Signal transduction inhibitors in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) therapy has evolved over the past few decades as modern chemo-immunotherapy significantly improved the response and survival of CLL patients. However, treatment toxicity of the intensive chemo-immunotherapy often limits its use in the mostly elderly population of patients. Further, the disease eventually relapses and additional therapy options are required. Of particular interest are molecular targeted therapies that interfere with critical signal transduction pathways controlling cell growth and survival. This review will provide an update on the most recent preclinical and clinical development of signal transduction targeted therapy in CLL.

Small molecular kinase inhibitors have been developed to target the proximal B-cell receptor signaling pathway (e.g. spleen tyrosine kinase inhibitors and Bruton's tyrosine kinase inhibitors) or the downstream phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin pathway. These agents showed unique in-vitro activities by inducing apoptosis and blocking interaction of CLL cells and the protective microenvironment. They have also shown promising clinical activity in early-phase clinical studies and appear to alter lymphocyte trafficking. Inhibitors of the B-cell CLL/lymphoma 2 (BCL-2) family of antiapoptotic proteins and Cdk inhibitors are in active clinical development. Strategies modulating the CLL interaction with the microenvironment niche are emerging. Further understanding of novel signaling pathways helps to identify additional potential therapeutic targets.

Signal transduction inhibitors are promising new strategy for targeted CLL treatment. Identification of novel molecular targets and therapeutic agents will further expand our therapeutic options.