Multivariate Analyses Indicate That the Cytokine Response to Lymphodepletion May be Better Associated Than Lymphodepletion Intensity with the Efficacy of CD19 CAR-T Cell Immunotherapy for Aggressive B-Cell Non-Hodgkin Lymphoma

• Published in: Biology of blood and marrow transplantation 2019-03, Vol.25 (3), p.S179-S180
• Main Authors: Hirayama, Alexandre V., Gauthier, Jordan, Hay, Kevin A., Voutsinas, Jenna M., Wu, Qian, Gooley, Ted A., Li, Daniel, Sheih, Alyssa, Purushe, Janaki, Cherian, Sindhu, Chen, Xueyan, Pender, Barbara S., Hawkins, Reed M., Vakil, Aesha, Phi, Tinh-Doan, Steinmetz, Rachel N., Acharya, Utkarsh H., Chapuis, Aude G., Dhawale, Tejaswini, Hendrie, Paul C., Kiem, Hans-Peter, Lynch, Ryan C., Ramos, Jorge, Shadman, Mazyar, Till, Brian G., Riddell, Stanley R., Maloney, David G., Turtle, Cameron J.
• Format: Article
• Language: English
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2018.12.322

CD19 chimeric antigen receptor (CAR)-T cell therapy has shown efficacy in Non-Hodgkin lymphoma (NHL), but the factors associated with durable remission have not been identified. We report multivariate analyses of factors impacting progression-free survival (PFS) in NHL patients (pts) treated with cyclophosphamide and fludarabine (Cy/Flu) lymphodepletion (LD) and CD19 CAR-T cells. We conducted a phase 1/2 open-label clinical trial (NCT01865617) with the primary objective of evaluating the feasibility and safety of a defined composition of CD19 CAR-T cells after LD in pts with R/R CD19+ B-cell malignancies. PFS was defined as the time from CAR-T cell infusion until disease progression or death. Multivariate models using elastic net were performed for analysis of response and PFS. Characteristics of the 57 pts in the study are shown in Tbl 1. Thirty-six (63%) received high-intensity (HI) Cy/Flu and 21 (37%) received low-intensity (LI) Cy/Flu LD (Tbl 1). All pts received 2 × 106 CD19 CAR-T cells/kg. The best overall response (OR) rate was 57%, with 48% complete remission (CR). Pts who achieved CR had a median PFS not reached (median follow-up [fu] 20.2 months; mo), with only 1 relapse beyond 12 mo after CAR-T cell infusion (Fig. 1). Eight of 9 pts with indolent NHL achieved CR (89%) and none relapsed (median fu 14.5 mo). For the 47 pts with aggressive NHL, the best OR rate was 51%, with 40% CR. The median PFS of aggressive NHL pts achieving CR was 20.0 mo (median fu 26.9 mo), and 24-mo probabilities of PFS and OS were 46% and 72%, respectively. In aggressive NHL, multivariate analysis showed that the probability of CR was associated with lower pre-LD serum LDH and greater increase in serum MCP-1 concentration from LD to the day of CAR-T cell infusion. HI LD was associated with more CAR-T cells in blood, but there was no difference in response in pts who received HI (CR 14/31, 45%) compared to LI LD (CR 5/16, 31%; P = .53). Multivariate analysis in aggressive NHL showed that lower pre-LD serum LDH and higher day 0 MCP-1 and peak IL-7 after CAR-T cell infusion were associated with better PFS. The IL-7 peak after CAR-T cell infusion (median day 4) correlated with day 0 IL-7, consistent with an effect of LD. MCP-1 and IL-7 increased after LD, independent of prior bridging therapy, and their concentrations correlated with Cy/Flu LD intensity. However, LD intensity was not independently associated with CR or PFS. Independent of LD intensity, a subset of pts had a ro