Does immunotherapy with blinatumomab result in longer disease-free survival compared with chemotherapy as postreinduction consolidation therapy prior to hematopoietic stem cell transplant in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-cell acute lymphoblastic leukemia?
In this randomized clinical trial that included 208 patients with high- and intermediate-risk first relapse of B-cell acute lymphoblastic leukemia and was terminated early, treatment with blinatumomab vs chemotherapy resulted in 2-year disease-free survival of 54% vs 39% of participants, but the difference was not statistically significant.
Postreinduction treatment with blinatumomab compared with chemotherapy, followed by hematopoietic stem cell transplant, did not result in a statistically significant difference in disease-free survival, but study interpretation is limited by early termination with possible underpowering for the primary end point.
Standard chemotherapy for first relapse of B-cell acute lymphoblastic leukemia (B-ALL) in children, adolescents, and young adults is associated with high rates of severe toxicities, subsequent relapse, and death, especially for patients with early relapse (high risk) or late relapse with residual disease after reinduction chemotherapy (intermediate risk). Blinatumomab, a bispecific CD3 to CD19 T cell–engaging antibody construct, is efficacious in relapsed/refractory B-ALL and has a favorable toxicity profile.
To determine whether substituting blinatumomab for intensive chemotherapy in consolidation therapy would improve survival in children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL.
Design, Setting, and Participants
This trial was a randomized phase 3 clinical trial conducted by the Children’s Oncology Group at 155 hospitals in the US, Canada, Australia, and New Zealand with enrollment from December 2014 to September 2019 and follow-up until September 30, 2020. Eligible patients included those aged 1 to 30 years with B-ALL first relapse, excluding those with Down syndrome, Philadelphia chromosome–positive ALL, prior hematopoietic stem cell transplant, or prior blinatumomab treatment (n = 669).
All patients received a 4-week reinduction chemotherapy course, followed by randomized assignment to receive 2 cycles of blinatumomab (n = 105) or 2 cycles of multiagent chemotherapy (n = 103), each followed by transplant.
Main Outcome and Measures
The primary end point was disease-free survival and the secondary end point was overall survival, both from the time of randomization. The threshold for statistical significance was set at a 1-sided P <.025.
Among 208 randomized patients (median age, 9 years; 97 [47%] females), 118 (57%) completed the randomized therapy. Randomization was terminated at the recommendation of the data and safety monitoring committee without meeting stopping rules for efficacy or futility; at that point, 80 of 131 planned events occurred. With 2.9 years of median follow-up, 2-year disease-free survival was 54.4% for the blinatumomab group vs 39.0% for the chemotherapy group (hazard ratio for disease progression or mortality, 0.70 [95% CI, 0.47-1.03]); 1-sided P = .03). Two-year overall survival was 71.3% for the blinatumomab group vs 58.4% for the chemotherapy group (hazard ratio for mortality, 0.62 [95% CI, 0.39-0.98]; 1-sided P = .02). Rates of notable serious adverse events included infection (15%), febrile neutropenia (5%), sepsis (2%), and mucositis (1%) for the blinatumomab group and infection (65%), febrile neutropenia (58%), sepsis (27%), and mucositis (28%) for the chemotherapy group.
Conclusions and Relevance
Among children, adolescents, and young adults with high- and intermediate-risk first relapse of B-ALL, postreinduction treatment with blinatumomab compared with chemotherapy, followed by transplant, did not result in a statistically significant difference in disease-free survival. However, study interpretation is limited by early termination with possible underpowering for the primary end point.
ClinicalTrials.gov Identifier: NCT02101853
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Corresponding Author: Patrick A. Brown, MD, Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB1 Room 2M51, Baltimore, MD 21287 (email@example.com).
Accepted for Publication: January 16, 2021.
Author Contributions: Drs Brown and Ji 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. Drs Hunger and Loh are co–senior authors.
Concept and design: Brown, Ji, Devidas, Borowitz, Raetz, Zugmaier, Sharon, Bernhardt, Terezakis, Gore, Whitlock, Pulsipher, Hunger, Loh.
Acquisition, analysis, or interpretation of data: Brown, Xu, Devidas, Hogan, Borowitz, Sharon, Gore, Pulsipher, Hunger, Loh.
Drafting of the manuscript: Brown, Ji, Xu, Devidas, Sharon, Pulsipher, Hunger.
Critical revision of the manuscript for important intellectual content: Brown, Hogan, Borowitz, Raetz, Zugmaier, Sharon, Bernhardt, Terezakis, Gore, Whitlock, Pulsipher, Hunger, Loh.
Statistical analysis: Brown, Ji, Xu, Devidas.
Obtained funding: Borowitz, Sharon.
Administrative, technical, or material support: Brown, Borowitz, Sharon, Bernhardt, Gore, Pulsipher, Hunger, Loh.
Supervision: Brown, Raetz, Zugmaier, Sharon, Terezakis, Gore, Whitlock, Pulsipher, Loh.
Other - patient contribution: Gore.
Conflict of Interest Disclosures: Dr Brown reported receiving personal fees from serving on scientific advisory committees for Novartis, Kura, Kite, Amgen, Servier, Jazz Pharmaceuticals, and Janssen outside the submitted work. Dr Borowitz reported providing consultancy for Amgen and receiving honoraria from Beckman Coulter. Dr Raetz reported receiving research funding from Pfizer and serving on a data and safety monitoring board for Celgene outside the submitted work. Dr Zugmaier reported receiving personal fees from Amgen for employment outside the submitted work and having patents pending (10696744, 10662243, 20190142846, 20190127465, 10130638, 20170327581, 9688760, 20170122947, 9486475, 20160208001, 9192665, 20150071928, 8840888, 20140228316, 20140227272, 20130287778, 20130287774, 20100112603, and 7700299) and issued (20190300609, 20110262440, and 20130323247). Dr Bernhardt reported receiving grants from Celgene and Bristol Myers Squibb and personal fees from Servier and Mesoblast outside the submitted work. Dr Terezakis reported receiving grants from ASELL outside the submitted work. Dr Gore reported providing consultancy for Amgen, Novartis, and Roche/Genentech; having equity ownership in Amgen, Blueprint Medicines, Celgene, Clovis, Mirati, and Sanofi Paris; receiving honoraria from Amgen and Roche/Genentech; and serving on a scientific advisory committee for Amgen and data safety and monitoring committees for Novartis and Celgene. Dr Whitlock reported receiving personal fees from Amgen honorarium for consulting outside the submitted work. Dr Pulsipher reported serving on scientific advisory committees for Novartis, Adaptive, and CSL Behring; providing consultancy for Novartis, Jazz Pharmaceuticals, Bellicum Pharmaceuticals, and Mesoblasta; and receiving research funding from Adaptive and Miltenyi and honoraria from Amgen and Medac. Dr Hunger reported consulting for Amgen, Bristol Myers Squibb, and Novartis; having equity ownership in Amgen; and receiving honoraria from Jazz Pharmaceuticals outside the submitted work. Dr Loh reported serving on a scientific advisory committee for MediSix Therapeutics outside the submitted work. No other disclosures were reported.
Funding/Support: This clinical trial was funded by grants from the National Institutes of Health/National Cancer Institute (National Clinical Trials Network Operations Center grant U10CA180886 and National Clinical Trials Network Statistics and Data Center grant U10CA180899) and the St Baldrick’s Foundation. Blinatumomab was provided to study participants by Amgen via a Collaborative Research and Development Agreement with the National Institutes of Health/National Cancer Institute/Cancer Therapy and Evaluation Program.
Role of the Funder/Sponsor: The Children’s Oncology Group investigators designed the trial. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program, Amgen, and the US Food and Drug Administration reviewed the trial, made recommendations for changes, and approved the final trial design. All amendments were reviewed and approved by the NCI and Amgen. The Children’s Oncology Group investigators conducted the trial and performed the collection, management, analysis, and interpretation of the data. The first and second authors (P.A.B. and L.J.) prepared the manuscript. All authors, the NCI, and Amgen reviewed and approved the manuscript. The decision to submit the manuscript for publication was made by the authors.
Data Sharing Statement: See Supplement 3.
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