Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia

• Type of Material: Article
• Authors: John E Levine, University of Michigan; Stephan A Grupp, University of Pennsylvania; Michael A Pulsipher, University of Southern California; Andrew C Dietz, University of Southern California; Susana Rives, Hosp St Joan Deu Barcelona; Douglas G Myers, Childrens Mercy Hosp Kansas City; Keith J August, Childrens Mercy Hosp Kansas City; Michael R Verneris, University of Minnesota, Minneapolis; Jochen Buechner, Oslo University Hospital; Theodore W Laetsch, University of Pennsylvania; Henrique Bittencourt, CHU Sainte-Justine; Andre Baruchel, University Hospital Robert Debré (APHP) and Université de Paris; Michael W Boyer, University of Utah; Barbara De Moerloose, Ghent University Hospital; Muna Qayed, Emory University; Stella M Davies, University of Cincinnati; Christine L Phillips, University of Cincinnati; Timothy A Driscoll, Duke University; Peter Bader, Univ Hosp Frankfurt; Krysta Schlis, Stanford University; Patricia A Wood, Novartis Pharmaceuticals Corporation; Rajen Mody, Michigan Medicine, Ann Arbor; Lan Yi, Novartis Pharmaceuticals Corporation; Mimi Leung, Novartis Pharmaceuticals Corporation; Lamis K Eldjerou, Novartis Pharmaceuticals Corporation; Carl H June, University of Pennsylvania; Shannon L Maude, University of Pennsylvania
• Language: English
• Date: 2021-01-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2020-002287
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 9
• Issue: 8
• Grant/Funding Information: These studies and writing assistance were funded by Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. Representatives of the sponsor participated in study design, collection, data interpretation, and development/submission of the manuscript.
• Keywords: BIOMARKERS; Immunology; receptors; Oncology; chimeric antigen; THERAPY; EFFICACY; pediatrics; Science & Technology; MANAGEMENT; Life Sciences & Biomedicine; CYTOKINE RELEASE SYNDROME; hematologic neoplasms; T-CELLS
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Background Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse. Methods A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel. Results Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion. Conclusions This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.