Entospletinib and obinutuzumab in patients with relapsed/refractory chronic lymphocytic leukemia and B-cell malignancies

摘要

Therapeutic resistance and intolerance of Bruton tyro- sine kinase (BTK) inhibitors is an emerging unmet med- ical need in chronic lymphocytic leukemia (CLL). 1,2 Entospletinib is a small molecule inhibitor of spleen tyro- sine kinase (SYK), which is integral to the activation of BTK and the B-cell receptor (BCR) signaling cascade. 3 SYK is overexpressed in CLL and its inhibition induces apoptosis of CLL cells in pre-clinical models. 4,5 We have shown that BAFF-mediated SYK activation triggered BCR signaling and rendered protection of CLL cells from spon- taneous apoptosis in vitro. 5 Single agent entospletinib was efficacious in treatment of patients with relapsed/refrac- tory (R/R) CLL who had progressed following chemoim- munotherapy. 6 Here we report the results of a single arm, open label, investigator-initiated phase I/II clinical trial which evaluated safety and efficacy of entospletinib in combination with obinutuzumab, a glycoengineered monoclonal anti-CD20 antibody, in patients with R/R CLL and non-Hodgkin lymphoma (NHL) (clinicaltrails gov. Identifier: NCT03010358).