAppendix in Supplement 3.

Additional Contributions: Medical writing support was provided by Kathryn Boorer, PhD, of KB Scientific Communications, LLC, funded by Amgen Inc; and Liz Leight, PhD, an employee of Amgen Inc.

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

Treatment Regimens for Adolescents and Young Adults With Ph Chromosome-Negative ALL

Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Blinatumomab for Children With High-risk Relapsed B-Cell Acute Lymphoblastic Leukemia

Consolidation With Blinatumomab vs Chemotherapy in First Relapse of B-Cell Acute Lymphoblastic Leukemia

See More

AMA CME Accreditation Information

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

Treatment Regimens for Adolescents and Young Adults With Ph Chromosome-Negative ALL

Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Blinatumomab for Children With High-risk Relapsed B-Cell Acute Lymphoblastic Leukemia

Consolidation With Blinatumomab vs Chemotherapy in First Relapse of B-Cell Acute Lymphoblastic Leukemia

See More

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