Disproportionality Analysis of Hematologic Adverse Event Signals Associated with Venetoclax in Combination with Senescence-Inducing Chemotherapy

Background: BH3 mimetics (such as venetoclax and navitoclax) are increasingly investigated in the context of the “one-two punch” anticancer strategy, wherein senescence-inducing therapies are combined with senolytic clearance. However, real-world pharmacovigilance evidence describing hematologic adverse event (AE) patterns and serious outcomes for venetoclax versus navitoclax in such combination settings remains limited. This study aims at providing an expectation based on the current reporting of the safety implications of senolytics combined with senescence-inducing therapy in clinical practice. Methods: We analyzed de-duplicated U.S. FDA Adverse Event Reporting System (FAERS) reports retrieved on 1 August 2025. Venetoclax reports (Q2 2016–Q2 2025) were categorized as monotherapy or combination with senescence-inducing chemotherapy (predefined based on published evidence of therapy-induced senescence TIS). Hematologic AEs were grouped into three categories (isolated low WBC, isolated low platelet count, and multi-lineage cytopenia). Disproportionality analyses were conducted using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) with 95% CIs and chi-squared testing. Navitoclax reports were analyzed descriptively due to limited volume. Results: A total of 47,508 venetoclax reports were included (34,485 monotherapy; 13,023 combination). Compared with monotherapy, combination therapy showed disproportionate reporting signals (ROR/PRR; reflecting reporting disproportionality rather than incidence or causal risk) for low WBC (ROR 2.87, PRR 2.59) and multi-lineage cytopenias (ROR 3.54, PRR 2.94), while isolated low platelet count was under-represented (ROR 0.31, PRR 0.32). For outcomes, combination therapy demonstrated higher reporting signals for life-threatening outcomes (ROR 7.06, PRR 6.56), hospitalization (ROR 1.74, PRR 1.39), and other outcomes (ROR 2.36, PRR 1.57), while death (ROR 0.55, PRR 0.65) and non-serious outcomes (ROR 0.26, PRR 0.29) were proportionally less reported (all p < 0.001). Navitoclax had 172 reports; hematologic cytopenias and serious outcomes were frequent, but analyses were descriptive only. Conclusions: In FAERS, venetoclax combined with senescence-inducing chemotherapy shows stronger reporting signals for leukopenia and multi-lineage cytopenias and for several serious outcome categories compared with monotherapy. These reporting patterns highlight the need for further care in terms of clinical implementation of the currently investigated senolytics prior to the consideration of the “one-two punch” strategy.