Targeted Therapy in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by a monoclonal population of mature, activated B lymphocytes. It is a heterogeneous disorder with a variable clinical course. Although in recent years the introduction of chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab (FCR) has induced response rates of 95% in previously untreated patients and increased the rates of failure-free survival, CLL remains incurable for many patients. However, a better understanding of the molecular basis of CLL has led to the development of several novel therapeutic strategies that target molecular pathways. These targeted therapies inhibit signaling pathways involved in growth and proliferation in CLL cells. Among the targeted therapies being investigated in CLL are the following: monoclonal antibodies against CD52 (alemtuzumab), CD20 (rituximab, ofatumumab), CD23 (lumiliximab), and CD40 (HCD122); agents that target molecular pathways, such as cyclin-dependent kinase inhibitors (flavopiridol); peptidase inhibitors (talabostat); Bcl-2-targeting agents (antisense oligonucleotide, oblimersen; small molecule inducing apoptosis, gossypol); heat shock protein 90 inhibitors that target 70-kDa zeta-associated protein (17-AAG, CNF2024); immunomodulating agents (lenalidomide; immunostimulatory oligonucleotides CpG); hypomethylating agents (decitabine; valproic acid); antiangiogenic agents (bevacizumab); and gene therapies. This chapter reviews the use of targeted therapies as single agents and in combination with chemotherapy for CLL. [ABSTRACT FROM AUTHOR]