Novel targeted drugs for relapsed/refractory chronic lymphocytic leukemia

In the last few years the treatment of patients with chronic lymphocytic leukaemia (CLL) has been revolutionized by introduction of several targeted signaling inhibitors, including B-cell receptor (BCR) ptthways inhibitors and BCL-2 inhibitors. These agents are superior to other forms of therapy in terms of overall survival and progression free survival in relapsed and refractory patientswith CLL. Moreover, many novel drugs are currently under evaluation. Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor indicated for  treatment-naïve or relapsed/refractory  patients. In addition to ibrutinib, more selective second generation inhibitors of BTK have demonstrated promising clinical activity in CLL. Those that are furthest along in clinical development include acalabrutinib, zanubrutinib (BGB-3111) and ONO-4059. These compounds are well tolerated and seem to be more potent than ibrutinib. Idelalisib is the first  phosphoinositide 3-kinase (PI3K) delta inhibitor approved by the FDA for the treatment of relapsed/refractory CLL. Second-generation PI3Kδ inhibitors are also in development to help reduce the severity of transaminase elevations and other toxicities observed with idelalisib. Duvelisib, another inhibitor of PI3K has been approved by FDA in September 2018 for the treatment of relapsed or refractory CLL after at least two prior therapies. Venetoclax is a selective inhibitor of the B-cell lymphoma 2 (Bcl-2) antiapoptotic protein. The drug was initially approved by the FDA  in 2016 for CLL patients with 17p deletion, who have received at least one prior therapy. In June 2018 the FDA expanded the approval to CLL patients with CLL progressed after receiving at least one previous treatment, regardless of genetic alteration. Due to high efficacy of novel targeted drugs allogenic hematopoietic stem cell transplantation is now indicated to later stages of relapsed or refractory CLL. CD19-directed CART therapy holds also great promise in CLL.