There has been a dramatic change in therapy for chronic lymphocytic leukemia (CLL) over the last 20 years. In 1990, available therapy produced complete responses in <5% of treated patients. This is in marked contrast to modern regimens, which are reported to reliably produce complete responses in approximately 40% to 50% of patients. This remarkable improvement has been attributable to combination chemoimmunotherapy agents that have contributed to the backbone of therapy for patients with CLL. However, the disease is still incurable and these modern treatment regimens have been somewhat limited to the treatment of younger, physically “fit” patients with CLL due to their increased toxicity, including enhanced myelosuppression and immunosuppression. In addition, because patients receive multiple therapies during the course of their lifetime, the mounting toxicities as well as decreased efficacy often limit the repeated use of these more aggressive combination therapies. Fortunately, over the past 5 years, there has been an explosion of new active agents that have demonstrated remarkable activity in patients with recurrent/refractory disease as well as those who harbor poor cytogenetic abnormalities. The current review focuses on some of the novel small molecules that have either been approved or are at the forefront of clinical development in the treatment of patients with CLL.
There has been a dramatic change in therapy for chronic lymphocytic leukemia over the last 20 years. The current study provides a review of some of the new small molecule inhibitors being used in the treatment of patients with chronic lymphocytic leukemia, with a focus on the B-cell receptor signaling-associated kinases (Bruton tyrosine kinase, phosphatidylinositol 3-kinase, and spleen tyrosine kinase) as well as inhibition of Bcl-2.