Early CAR^- CD4⁺ T-lymphocytes recovery following CAR-T cell infusion: A worse outcome in diffuse large B cell lymphoma

CAR(-) CD4(+) T cell lymphopenia is an emerging issue following CAR-T cell therapy. We analyzed the determinants of CD4(+) T cell recovery and a possible association with survival in 31 consecutive patients treated with commercial CAR-T for diffuse large B-cell (DLBCL) or mantle cell lymphoma. Circulating immune subpopulations were characterized through multiparametric-flow cytometry. Six-month cumulative incidence of CAR(- )CD4(+) T cell recovery (>= 200 cells/mu L) was 0.43 (95% confidence interval [CI]: 0.28-0.65). Among possible determinants of CD4(+) T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). Higher CD4(+) T cell counts resulted with TSA at month-1, -2 and -3. Moderate-to-severe infections were registered with prolonged CD4(+) T cell lymphopenia. Early, month-1 CD4(+ )T cell recovery was associated with a worse outcome in the DLBCL cohort, upheld in a multivariate regression model for overall survival (HR: 4.46 [95% CI: 1.12-17.71], p = 0.03). We conclude that a faster CAR(- )CD4(+) T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR(-) CD4(+) T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.