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Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. ​

Literature Information ​

DOI10.1056/NEJMoa1707447
PMID29226797
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2017
Times Cited2838
KeywordsAxicabtagene Ciloleucel, Large B-Cell Lymphoma, CAR T-Cell Therapy, Clinical Trial, Efficacy
Literature TypeClinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages2531-2544
Issue377(26)
AuthorsSattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go

TL;DR ​

In a phase 2 trial involving 111 patients with refractory large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) demonstrated an 82% objective response rate and a 54% complete response rate, with 42% of patients maintaining their response at a median follow-up of 15.4 months. The findings highlight the efficacy of axi-cel as a treatment option in this patient population, despite notable adverse events such as myelosuppression and cytokine release syndrome.

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Axicabtagene Ciloleucel · Large B-Cell Lymphoma · CAR T-Cell Therapy · Clinical Trial · Efficacy

Abstract ​

BACKGROUND In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

METHODS In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

RESULTS Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

CONCLUSIONS In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

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Primary Questions Addressed ​

  1. What are the long-term outcomes and potential for re-treatment in patients who initially respond to axi-cel therapy for refractory large B-cell lymphoma?
  2. How does the safety profile of axi-cel compare to other CAR T-cell therapies currently in use for similar indications?
  3. What specific biomarkers were assessed in this study, and how might they inform future treatment strategies for refractory large B-cell lymphoma?
  4. What are the implications of the cytokine release syndrome and neurologic events observed in patients receiving axi-cel therapy for clinical practice?
  5. How do patient characteristics, such as age and comorbidities, influence the response rates and safety outcomes of axi-cel therapy in this population?

Key Findings ​

Research Background and Objective ​

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that has shown promise in treating refractory large B-cell lymphoma (LBCL). This study aimed to evaluate the efficacy and safety of axi-cel in patients with refractory LBCL who have failed conventional therapies, as demonstrated in a phase 1 trial.

Main Methods/Materials/Experimental Design ​

The study was a multicenter, phase 2 trial involving 111 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL). The methodology included:

  1. Patient Enrollment: Participants were selected based on specific criteria, including histologically confirmed refractory disease.
  2. Conditioning Regimen: Patients received a conditioning regimen of low-dose cyclophosphamide and fludarabine before receiving axi-cel at a target dose of 2×10^6 CAR T cells per kg.
  3. Endpoints:
    • Primary Endpoint: Objective response rate (ORR), combining complete and partial responses.
    • Secondary Endpoints: Overall survival, safety, and biomarker assessments.
Mermaid diagram

Key Results and Findings ​

  • Manufacturing and Administration: Axi-cel was successfully manufactured for 110 out of 111 patients (99%) and administered to 101 patients (91%).
  • Efficacy: The objective response rate was 82% (95% CI, 73-89), with a complete response rate of 54%. With a median follow-up of 15.4 months, 42% of patients maintained a response, and the overall survival rate at 18 months was 52%.
  • Safety: Common grade 3 or higher adverse events included neutropenia (78%), anemia (43%), and thrombocytopenia (38%). Cytokine release syndrome occurred in 93% of patients, with 13% experiencing grade 3 or higher events.

Main Conclusions/Significance/Innovation ​

The study concluded that axi-cel therapy is effective for patients with refractory LBCL, demonstrating a high and durable response rate with an acceptable safety profile. The results indicate that axi-cel could be a viable treatment option for patients who have exhausted other therapies, offering a significant improvement over historical controls, which reported much lower response rates.

Research Limitations and Future Directions ​

  • Limitations: The study lacked a control group and did not extensively analyze molecular and cytogenetic characteristics that could affect outcomes.
  • Future Directions: Further studies are needed to explore the influence of disease biology on CAR T-cell therapy outcomes, optimize CAR constructs, and investigate combination therapies with immunomodulatory agents to enhance efficacy and safety.

Summary Table of Key Findings ​

AspectDetails
Objective Response Rate82% (Complete Response Rate: 54%)
Overall Survival Rate52% at 18 months
Common Adverse EventsNeutropenia (78%), Anemia (43%), Thrombocytopenia (38%)
Cytokine Release SyndromeOccurred in 93% of patients (13% grade 3 or higher)
Patient Enrollment111 patients enrolled, 101 treated

This structured summary provides an overview of the pivotal findings and implications of the study on axi-cel therapy in refractory large B-cell lymphoma.

References ​

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Literatures Citing This Work ​

  1. Haematological cancer: Favourable outcomes with CAR T cells. - Diana Romero - Nature reviews. Clinical oncology (2018)
  2. Approvals in 2017: gene therapies and site-agnostic indications. - Gideon M Blumenthal;Richard Pazdur - Nature reviews. Clinical oncology (2018)
  3. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. - Zhenguang Wang;Weidong Han - Biomarker research (2018)
  4. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. - Sattva S Neelapu;Sudhakar Tummala;Partow Kebriaei;William Wierda;Frederick L Locke;Yi Lin;Nitin Jain;Naval Daver;Alison M Gulbis;Sherry Adkins;Katayoun Rezvani;Patrick Hwu;Elizabeth J Shpall - Nature reviews. Clinical oncology (2018)
  5. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. - W Jurczak;P L Zinzani;G Gaidano;A Goy;M Provencio;Z Nagy;T Robak;K Maddocks;C Buske;S Ambarkhane;M Winderlich;M Dirnberger-Hertweck;R Korolkiewicz;K A Blum - Annals of oncology : official journal of the European Society for Medical Oncology (2018)
  6. Engineering chimeric antigen receptor-T cells for cancer treatment. - Baixin Ye;Creed M Stary;Xuejun Li;Qingping Gao;Chunsheng Kang;Xiaoxing Xiong - Molecular cancer (2018)
  7. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. - Karlo Perica;Kevin J Curran;Renier J Brentjens;Sergio A Giralt - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2018)
  8. A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells. - Takahiro Kamiya;Desmond Wong;Yi Tian Png;Dario Campana - Blood advances (2018)
  9. Current Strategies to Enhance Anti-Tumour Immunity. - Katherine W Cook;Lindy G Durrant;Victoria A Brentville - Biomedicines (2018)
  10. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. - May Daher;Katayoun Rezvani - Current opinion in immunology (2018)

... (2828 more literatures)

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