From Platelet Toxicity to Precision Targeting: Evolving Strategies to Overcome Thrombocytopenia in BCL-2/BCL-XL Inhibition.

Background: Simultaneous blockade of the anti-apoptotic proteins BCL-2 and BCL-XL has been shown to be efficacious in preclinical and clinical trials for tumors that are co-dependent on their survival pathways, although clinical development has been limited owing to dose-limiting thrombocytopenia associated with BCL-XL inhibition. Discussion: Recent developments have provided strategies that are largely complementary, attempting to separate anti-tumor activity from platelet toxicity: (I) targeted protein degraders (PROTACs) that recruit E3 ligases weakly expressed in platelets to spare platelet BCL-XL, (II) prodrug and formulation strategies that preferentially deliver active drug concentrations to the tumor, (III) dosing and scheduling to leverage catalytic or durable mechanisms of action, and (IV) rational combination regimens that reduce per-agent exposure while retaining or enhancing anti-tumor activity. This perspective will integrate the mechanistic rationale, preclinical support, and emerging clinical evidence supporting these mechanisms and propose the next steps and sequencing for future experimental or clinical directions to explore safe and active dual BCL-2/BCL-XL therapies. Conclusion: Collectively, these emerging strategies offer an opportunity to develop dual BCL-2/BCL-XL inhibitors with greater anti-tumor activity while minimizing thrombocytopenia and potentially broadening their clinical application.