Importance: 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. Objective: 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). Interventions: 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. Results: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02101853.
|Original language||English (US)|
|Number of pages||10|
|Journal||JAMA - Journal of the American Medical Association|
|State||Published - Mar 2 2021|
Bibliographical noteFunding Information:
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.
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
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PubMed: MeSH publication types
- Clinical Trial, Phase III
- Comparative Study
- Journal Article
- Multicenter Study
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural