Impact of Sex on Clinical Outcomes after CD19 CAR T-Cell Therapy for Large B-Cell Lymphoma: Response and Survival Are Significantly Superior in Female Compared to Male Patients
Authors: Buecklein Veit L. , Rejeski Kai , Perez Ariel , Iacoboni Gloria , Jurinovic Vindi , Kharboutli Soraya , Blumenberg Viktoria , Ackermann Josephine , Frölich Lisa , Johnson Grace , Patel Kedar , Arciola Brian , Mhaskar Rahul , Schmidt Christian , Wood Anthony , Hoster Eva , Mackensen Andreas , Locke Frederick L. , von Bergwelt-Baildon Michael , Mueller Fabian , Barba Pere , Jain Michael D. , Subklewe Marion 
Published: December 2023

Sex differences in the incidence and mortality are evident in a wide range of cancers. This is not only due to sex-related variations in behavioral cancer risk factors, but also due to biological and molecular effects of sexual differentiation. Focusing on immunotherapeutic approaches like immune checkpoint inhibition or allogeneic stem cell transplantation, several reports have associated male sex with inferior outcomes. However, the exact impact remains controversial, and underlying mechanisms are incompletely understood.

Here, we sought to explore the effects of the patient's biological sex on the outcomes of CD19 CAR-T cell therapy. To this end, we retrospectively analyzed disease and laboratory features together with survival in a cohort of 214 patients treated with axicabtagene ciloleucel (Axi-cel) for relapsed/refractory large B-cell lymphoma (LBCL) in the third- or later-line setting at four CAR-T centers. Predictors of progression-free survival (PFS) were analyzed by uni- and multivariate comparisons.

The analyzed patient cohort comprised 119 male and 95 female patients, with a median age of 64 years (range 19-79). Most baseline patient characteristics were not significantly different for male and female patients (see attached table). Ferritin levels prior to lymphodepletion, however, were significantly higher in males (median 505 ng/ml vs. 325 ng/ml in females, p=0.025). The incidences of ASTCT grade ≥ 3 cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were not significantly different between females and males. However, objective response rates were significantly higher in female patients (88% vs. 75% in males, p=0.03). Additionally, females had a significantly superior PFS compared to males (median PFS not reached [95% CI 12.2 - NA months] in females vs. 4.2 months [95% CI 3.2 - 9.2 months] in males, Hazard ratio 1.8 [1.2 - 2.6], p=0.005, 1-year PFS estimate 61% in females vs. 39% in males). Overall survival (OS) was also significantly longer in females (median OS not reached in females vs. 22.6 months [95% CI 13.3 months - not reached] in males, Hazard ratio 1.7 [1.1 - 2.9], p=0.028).

We confirmed the relevance of the patient's sex in multivariate analysis. We used Lasso modelling of variables with significant (p&lt;0.05) association with PFS from univariate Cox regression analyses (ECOG, LDH, CRP and ferritin levels, Ann Arbor stage, bulky or extranodal disease [END], No. of therapy lines prior to CAR-T cell therapy and response to bridging therapy). Male sex, non-response to bridging, stage III/IV disease, END and No. of therapy lines remained independent risk factors for inferior PFS (Lasso coefficients &gt;0.1), with male sex and non-response to bridging having the most significant effect (Lasso coefficient 0.54 for both variables).

Finally, employing logistic regression of the independent variables from multivariate analysis, propensity score matching was used to better delineate the effect of sex on PFS. Sufficient balance was achieved between male and female patients, with all standardized mean differences below 0.12 after matching. In the matched analysis, PFS remained significantly superior for female patients (1-year PFS estimate 61% in females vs. 40% in males, log-rank p=0.008). For OS, the observed difference was of borderline significance in the matched dataset (1-year OS estimate 77% in females vs. 61% in males, log-rank p=0.051).

Taken together, we demonstrate that female patients have significantly superior outcomes following Axi-cel therapy for r/r LBCL, even after careful adjustment for variables known to impact treatment results. A deeper understanding of the underlying mechanisms of these outcome disparities might enable the optimization of T cell-based treatment platforms in the future, both in female and male patients. Male patients may potentially benefit from intensified CAR-T (combination) treatment strategies.