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

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As reported at the 2017 American Society of Hematology (ASH) Meeting & Exposition and in The New England Journal of Medicine by Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center, and colleagues, a phase II trial has shown high activity of autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with axicabtagene ciloleucel (Yescarta) in patients with refractory large B-cell lymphoma after conventional therapy failure.1 The findings from this study supported the October 2017 approval of axicabtagene ciloleucel in this setting.

Study Details

In this multicenter, phase II trial, 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite recommended prior therapy received treatment starting from November 2015 to September 2016 at 21 sites in the United States and 1 site in Israel. After leukapheresis and axicabtagene ciloleucel manufacturing, patients received fixed low-dose conditioning chemotherapy consisting of fludarabine at 30 mg/m2/d and cyclophosphamide at 500 mg/m2/d on days −5, −4, and −3 before administration of a single intravenous infusion of axicabtagene ciloleucel at a target dose of 2 × 106 CAR T cells/kg on day 0. The primary endpoint was the rate of objective response.

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Among the 111 patients who were enrolled, axicabtagene ciloleucel was successfully manufactured for 110 (99%) and administered to 101 (91%). A total of 77 patients with diffuse large B-cell lymphoma and 24 patients with primary mediastinal B-cell lymphoma or transformed follicular lymphoma received axicabtagene ciloleucel. The median age of treated patients was 58 years (range = 23–76 years), 85% had stage III or IV disease, 77% had disease resistant to second-line or later therapies, 21% had relapse after transplantation, 69% had received at least 3 previous therapies, and 26% had a history of primary refractory disease.

Outcomes in Primary and Updated Analyses

The date of data cutoff for the primary analysis was in January 2017, with a median follow-up of 8.7 months. The primary analysis was conducted when 92 patients could be evaluated 6 months after axicabtagene ciloleucel infusion. The objective response rate among these 92 patients was 82% (95% confidence interval [CI] = 72%–89%; P < .001 vs 20% historical control rate), with a complete response observed in 52%. Among the 101 patients who received axicabtagene ciloleucel, the objective response rate was 82%, with a complete response in 54%. The median time to response was 1.0 month. Higher CAR T-cell levels in blood were associated with response.


  • In a primary analysis, axicabtagene ciloleucel treatment was associated with a response rate of 82%, with a complete response in 52%.
  • With a median follow-up of 15.4 months, 42% of patients continued to have a response, with a complete response in 40%.

Response rates were consistent across subgroups according to age, disease stage, International Prognostic Index score, presence or absence of bulky disease, cell-of-origin subtype, and use of tocilizumab (Actemra) or glucocorticoids, as well as among 26 patients with a history of primary refractory disease (response rate = 88%) and 21 patients who had autologous stem cell transplantation (response rate = 76%).

The cutoff date for the updated analysis was in August 2017, with a median follow-up of 15.4 months. At this analysis, 42% of patients continued to have a response, with 40% continuing to have a complete response. The median duration of response was 11.1 months. The median progression-free survival was 5.8 months, with rates of 49% at 6 months, 44% at 12 months, and 41% at 15 months. The median overall survival was not reached, with rates of 78% at 6 months, 59% at 12 months, and 52% at 18 months.

Adverse Events

At primary analysis, the most common adverse events of any grade were pyrexia (85%), neutropenia (84%), and anemia (66%). Adverse events ≥ grade 3 occurred in 95%, with the most common being neutropenia (78%), anemia (43%), thrombocytopenia (38%), febrile neutropenia (31%), decreased white blood cell count (29%), and encephalopathy (21%). Cytokine-release syndrome occurred in 94 patients (93%), including grade 1 or 2 in 81% and grade 3 or 4 in 13%. Grade ≥ 3 neurologic events occurred in 28%. Death occurred in three patients during treatment. Serious events occurred in 10 patients (including 9 infections in 8 patients) after data cutoff for the primary analysis.

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The investigators concluded: “In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axicabtagene ciloleucel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine-release syndrome, and neurologic events.”

Dr. Neelapu and Frederick L. Locke, MD, of H. Lee Moffitt Cancer Center and Research Institute, contributed equally to The New England Journal of Medicine article. ■

DISCLOSURE: The study was funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program. For full disclosures of the study authors, visit


1. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.




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