Abstract A058: Clinical and preclinical evidence indicate gender-based differences in the sensitivity of B-cell lymphoid tumors to BTK inhibitors
Eleonora Cannas, Flaminia Facella, Afua A. Mensah, Arianna Calcinotto, Fabio Conforti, Alberto J. Arribas, Daniele Laszlo, Francesco BertoniAbstract
Background:
Female or male sex is associated with differences in the incidence of lymphomas and chronic lymphocytic leukemia in the general population, and it can also influence treatment outcomes. This effect may be multifactorial, including changes in how drugs are cleared from the blood, as reported for rituximab, as well as cellular-level effects. In this study, we examined potential gender-based differences in response to Bruton tyrosine kinase inhibitors (BTKi) in both clinical and preclinical settings.
Methods:
We performed a meta-analysis of randomized clinical trials (RCTs) evaluating BTKi, stratifying outcomes by sex. B-cell lymphoma cell lines from male and female patients were examined for estrogen and androgen receptor expression at the RNA level, cultured in medium containing charcoal-stripped or normal serum, and treated with BTK inhibitors (ibrutinib or zanubrutinib), with or without β-estradiol. Cell viability and growth were assessed using MTT/Incucyte assays after both short- and long-term exposures.
Results:
Seven RCTs, comprising eight treatment-arm comparisons and a total of 3,574 patients (33% female), were included in the meta-analysis. A greater improvement in progression-free survival (PFS) hazard ratio (HR) favoring the BTKi arm was observed in females compared with males in seven of the eight comparisons analyzed. The pooled meta-analytic PFS-HR was 0.18 (95% CI, 0.14–0.22) in females and 0.26 (95% CI, 0.22–0.29) in males (p for heterogeneity = 0.01). In BTKi-sensitive cell lines (OCI-Ly10, REC1, SSK41, Jeko1, Karpas1718), culture in medium supplemented with charcoal-stripped serum (i.e., deprived of hormones)decreased BTKi sensitivity across all models, suggesting a possible hormone-dependent influence on drug response. In B cell lymphoma cell lines, AR, encoding the androgen receptor, and ESR1, encoding the estrogen receptor α (ERα), were mostly and poorly expressed. Conversely, ESR2, encoding ERβ, was widely expressed, indicating a more likely role for estrogen than canonical androgen signaling in mediating possible hormone-dependent responses to BTKi. In agreement, the addition of β-estradiol had no effect on its own but restored and increased ibrutinib sensitivity in male-derived models (REC1, Karpas1718), while no effect was seen in female-derived cells (OCI-Ly10, SP49). These findings link estrogen signaling to BTKi efficacy and reflect the sex bias observed in clinical cases.
Conclusions:
We found a sex-based difference in the outcomes of patients with lymphoid neoplasms treated with BTK inhibitors, which may be partly caused by a direct effect of β-estradiol on lymphoma cells. Ongoing studies aim to better understand this effect observed in the clinical setting.
Citation Format:
Eleonora Cannas, Flaminia Facella, Afua A. Mensah, Arianna Calcinotto, Fabio Conforti, Alberto J. Arribas, Daniele Laszlo, Francesco Bertoni. Clinical and preclinical evidence indicate gender-based differences in the sensitivity of B-cell lymphoid tumors to BTK inhibitors [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A058.