Rationale for Pairing Sonrotoclax With Zanubrutinib in Relapsed or Refractory CLL

Dr. Mazyar Shadman discusses the scientific rationale for combining sonrotoclax with zanubrutinib for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL). He explains that BTK and BCL2 inhibitors have complementary mechanisms of action, making them well suited for combination therapy. Inhibition of the B-cell receptor pathway by a BTK inhibitor increases CLL cell dependence on BCL2 for survival, enhancing sensitivity to BCL2 inhibition. Dr. Shadman also highlights the favorable safety profile of the regimen, noting that the two drug classes have largely non-overlapping toxicities and do not increase risks such as cardiotoxicity or bleeding. Zanubrutinib is the only BTK inhibitor to demonstrate superior progression-free survival compared with ibrutinib, while sonrotoclax is a next-generation, highly potent, selective BCL2 inhibitor. Together, these characteristics provide a strong biological and clinical rationale for evaluating this fixed-duration, all-oral combination in relapsed or refractory CLL.