Car t-cell therapy for the management of refractory/relapsed high-grade b-cell lymphoma: a practical overview

ABSTRACT The goal of this review is to firstly address the concept of chimeric antigen receptor T-cell (CAR T-cell) therapy and where it fits in the evolving landscape of the management of

patients with refractory/relapsed diffuse large B-cell lymphoma. The recognition of the indications for CAR T-cell therapy for patients with aggressive B-cell lymphoma will be discussed,

including a review of the algorithms and selection criteria for CAR T-cell therapy and finally, the role of bridging therapy and the timing of CAR T-cell therapy in augmenting chances of a

successful outcome. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution

Subscribe to this journal Receive 12 print issues and online access $259.00 per year only $21.58 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full

article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs *

Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THERAPEUTIC OPTIONS FOR LARGE B-CELL LYMPHOMA RELAPSING AFTER CD19-DIRECTED CAR T-CELL THERAPY Article 16 December 2023

LONG-TERM OUTCOMES FOLLOWING CAR T CELL THERAPY: WHAT WE KNOW SO FAR Article 13 April 2023 CAR T CELL THERAPY FOR PATIENTS WITH SOLID TUMOURS: KEY LESSONS TO LEARN AND UNLEARN Article 30

October 2023 REFERENCES * Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly

patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–16. Article  CAS  PubMed  Google Scholar  * Pfreundschuh M, Kuhnt E,

Trumper L, Osterborg A, Trneny M, Shepherd L, et al. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of

an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011;12:1013–22. CAS  PubMed  Google Scholar  * Schmitz N, Nickelsen M, Ziepert M, Haenel M,

Borchmann P, Schmidt C, et al. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell

lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012;13:1250–9. Article  CAS  PubMed  Google Scholar  * Friedberg JW. Relapsed/refractory diffuse large

B-cell lymphoma. Hematol Am Soc Hematol Educ Program. 2011;2011:498–505. Article  Google Scholar  * Zelenetz AD, Gordon LI, Wierda WG, Abramson JS, Advani RH, Andreadis CB, et al. Diffuse

large B-cell lymphoma version 1.2016. J Natl Compr Canc Netw. 2016;14:196–231. Article  PubMed  Google Scholar  * Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et

al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–8. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Lerner RE, Thomas W, Defor TE, Weisdorf DJ, Burns LJ. The International Prognostic Index assessed at relapse predicts outcomes of autologous transplantation for diffuse large-cell

non-Hodgkin’s lymphoma in second complete or partial remission. Biol Blood Marrow Transplant. 2007;13:486–92. Article  PubMed  Google Scholar  * Ayers EC, Li S, Medeiros LJ, Bond DA,

Maddocks KJ, Torka P. et al. Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure. Cancer. 2019;126:293–303. Article  PubMed  Google

Scholar  * Nagle SJ, Woo K, Schuster SJ, Nasta SD, Stadtmauer E, Mick R, et al. Outcomes of patients with relapsed/refractory diffuse large B-cell lymphoma with progression of lymphoma after

autologous stem cell transplantation in the rituximab era. Am J Hematol. 2013;88:890–4. Article  CAS  PubMed  Google Scholar  * Ghobadi A. Chimeric antigen receptor T cell therapy for

non-Hodgkin lymphoma. Curr Res Transl Med. 2018;66:43–9. Article  PubMed  PubMed Central  Google Scholar  * Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor

T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125:4017–23. Article  CAS  PubMed  PubMed Central  Google Scholar  * Hinrichs CS, Restifo NP. Reassessing target antigens for

adoptive T-cell therapy. Nat Biotechnol. 2013;31:999–1008. Article  CAS  PubMed  PubMed Central  Google Scholar  * Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for

hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017;65:93–102. Article  CAS  PubMed  Google Scholar  * Grupp

S. Beginning the CAR T cell therapy revolution in the US and EU. Curr Res Transl Med. 2018;66:62–4. Article  PubMed  Google Scholar  * Ruella M, June CH. Chimeric antigen receptor T cells

for B cell neoplasms: choose the right CAR for you. Curr Hematol Malig Rep. 2016;11:368–84. Article  PubMed  Google Scholar  * Abramson JS, Gordon LI, Palomba ML, Lunning MA, Arnason JE,

Forero-Torres A, et al. Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. J Clin Oncol.

2018;36:7505–7505. Article  Google Scholar  * Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large

B-cell lymphoma. N Engl J Med. 2017;377:2531–44. Article  CAS  PubMed  PubMed Central  Google Scholar  * Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al.

Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45–56. Article  CAS  PubMed  Google Scholar  * Nastoupil LJ, Jain MD, Spiegel JY,

Ghobadi A, Lin Y, Dahiya S, et al. Axicabtagene ciloleucel (Axi-cel) CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: real world experience.

Blood. 2018;132:91–91. Article  Google Scholar  * Riedell PA, Walling C, Nastoupil LJ, Pennisi M, Maziarz RT, McGuirk JP, et al. A multicenter retrospective analysis of outcomes and

toxicities with commercial axicabtagene ciloleucel and tisagenlecleucel for relapsed/refractory aggressive B-cell lymphomas. Biol Blood Marrow Transplant. 2020;26:S41–2. Article  Google

Scholar  * Yakoub-Agha I, Chabannon C, Bader P, Basak GW, Bonig H, Ciceri F. et al. Management of adults and children undergoing CAR T-cell therapy: best practice recommendations of the

European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica. 2019;105:297–316. Article  Google Scholar  *

Thieblemont C, Le Gouill S, Di Blasi R, Cartron G, Morschhauser F, Bachy E, et al. Real-world results on CD19 CAR T-cell for 60 French patients with relapsed/refractory diffuse large B-cell

lymphoma included in a temporary authorization for use program. Hematological Oncol. 2019;37:301–301. Article  Google Scholar  * Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD,

DeFilipp Z. et al. Tisagenlecleucel CAR-T cell therapy in secondary CNS lymphoma. Blood. 2019;134:860–6. * Bennani NN, Maurer MJ, Nastoupil LJ, Jain MD, Chavez JC, Cashen AF, et al.

Experience with axicabtagene ciloleucel (Axi-cel) in patients with secondary CNS involvement: results from the US lymphoma CAR T consortium. Blood. 2019;134:763–763. Article  Google Scholar

  * Frigault MJ, Dietrich J, Martinez-Lage M, Leick M, Choi BD, DeFilipp Z, et al. Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma. Blood. 2019;134:860–6. Article  CAS  PubMed

  PubMed Central  Google Scholar  * Sim AJ, Jain MD, Figura NB, Chavez JC, Shah BD, Khimani F, et al. Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene

ciloleucel in diffuse large B-cell lymphoma. Int J Radiat Oncol. 2019;105:1012–21. Article  CAS  Google Scholar  * Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al.

Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017;25:285–95. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high

serum interleukin-15 levels. J Clin Oncol. 2017;35:1803–13. Article  CAS  PubMed  PubMed Central  Google Scholar  * Turtle CJ, Hanafi L-AA, Berger C, Hudecek M, Pender B, Robinson E. et al.

Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116. * Turtle CJ, Hay KA,

Hanafi L-A, Li D, Cherian S, Chen X. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor–modified T cells after failure

of ibrutinib. J Clin Oncol. 2017;35:3010–20. * Neelapu SS. CAR-T efficacy: is conditioning the key? Blood. 2019;133:1799–1800. Article  CAS  PubMed  Google Scholar  * Brudno JN, Kochenderfer

JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321–30. Article  CAS  PubMed  PubMed Central  Google Scholar  * Gauthier J, Turtle CJ.

Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. Curr Res Transl Med. 2018;66:50–2. Article  PubMed  PubMed Central  Google Scholar  *

Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol.

2018;15:47–62. Article  CAS  PubMed  Google Scholar  * Novartis Pharmaceuticals Corporation. Kymriah® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017. * EMA.

Committee for advanced therapies: guideline on the quality, non­clinical and clinical aspects of gene therapy medicinal products. Amsterdam: European Medicines Agency; 2018. Google Scholar 

* US FDA. Testing of retroviral vector-based human gene therapy products for replication competent retrovirus during product manufacture and patient follow-up (final guidance document).

White Oak, MD: Food and Drug Administration; 2020. Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Service d’Hématologie Clinique et Thérapie Cellulaire,

Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France Mohamad Mohty, Remy Dulery, Florent Malard & Eolia Brissot * Clinical Research Division, Integrated

Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Jordan Gauthier * Department of Medicine, Division of Medical Oncology, University of Washington,

Seattle, WA, USA Jordan Gauthier * Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia Mahmoud Aljurf * Department of Internal Medicine, American

University of Beirut, Beirut, Lebanon Ali Bazarbachi * Institut Paoli-Calmettes, Inserm CBT-1409 & Aix-Marseille Université, Marseille, France Christian Chabanon * Blood and Marrow

Transplantation Program, Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL, USA Mohamed A. Kharfan-Dabaja * Hematology and Stem Cell Transplantation Section, Division of

Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN, USA Bipin N. Savani * Bone Marrow Transplantation

Center, The First Affiliated Hospital, School of Medicine, Institute of Hematology, Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Zhejiang University,

Hangzhou, 310058, China He Huang * Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA Saad S. Kenderian * Weill Cornell Medical College, New York, NY, USA

Miguel-Angel Perales * Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Miguel-Angel Perales * CHU de Lille,

LIRIC, INSERM U995, Université de Lille, Lille, 59000, France Ibrahim Yakoub-Agha * The Chaim Sheba Medical Center, Tel-Hashomer, Affiliated with the Sackler School of Medicine, Tel-Aviv

University, Tel-Aviv, Israel Arnon Nagler Authors * Mohamad Mohty View author publications You can also search for this author inPubMed Google Scholar * Remy Dulery View author publications

You can also search for this author inPubMed Google Scholar * Jordan Gauthier View author publications You can also search for this author inPubMed Google Scholar * Florent Malard View

author publications You can also search for this author inPubMed Google Scholar * Eolia Brissot View author publications You can also search for this author inPubMed Google Scholar * Mahmoud

Aljurf View author publications You can also search for this author inPubMed Google Scholar * Ali Bazarbachi View author publications You can also search for this author inPubMed Google

Scholar * Christian Chabanon View author publications You can also search for this author inPubMed Google Scholar * Mohamed A. Kharfan-Dabaja View author publications You can also search for

this author inPubMed Google Scholar * Bipin N. Savani View author publications You can also search for this author inPubMed Google Scholar * He Huang View author publications You can also

search for this author inPubMed Google Scholar * Saad S. Kenderian View author publications You can also search for this author inPubMed Google Scholar * Miguel-Angel Perales View author

publications You can also search for this author inPubMed Google Scholar * Ibrahim Yakoub-Agha View author publications You can also search for this author inPubMed Google Scholar * Arnon

Nagler View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors contributed substantially to the conception, writing, critical review

and final approval of the manuscript. CORRESPONDING AUTHOR Correspondence to Mohamad Mohty. ETHICS DECLARATIONS CONFLICT OF INTEREST MM reports grants and/or lecture honoraria from Janssen,

Sanofi, Maat Pharma, JAZZ pharmaceutical, Celgene, Amgen, BMS, Takeda, Pfizer, and Roche, all outside the submitted work. FM reports lecture honoraria from Therakos/Mallinckrodt, Biocodex,

Janssen, Keocyte, Sanofi, JAZZ pharmaceutical and Astellas, all outside the submitted work. AB reports honoraria from Abbvie, Novartis, Takeda, Roche, Celgene, Pfizer, Janssen and Amgen and

Research support from Novartis, Takeda, Roche, Celgene and Janssen. CC reports honoraria from Kite/Gilead and Novartis. SSK is inventor on patents and royalties licensed to Novartis,

Humanigen, and Mettaforge. He receives research support from Kite, Gilead, Novartis, Juno, Celgene, Humanigen, Tolero, Lentigen, Sunesis, and Morphosys. He has served on SAB for Humanigen,

Kite, and Juno. M-AP reports honoraria from Abbvie, Bellicum, Bristol-Myers Squibb, Celgene, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda. He serves on DSMBs for Servier

and Medigene, and the scientific advisory boards of MolMed and NexImmune. He has received research support for clinical trials from Incyte, Kite (Gilead) and Miltenyi. IY-A reports

honorarium from Gilead/Kite, Celgene, Novartis and Jansse. The other authors did not disclose any relevant conflict of interest in relation to this work ADDITIONAL INFORMATION PUBLISHER’S

NOTE Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE

CITE THIS ARTICLE Mohty, M., Dulery, R., Gauthier, J. _et al._ CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview. _Bone Marrow

Transplant_ 55, 1525–1532 (2020). https://doi.org/10.1038/s41409-020-0892-7 Download citation * Received: 10 March 2020 * Revised: 26 March 2020 * Accepted: 27 March 2020 * Published: 18

April 2020 * Issue Date: August 2020 * DOI: https://doi.org/10.1038/s41409-020-0892-7 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative