Chronic lymphocytic leukemia: biology, disease progression, and current treatment strategies

Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations. Current treatment approaches are not curative for CLL, except allogeneic hematopoietic stem cell transplantation, which is rarely offered to the majority of patients aged 70 years and older. Currently, there is no evidence that the initiation of therapy for asymptomatic early-stage disease improves the overall survival, even for patients with high-risk disease. The identification that the B-cell receptor (BCR) signaling pathway is aberrantly and constitutively activated in CLL has recently led to the development of BCR signaling inhibitors, ibrutinib and idelalisib. In addition, a novel BCL-2 antagonist, venetoclax, appears promising when used alone or in combination with anti-CD20 antibodies. The advent of novel small-molecule inhibitors has revolutionized the treatment approaches for patients with CLL.