Frontline Treatment for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Targeted Therapy vs. Chemoimmunotherapy

The treatment options for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have expanded significantly in the last few years, including the use of new classes of oral small molecular inhibitors targeting the B cell receptor signaling pathway or the apoptosis machinery. Targeted therapy with or without immunotherapy has quickly emerged as a new standard for frontline treatment of CLL/SLL, though the previous standard chemoimmunotherapy (CIT) remains a treatment option. In this review, we present data from key clinical trials to evaluate the benefits and risks associated with different frontline treatment approaches. We reviewed recently published and presented clinical trials on frontline CLL/SLL treatment, with particular focus on the comparison of CIT vs. targeted therapies, including inhibitors of Bruton’s tyrosine kinase (BTK) or of the anti-apoptotic protein Bcl-2. Various BTK inhibitors as continuous treatment with or without anti-CD20 monoclonal antibodies have compared favorably to the conventional CITs in previously untreated CLL/SLL patients of various ages and comorbidities. Fixed duration treatment with the Bcl-2 inhibitor venetoclax combined with anti-CD20 monoclonal antibodies also showed superiority in clinical outcomes compared to CIT. Subgroup analysis interestingly showed that IgHV-mutated CLL/SLL might still derive similar benefits from CIT. Ongoing clinical trials are investigating combined targeted therapies of venetoclax plus a BTK inhibitor to try to further improve the efficacy while limiting the duration of treatment. Targeted therapies are becoming the new standard of care for frontline treatment of CLL/SLL although conventional CIT remains an option group of fit patients with low risk features. Novel strategies are being studied using targeted therapy combinations to optimize the depth of response in a time-limited fashion.