Purpose of Review
This article will review the use of anti-CD19 CAR-T therapy used in relapsed/refractory diffuse large B cell lymphoma.
The clinical outcomes, safety analysis, and other relevant considerations will be discussed with an emphasis on the most recently published data regarding the ZUMA-1, JULIET, and TRANSCEND NHL-001 trials.
Anti-CD19 CAR-T therapy is an exciting new therapy now approved and available to patients with relapsed/refractory diffuse large B cell lymphoma. Secondary to the increasing success and availability of these products, caregivers should expect to become familiar with the indications, toxicity, and limitations of these treatment options and when patients should be considered for referral.
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Gisselbrecht C, Glass B, Mounier N, Gill DS, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.
• 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:blood-2017-03-769620. This study outlined the poor outcomes in patients diagnosed with refractory NHL and highlighted the need for better therapeutic options in this high-risk population.
June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Sci Transl Med. 2015;7(280):280ps7.
Geldres C, Savoldo B, Dotti G, editors. Chimeric antigen receptor-redirected T cells return to the bench. Semin Immunol; 2016: Elsevier.
Kochenderfer JN, Rosenberg SA. Treating B-cell cancer with T cells expressing anti-CD19 chimeric antigen receptors. Nat Rev Clin Oncol. 2013;10(5):267–76.
Scheuermann R, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leukemia & lymphoma. 1995;18(5–6):385–97.
Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat Biotechnol. 2002;20(1):70–5.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically-engineered to recognize CD19. Blood. 2010:blood-2010-04-281931.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.
Brentjens RJ, Rivière I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011:blood-2011-04-348540.
Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–9.
Dardonville Q, Davoine C, Dahan M, Grosjean G, Bermudez E, Ifrah N, et al. Chimeric antigen receptor-t cells (CAR-T) horizon scanning: emerging targets in oncology and hematology. Am Soc Clin Oncol; 2018.
•• 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(26):2531–44 This phase 2 study helped validate the efficacy of CD19-targeted CAR-T therapy in patients diagnosed with refractory diffuse large B cell lymphoma.
Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Am Soc Hematology; 2017.
Schuster S, Bishop MR, Tam C, Waller EK, Borchmann P, McGuirk J, et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL)—an interim analysis. Hematol Oncol. 2017;35:27.
• 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. Am Soc Clin Oncol; 2018. This study demonstrated Liso-Cel shows durable responses in patients with heavily pretreated R/R DLBCL.
Kochenderfer JN, Somerville RP, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25(10):2245–53.
Kochenderfer JN, Somerville RP, 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 Off J Am Soc Clin Oncol. 2017;35(16):1803–13.
Locke FL, Ghobadi A, Jacobson CA, Jacobsen ED, Miklos DB, Lekakis LJ, et al. Durability of response in ZUMA-1, the pivotal phase 2 study of axicabtagene ciloleucel (Axi-Cel) in patients (Pts) with refractory large B-cell lymphoma. Am Soc Clin Oncol; 2018.
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Reagan PM, Miklos DB, et al. A comparison of one year outcomes in ZUMA-1 (axicabtagene ciloleucel) and SCHOLAR-1 in patients with refractory, aggressive non-Hodgkinlymphoma (NHL). Am Soc Hematology; 2017.
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobsen ED, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-Cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Am Soc Hematology; 2017.
•• Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54 This single institution case series of CTL019 demonstrated the durability of response that may be observed in patients obtaining a complete response with CD19 CAR-T cell therapy.
Turtle CJ, Hanafi L-A, 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(355):355ra116.
Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Wang M, et al. High durable CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001): defined composition allows for dose-finding and definition of pivotal cohort. Am Soc Hematology; 2017.
Abramson JS, Palomba L, Gordon LI, Lunning M, Arnason J, Forero-Torres A, et al. Transcend NHL 001: immunotherapy with the CD19-directed CAR T-cell product JCAR017 results in high complete response rates in relapsed or refractory B-cell non-Hodgkin lymphoma. Am Soc Hematol; 2016.
Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016:blood-2016-04-703751.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. How I treat: current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014:blood-2014-05-552729.
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor–transduced T cells. Blood. 2011:blood-2011-10-384388.
Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J (Sudbury, Mass). 2014;20(2):119.
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(1):47–62.
Schwartz RN, Stover PL, Dutcher JP. Managing toxicities of high-dose interleukin-2. interventions (Table 3). 2002;13:14.
Goebeler M-E, Knop S, Viardot A, Kufer P, Topp MS, Einsele H, et al. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. J Clin Oncol. 2016;34(10):1104–11.
Czock D, Keller F, Rasche FM, Häussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61–98.
Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, Forero-Torres A, et al. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001). Am Soc Clin Oncol; 2017.
Ranganathan R. Chimeric antigen receptor T cells targeting the lambda light chain of human immunoglobulin as a viable target for B cell non-Hodgkin lymphoma. Am Soc Clin Oncol; 2018.
Olson NE, Ragan SP, Ponko S, Trede NS, Stern HM, Sutherland CL. Tumor gene signature associated with neurotoxicity in R/R B-ALL patients treated with JCAR015, a CD19-directed CAR T cell product. Am Soc Clin Oncol; 2018.
Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Clinical and biologic covariates of outcomes in ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL). Ame Soc Clin Oncol; 2017.
Wu C-Y, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule–gated chimeric receptor. Science. 2015;350(6258):aab4077.
Gilbert A, Santoro S, Tse T, Candelario-Chopra T, Gomes T, Campos J, et al. Evaluating the reversible control of an engineered CAR T cell ON-switch. Am Soc Clin Oncol; 2017.
Bauche C. Development of a new switchable CAR system. J Clin Oncol. 2015;36(e14024-e14024).
Ying ZT, Long L, Liu H, Zhang M, He P, Rizzieri D, et al. ET190L1-ARTEMIS T cell therapy to induce complete remission of relapsed and refractory (r/r) B-cell lymphoma with no cytokine release syndrome in the first-in-human clinical study. Am SocClin Oncol; 2018.
Brudno JN, Hartman SD, Pittaluga S, Stroncek D, Lam N, Kanakry JA, et al. Clinical anti-lymphoma activity and toxicity of T cells expressing a novel anti-CD19 chimeric antigen receptor with fully-human variable regions. Am Soc Clin Oncol; 2018.
Siddiqi T, Abramson JS, Palomba ML, Gordon LI, Lunning MA, Arnason JE, et al. Correlation of patient characteristics and biomarkers with clinical outcomes of JCAR017 in R/R aggressive B-NHL (TRANSCEND NHL 001 study). Am Soc Clin Oncol; 2018.
Sarkar R, Gloude NJ, Murphy JD. Cost-effectiveness of chimeric antigen receptor T-cell therapy in pediatric relapsed/refractory acute lymphoblastic leukemia. Am Soc Clin Oncol; 2018.
Snider JT, Brauer M, Batt K, Karaca-Mandic P, Zhang J, Goldman DP. The social value of tisagenlecleucel, a CAR-T cell therapy, for the treatment of relapsed or refractory pediatric acute lymphoblastic leukemia in the United States: what are consequences of treatment delays? : Am Soc Clin Oncol; 2018.
Oluwole OO, Bishop MR, Gisselbrecht C, Gordon LI, Kersten MJ, Maloney DG, et al. ZUMA-7: a phase 3 randomized trial of axicabtagene ciloleucel (Axi-Cel) versus standard-of-care (SOC) therapy in patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL). Am Soc Clin Oncol; 2018.
Gauthier J HA, Hay K, et al. Factors associated with duration of response after CD19-specific CAR-T cell therapy for refractory/relapsed B-cell non-Hodgkin lymphoma. J Clin Oncol.36(abtr 7567).
Mueller KT, Grupp SA, Maude SL, Levine JE, Pulsipher M, Boyer MW, et al. Immunogenicity of tisagenlecleucel in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) patients. Am Soc Clin Oncol; 2018.
Yao Y, Yao X, Zhu S, Zhu W, Li Z, Wang Q, et al. Target cell killing effects of CD20 targeting chimeric antigen receptor T cells derived from the type II anti-CD20 antibody. Am Soc Clin Oncol; 2017.
Dufort F, Su L, Wu L, Birt A, Lobb R, Ambrose C, et al. Activity of CAR19 T cells secreting impact fusion proteins against hematopoietic and solid tumors. Am Soc Clin Oncol; 2018.
This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma
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Havard, R., Stephens, D.M. Anti-CD19 Chimeric Antigen Receptor T Cell Therapies: Harnessing the Power of the Immune System to Fight Diffuse Large B Cell Lymphoma. Curr Hematol Malig Rep 13, 534–542 (2018). https://doi.org/10.1007/s11899-018-0482-6
- Chimeric antigen receptor