Resistance pathways and next-generation treatments in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is still the most common form of lymphoid malignancy, however, despite numerous developments in therapeutic approaches over the last ten years, CLL continues to pose important clinical challenges. The majority of currently available treatments target B-cell receptor signaling through either targeting Bruton Tyrosine Kinase (BTK) or B-cell Lymphoma 2 (BCL-2), while Phosphoinositide 3-Kinase (PI3K) inhibitors play a more limited role in current clinical practice. These agents have significantly changed the course of CLL disease; nevertheless, drug resistance, especially to covalent BTK inhibitors and venetoclax, remains an important problem that has led to the development of several new approaches: targeting BTK via a noncovalent approach, BTK degradation, Chimeric Antigen Receptor T (CAR-T) cell therapy, and bispecific antibodies. Moreover, novel discoveries concerning the microenvironment of CLL have been reported, revealing how components such as neutrophil reprogramming and myeloid-derived suppressor cells (MDSCs) can promote cancer cell survival and lead to resistance to treatment. Thus, from the discussion above, it is clear that the resistance problem has become complicated and complex and requires the targeting of not only cancer cells but also the environment surrounding them. Future treatments will likely involve combination therapy based on predictive biomarkers.