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Cited by 4,112CAR-T cell therapy researchLymphoma Diagnosis and TreatmentT-cell and B-cell Immunology

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

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Schuster, Stephen J., Bishop, Michael R., Tam, Constantine S., Waller, Edmund K., Borchmann, Peter, McGuirk, Joseph P., Jäger, Ulrich, Jaglowski, Samantha +16 more·2019·New England Journal of Medicine
DOI 10.1056/nejmoa1804980
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Abstract

BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study. METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee. RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found. CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

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Crossref · 10.1056/nejmoa1804980

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  • CAR T-cells elicited complete responses in 32-67% of lymphoma patients and showed better complete response rates in patients with leukemia.

    “These CAR T-cells were able to elicit complete responses (CR) in 32-67% of lymphoma patients and showed better CR rates in patients with leukemia (16-19).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [17]

    The Efficacy section (p. 4) reports complete responses in 40% of treated adults with diffuse large B-cell lymphoma, including 32% at month 3. The paper does not report a 67% lymphoma complete-response rate. It describes high efficacy in children and young adults with leukemia (p. 2), but does not establish that their complete-response rate was higher. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing.

    “First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing (9-18,21,22).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [17]

  • Despite high initial response rates, only up to 40% of patients achieve complete and long-term remission.

    “However, despite high initial response rates, complete and long-term remission is only achieved in up to 40% of patients13–16.”

    From A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy (2023) · cites this paper as [16]

  • Efficacy results seem similar in patients with LBCL treated with CD19 CAR T cells costimulated by 4-1BB instead of CD28, with or without fixing the ratio of CD4:CD8 cells.

    “Efficacy results seem similar in patients with LBCL treated with CD19 CAR T cells costimulated by 4-1BB instead of CD28, with or without fixing the ratio of CD4:CD8 cells.”

    From Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma (2021) · cites this paper as [5]

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1 of the 29 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. [22]22. otal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood 2017; 130: 577. abstract.
  2. [26]26. Maude SL, Grupp SA, Pulsipher MA, et al. Analysis of safety data from 2 multicenter trials of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Haematologica 2017; 102: 197-8.

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Authors
Schuster, S. J., Bishop, M. R., Tam, C. S., Waller, E. K., Borchmann, P., McGuirk, J. P., Jäger, U., Jaglowski, S., Andreadis, C., Westin, J. R., Fleury, I., Bachanova, V., Foley, S. R., Ho, P. J., Mielke, S., Magenau, J. M., Holte, H., Pantano, S., Pacaud, L. B., Awasthi, R., Chu, J., Anak, Ö., Salles, G., & Maziarz, R. T.
Affiliations
  • The University of Sydney (AU)
  • From the Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia (S.J.S.); the Hematopoietic Cellular Therapy Program, University of Chicago Medicine, Chicago (M.R.B.); Peter MacCallum Cancer Centre, St. Vincent’s Hospital and University of Melbourne, Melbourne, VIC (C.S.T.), and the Royal Prince Alfred Hospital and Department of Medicine, University of Sydney, Sydney (P.J.H.) — both in Australia; Winship Cancer Institute of Emory University, Bone Marrow and Stem Cell...
  • Oslo University Hospital (NO)
  • Novartis (Switzerland) (CH)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2019-01-03
Volume
380
Issue
1
Pages
45-56
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1804980
OpenAlex
W2903062212
Cited by
4,112
References
29
Citations by year
2026: 363 · 2025: 507 · 2024: 593 · 2023: 593 · 2022: 693 · 2021: 624 · 2020: 502 · 2019: 218 · 2018: 3 · 2015: 1 · 2013: 1 · 2012: 2
FWCI
125.46
Type
journal article
Language
en
Open access
Licence
www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • HAL (submittedVersion)
Funders
Novartis Pharmaceuticals Corporation
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
tisagenlecleucel, CAR T-cell therapy, diffuse large B-cell lymphoma, relapsed/refractory lymphoma, CD19, autologous stem cell transplantation, cytokine release syndrome, neurological adverse events, relapse-free survival, complete response, immune checkpoint molecules
MeSH terms
Receptors, Chimeric Antigen, Progression-Free Survival, Adult, Aged, Female, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Recurrence, Survival Analysis, Immunotherapy, Adoptive, Lymphoma, Large B-Cell, Diffuse, Young Adult, Neoplasm Grading

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