Targeted therapies for CLL: Practical issues with the changing treatment paradigm.

Chemoimmunotherapy (CIT) such as FCR (fludarabine, cyclophosphamide, rituximab) has been the standard first-line therapy for younger patients with CLL. In the last few years, several novel targeted therapies have been developed for patients with CLL. These include B-cell receptor (BCR) inhibitors such as Bruton tyrosine kinase (BTK) inhibitors, PI3 kinase inhibitors, and Syk inhibitors, novel anti-CD20 monoclonal antibodies such as ofatumumab and obinutuzumab, and Bcl-2 antagonists such as venetoclax (ABT-199). Strategies targeting the immune system such as lenalidomide, chimeric antigen receptor (CAR) T cells, and more recently, checkpoint inhibitors, are in clinical development. Ibrutinib and idelalisib are already approved for patients with relapsed and refractory CLL. Ibrutinib is also approved for first-line treatment of CLL patients with del(17p). Several ongoing phase III clinical trials with novel therapies will further define the role of targeted agents in CLL.