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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 and Cameron J. Turtle

Key Points

  • LDH, MCP-1, and IL-7 are independently associated with PFS in patients with aggressive NHL after CD19 CAR T-cell immunotherapy.

  • Higher intensity of cyclophosphamide and fludarabine lymphodepletion is associated with higher probability of a favorable cytokine profile.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

Factors associated with durable remission after CD19 chimeric antigen receptor (CAR)-modified T-cell immunotherapy for aggressive B-cell non-Hodgkin lymphoma (NHL) have not been identified. We report multivariable analyses of factors affecting response and progression-free survival (PFS) in patients with aggressive NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by 2 × 106 CD19-directed CAR T cells/kg. The best overall response rate was 51%, with 40% of patients achieving complete remission. The median PFS of patients with aggressive NHL who achieved complete remission was 20.0 months (median follow-up, 26.9 months). Multivariable analysis of clinical and treatment characteristics, serum biomarkers, and CAR T-cell manufacturing and pharmacokinetic data showed that a lower pre-lymphodepletion serum lactate dehydrogenase (LDH) level and a favorable cytokine profile, defined as serum day 0 monocyte chemoattractant protein-1 (MCP-1) and peak interleukin-7 (IL-7) concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion, and higher intensity of cyclophosphamide and fludarabine lymphodepletion was associated with higher probability of a favorable cytokine profile. PFS was superior in patients who received high-intensity lymphodepletion and achieved a favorable cytokine profile compared with those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH levels above normal, a favorable cytokine profile after lymphodepletion was associated with a low risk of a PFS event. Strategies to augment the cytokine response to lymphodepletion could be tested in future studies of CD19 CAR T-cell immunotherapy for aggressive B-cell NHL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

  • Submitted November 28, 2018.
  • Accepted February 12, 2019.
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