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

Literature Information ​

DOI10.1056/NEJMoa1804980
PMID30501490
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2019
Times Cited1950
KeywordsCAR T-cell therapy, Diffuse large B-cell lymphoma, Relapsed, Refractory, tisagenlecleucel
Literature TypeClinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages45-56
Issue380(1)
AuthorsStephen J Schuster, Michael R Bishop, Constantine S Tam, Edmund K Waller, Peter Borchmann, Joseph P McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R Westin, Isabelle Fleury, Veronika Bachanova, S Ronan Foley, P Joy Ho, Stephan Mielke, John M Magenau, Harald Holte, Serafino Pantano, Lida B Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T Maziarz

TL;DR ​

This international phase 2 pivotal study evaluated the efficacy of tisagenlecleucel, a CAR T-cell therapy targeting CD19, in adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had progressed after stem-cell transplantation. The study found a 52% overall response rate, including 40% complete responses, and a 65% rate of relapse-free survival at 12 months, highlighting the potential of tisagenlecleucel as a promising treatment option for this challenging patient population.

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CAR T-cell therapy · Diffuse large B-cell lymphoma · Relapsed · Refractory · tisagenlecleucel

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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Primary Questions Addressed ​

  1. What are the long-term outcomes for patients who achieve a complete response with tisagenlecleucel in the treatment of diffuse large B-cell lymphoma?
  2. How does the efficacy of tisagenlecleucel compare to other CAR T-cell therapies for relapsed or refractory diffuse large B-cell lymphoma?
  3. What factors influence the rate of cytokine release syndrome and other adverse events in patients treated with tisagenlecleucel?
  4. Are there specific biomarkers that can predict response to tisagenlecleucel in patients with diffuse large B-cell lymphoma?
  5. What are the implications of the 65% relapse-free survival rate at 12 months for future treatment strategies in this patient population?

Key Findings ​

Key Insights ​

  1. Research Background and Objectives: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive form of non-Hodgkin lymphoma, particularly challenging when it is refractory to primary and second-line therapies or has relapsed after stem-cell transplantation. Patients facing these scenarios generally have a poor prognosis, motivating the exploration of innovative treatment approaches. The study aimed to assess the efficacy and safety of tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy specifically targeting CD19-expressing B cells, in adult patients with relapsed or refractory DLBCL who were ineligible for or had progressed after autologous hematopoietic stem-cell transplantation.

  2. Major Methods and Findings: An international, phase 2 pivotal study was designed to evaluate tisagenlecleucel in a cohort of adult patients. A total of 93 patients were infused with the CAR T-cell therapy and subsequently monitored for treatment response. The primary endpoint was the best overall response rate (ORR), defined as the percentage of patients achieving a complete or partial response as evaluated by an independent review committee. The findings indicated a best ORR of 52%, with 40% of patients achieving complete responses and 12% partial responses. The durability of responses was notable, with a 12-month relapse-free survival rate of 65%, which improved to 79% among patients who achieved complete responses. Adverse events included cytokine release syndrome (22%), neurologic events (12%), and prolonged cytopenias (32%), but no deaths were connected to the treatment itself.

  3. Core Conclusions: The study concluded that tisagenlecleucel demonstrates high rates of durable responses in adults with relapsed or refractory DLBCL, indicating its potential as an effective treatment option for this difficult-to-treat population. The results underscore the therapy's capability to elicit significant clinical responses even in patients with limited therapeutic alternatives.

  4. Research Significance and Impact: This research highlights the transformative potential of CAR T-cell therapy in hematological malignancies, particularly for patients with DLBCL who have exhausted conventional treatment options. The durable efficacy and manageable safety profile of tisagenlecleucel could reshape treatment paradigms, offering hope for better survival outcomes in a patient demographic that historically faces a grim prognosis. Furthermore, the study reinforces the importance of innovative immunotherapies in the ongoing battle against cancer, motivating further research and potential enhancements in CAR T-cell therapies and their applications in various malignancies.

Literatures Citing This Work ​

  1. Oligoclonal T Cells Transiently Expand and Express Tim-3 and PD-1 Following Anti-CD19 CAR T Cell Therapy: A Case Report. - Christopher Ronald Funk;Christopher T Petersen;Neera Jagirdar;Sruthi Ravindranathan;David L Jaye;Christopher R Flowers;Amelia Langston;Edmund K Waller - International journal of molecular sciences (2018)
  2. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. - Daniel W Lee;Bianca D Santomasso;Frederick L Locke;Armin Ghobadi;Cameron J Turtle;Jennifer N Brudno;Marcela V Maus;Jae H Park;Elena Mead;Steven Pavletic;William Y Go;Lamis Eldjerou;Rebecca A Gardner;Noelle Frey;Kevin J Curran;Karl Peggs;Marcelo Pasquini;John F DiPersio;Marcel R M van den Brink;Krishna V Komanduri;Stephan A Grupp;Sattva S Neelapu - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2019)
  3. Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers. - Rajat K Das;Lauren Vernau;Stephan A Grupp;David M Barrett - Cancer discovery (2019)
  4. Geriatric Hematology Research presented at the 2018 American Society of Hematology Annual Meeting: Young International Society of Geriatric Oncology Perspective Paper. - Kah Poh Loh;Konstantinos Christofyllakis;Li-Wen Huang;Alice Mims - Journal of geriatric oncology (2019)
  5. Modelling CAR-T therapy in humanized mice. - Yongxia Wu;Xue-Zhong Yu - EBioMedicine (2019)
  6. The response to lymphodepletion impacts PFS in patients with aggressive non-Hodgkin lymphoma treated with CD19 CAR T cells. - Alexandre V Hirayama;Jordan Gauthier;Kevin A Hay;Jenna M Voutsinas;Qian Wu;Ted Gooley;Daniel Li;Sindhu Cherian;Xueyan Chen;Barbara S Pender;Reed M Hawkins;Aesha Vakil;Rachel N Steinmetz;Utkarsh H Acharya;Ryan D Cassaday;Aude G Chapuis;Tejaswini M Dhawale;Paul C Hendrie;Hans-Peter Kiem;Ryan C Lynch;Jorge Ramos;Mazyar Shadman;Brian G Till;Stanley R Riddell;David G Maloney;Cameron J Turtle - Blood (2019)
  7. Chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma: opportunities and challenges. - Shinichi Makita;Katsuaki Imaizumi;Saiko Kurosawa;Kensei Tobinai - Drugs in context (2019)
  8. EZH2 Inhibition in Ewing Sarcoma Upregulates GD2 Expression for Targeting with Gene-Modified T Cells. - Sareetha Kailayangiri;Bianca Altvater;Stefanie Lesch;Sebastian Balbach;Claudia Göttlich;Johanna Kühnemundt;Jan-Henrik Mikesch;Sonja Schelhaas;Silke Jamitzky;Jutta Meltzer;Nicole Farwick;Lea Greune;Maike Fluegge;Kornelius Kerl;Holger N Lode;Nikolai Siebert;Ingo Müller;Heike Walles;Wolfgang Hartmann;Claudia Rossig - Molecular therapy : the journal of the American Society of Gene Therapy (2019)
  9. Dysregulation of Cell Survival in Diffuse Large B Cell Lymphoma: Mechanisms and Therapeutic Targets. - Yi Miao;L Jeffrey Medeiros;Zijun Y Xu-Monette;Jianyong Li;Ken H Young - Frontiers in oncology (2019)
  10. Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies. - Nirav N Shah;Theresa Maatman;Parameswaran Hari;Bryon Johnson - Frontiers in oncology (2019)

... (1940 more literatures)

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