Background: Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated improved survival in patients with relapsed, refractory (R/R) large B cell lymphoma (LBCL). Hormones influence the sexual differences in the tumor microenvironment by regulating epigenetic and transcriptional differentiation and highlight a sex-based therapeutic target for cancer immunotherapy. While significant evidence exists related to sex differences in immune responses, impact of estradiol and androgen-deprivation on immune cell upregulation, and sex-based differences in the efficacy and toxicity with immune checkpoint inhibitors, sex-based disparities in CAR-T outcomes remains elusive.

Methods: Utilizing publicly available, retrospective CIBMTR registry datasets, we compared CAR-T outcomes between adult male and female CAR-T recipients with LBCL. Primary outcome of the study was progression free survival (PFS). Patients were censored at 12 months follow-up time from date of infusion. Secondary outcomes included overall survival (OS), relapse, non-relapse mortality (NRM), cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS) defined according to ASTCT criteria. Kaplan-Meier method was used to estimate survival probabilities and cumulative incidence. Log-rank test compared survival distributions by sexes. Multivariate analysis was adjusted for pre-specified confounders. All outcomes were censored at 365 days (12 months) to focus on 1-year outcomes. Analyses were performed using Python 3.x with lifelines package for survival analysis. Statistical significance was defined as p<0.05.

Results: We identified 487 patients who received CD19+CAR-T between 2017 and 2022, of which 55 were excluded (4 due to missing follow-up data, 51 due to follow-up ≤90 days). Of the 432 patients, 35.4% (n=153) were female and 64.6% (n=279) were male. Median age was 60.5 years (IQR: 51.1-67.8), similar between the 2 sexes (61.5 in females and 60.2 in males; p=0.226). Among the histologies, 84.2% (n=364) patients had diffuse large B-cell lymphomas (DLBCL), 11.1% (n=48) had T-Cell/histiocyte rich large B-cell lymphoma, and 4.6% (n=20) had primary central-nervous system lymphoma. In terms of remission, 20.8% (n=88) were in CR and 71.2% (n=301) had either PR or had relapsed disease prior to CAR-T. Most patients, 83.1% (n=359) received axi-cel, 16% (n=69) tisa-cel and 0.9% (n=4) liso-cel.

Cumulative incidence (C.I.) of relapse at 12 months was 47.1% (95%CI, 41.1%-53.4%) in males and 31.4% (95%CI, 24.2%-40.2%) in females (p=0.001). C.I. of NRM at 12 months was 1.1% in males and 3% in females (p=0.225). C.I. of grade³3 CRS at 12 months was 4% in males and 7.3% in females (p=0.134) whereas it was 13.9% for grade³3 ICANS in males and 17.5% in females (p=0.333). PFS at 12 months was 52.2% (95% CI, 46.0%-58.1%) in males compared to 65.1% (95% CI, 56.4%-72.4%) in females (log-rank p=0.006). OS at 12 months was 74.2% (95% CI, 68.3%-79.2%) in males and 83.5% (95% CI, 76.1%-88.7%) in females (p=0.085). In univariate analysis, as compared to females, male sex was associated with a significantly inferior PFS (Hazards Ratio [HR], 1.79; 95%CI, 1.26-2.54; p=0.001) as well as a trend towards inferior OS (HR, 1.51; 95%CI, 0.94-2.44; p=0.087).

Multivariate analysis adjusted for age, KPS, prior lines of therapy, prior autologous transplant, and disease risk showed significantly greater relapse risk among males compared to females (HR, 1.81; 95% CI, 1.27-2.58; p=0.001). There were no significant differences between the 2 sexes in terms of grade>3 CRS, grade>3 ICANS, and NRM. Male sex had significantly inferior PFS than females (HR, 1.60; 95% CI, 1.15-2.23; p=0.005). There was no significant difference in OS between the 2 sexes (HR, 1.48; 95% CI, 0.92-2.38; p=0.108).

Conclusion: Our results show that female sex confers a significantly lowered relapse risk, compared to males, translating into a PFS advantage. Albeit the mortality benefit with female sex was numerically 1.5-fold, it did not reach statistical significance. The inferior survival for males is consistent with outcomes described in other transplantation literature. The findings indicate that sex, age, sex hormones/menopause status, and socio-cultural gender differences should be incorporated into CAR-T clinical decision making and that broad-based sex differences could potentially exist and pave the way for further investigation into the role played by sex in CAR-T outcomes.

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2025
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