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The response to lymphodepletion impacts PFS in aggressive non-Hodgkin lymphoma patients 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 aggressive NHL after CD19 CAR-T cell immunotherapy.

  • Higher intensity of Cy/Flu lymphodepletion is associated with higher probability of a favorable cytokine profile.

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 impacting response and progression-free survival (PFS) in aggressive NHL patients treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion followed by 2x106 CD19 CAR-T cells/kg. The best overall response rate (ORR) was 51%, with 40% of patients achieving complete remission (CR). The median PFS of aggressive NHL patients who achieved CR 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 LDH and a favorable cytokine profile, defined as serum day 0 MCP-1 and peak IL-7 concentrations above the median, were associated with better PFS. MCP-1 and IL-7 concentrations increased after lymphodepletion and higher intensity of Cy/Flu 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 to those who received the same intensity of lymphodepletion without achieving a favorable cytokine profile. Even in high-risk patients with pre-lymphodepletion serum LDH 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.

  • Submitted November 29, 2018.
  • Accepted February 12, 2019.