Therapeutic advances in chronic lymphocytic leukemia: A focus on molecular pathogenesis, targeted therapies, and...

This article concisely evaluates current targeted therapies that have received regulatory approval for chronic lymphocytic leukemia (CLL). Mechanisms of molecular pathogenesis and their therapeutic implications, current and novel targeted therapies, and supportive care are discussed.

CLL is a common lymphoproliferative neoplasm of mature but immunologically incompetent B cells in older adults. Over the past 2 decades, robust research has shown that CLL pathogenesis is a multistep process that includes, but is not limited to, (1) clonal selection, expansion, and transformation; (2) aberrant B cell signaling pathways; (3) sequence heterogeneity in the gene encoding the immunoglobulin heavy chain variable region (IGHV); (4) impaired apoptosis; and (5) interactions between CLL cells and their microenvironment. The development of oral targeted therapies against some of these molecular abnormalities has led to improved survival outcomes over traditional chemoimmunotherapy. Current oral targeted therapies that have received regulatory approval include continuous therapy with Bruton's tyrosine kinase inhibitors (BTKis) and fixed-duration therapy with the B cell leukemia/lymphoma-2 inhibitor (BCL-2i) venetoclax. These agents may be used either alone or in combination in the treatment-naive setting, as well as in relapsed or refractory disease. This review contributes to understanding of the molecular pathogenesis of CLL with therapeutic implications. It summarizes key advances in oral targeted therapies and emerging innovative targeted therapies (eg, novel BTKis, BTK degraders, and novel BCL-2is) and highlights supportive care in optimizing treatment-related adverse effects.

Treatment options for CLL continue to evolve. Current treatment selection is based on clinical and patient-specific considerations. Emerging novel therapies to overcome treatment resistance and strategies to optimize supportive care generate opportunities for pharmacists to advance practice and improve patient safety.