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 2×106 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.
