CLL Treatment Enters a New Era of Targeted Combinations

Chronic lymphocytic leukemia (CLL) treatment has undergone a dramatic transformation over the past decade, with novel targeted therapies largely replacing chemoimmunotherapy and expanding the options available to patients. In an interview with Targeted Oncology, Jeff Sharman, MD, of Sarah Cannon Research Institute at Willamette Valley Cancer Institute, discusses how the field is now moving beyond single-agent approaches toward rational combinations targeting BTK, BCL2, and CD20.

Sharman highlights the growing use of multidrug regimens, including combinations of Bruton tyrosine kinase (BTK) inhibitors with BCL2 inhibitors and triplet approaches, and considers how ongoing studies may help define the optimal treatment strategy for patients with different molecular characteristics. He also points to the encouraging outcomes seen in selected patients receiving modern targeted therapies, noting that overall mortality may now approach that of age-matched controls.

Despite these advances, Sharman identifies resistance to BTK inhibitors as a key remaining challenge in CLL. He discusses emerging treatment options for patients with BTK-resistant disease, including noncovalent BTK inhibitors such as pirtobrutinib (Jaypirca) and investigational agents including nemtabrutinib, as well as next-generation BTK degraders and BCL2 inhibitors such as sonrotoclax (Beqalzi) and lisaftoclax.

Sharman also explores the potential role of bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy in CLL, including the possibility that these approaches could find a greater role in earlier or consolidation settings. Looking ahead, Sharman discusses data from the phase 3 CLL17 (NCT04608318) and MAJIC (NCT05057494) trials and the potential for sonrotoclax to further expand the treatment landscape.