Treatment of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) cells proliferate in secondary lymphoid organs (lymph nodes and spleen), where B-cell receptor signaling promotes the expansion of the monoclonal B lymphocytes. B-cell receptor signaling is the target of kinase inhibitors, which have transformed CLL therapy during the past decade. Bruton’s tyrosine kinase (BTK) and isoform-selective phosphatidylinositol 3-kinase (PI3K) inhibitors disrupt B-cell receptor signaling and other circuits between CLL cells and the tissue microenvironment. BCL2 (B-cell lymphoma 2), an antiapoptotic molecule strongly expressed in CLL cells, has emerged as another important therapeutic target. The transition from chemotherapy-based regimens to new, molecularly targeted agents is based on a series of clinical trials, most of them published in the Journal,^1-10 showing a survival benefit from BTK inhibitors (ibrutinib and acalabrutinib) and the BCL2 antagonist venetoclax, as compared with older CLL therapies (chemotherapeutic agents,⁵ antiCD20 antibodies,^2,3,11 or combinations of these agents^7-10,12-14). These benefits are profound in patients with high-risk CLL and are less pronounced in those with low-risk CLL. However, the new treatment approaches also come with challenges (i.e., the emergence of drug resistance, serious side effects, and high costs). Combination therapies to achieve deeper remissions, allowing for fixed-duration or intermittent treatment, will help to optimize the use of the new targeted drugs.