Abstract 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/μL) 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.
