Female Sex Effect on Anti-CD19 CART Cell Therapy for Relapsed/Refractory B-Cell Lymphoma: A Grupo Español De Trasplante y Terapia Celular (GETH-TC) Study

Introduction Recent studies have shown the potential implication of sexual disparity on the immune system, emphasizing the significant roles of androgens and estrogens in immune cell function and their potential implications for immune responses and antitumor immunity. Anti-CD19 CART therapy is a new immunotherapy pillar for patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). However, this treatment has major limitations, including high individual variability with life-threatening toxicities, antigen escape, poor tumor infiltration, T cell exhaustion, and an immunosuppressive microenvironment. The underlying mechanisms responsible for these issues remain unknown and may potentially involve sex-based differences. To date, no studies addressed sex differences in CART therapy. Methods Data from consecutive patients with R/R LBCL from the Grupo Español de Trasplante y Terapia Celular (GETH-TC) who received commercial anti-CD19 CART infusion between November 2018 and December 2022 were retrospectively collected from electronic medical records at 12 Spanish institutions. Patients were divided by sex into two groups for analysis and stratified by patient/disease characteristics and CART cell product. A t-test comparison between the two cohorts was performed. The primary endpoint was comparing 1-year progression-free survival (1y-PFS) between the groups. Secondary endpoints were overall survival (OS), relapse incidence/progression of disease (RI/POD), non-relapse mortality (NRM), cytokine release syndrome (CRS) and immune-effector cells associated neurotoxicity (ICANS) cumulative incidence. Patient sex variable was added into the Cox Proportional-Hazards model for a multivariate analysis for each endpoint in addition to all the variables which were statistically significant in univariate analysis (α=0.05). Results A total of 479 patients received anti-CD19 CART infusion. Among them, 185 patients (39%) were female and 294 patients (61%) were male. No statistically significant differences were found in patient, disease and CART characteristics between the two cohorts ( Table 1). At 1-year post-infusion, PFS and OS were 39% (95% confidence interval [CI]: 34-44%) and 57% (95% CI: 51-62%), respectively. ( Fig. 1). On multivariate analysis, female sex had a favorable impact on 1-year PFS (HR=1.33; 95% CI: 1.01-1.75, p=0.04) but not on OS. A subset analysis on females revealed no significant differences in outcomes based on pre and postmenopausal age (p=0