Ibrutinib Is Effective in Relapsed CLL

Current treatments for relapsed chronic lymphocytic leukemia (CLL) rarely lead to durable remissions. Although CLL is a genetically heterogeneous disease, CLL cells have a shared dependence on B-cell receptor (BCR) signaling for survival. Bruton tyrosine kinase (BTK) is a critical downstream effector of BCR signaling that has emerged as an attractive therapeutic target for BCR-dependent cancers. Byrd and colleagues performed a multicenter phase IB/II study of ibrutinib, an orally available covalent BTK inhibitor, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. The primary endpoint of the trial was safety, and secondary endpoints included overall response rate and progression-free survival. Long-term ibrutinib therapy was well tolerated, with mainly grade 1 or 2 adverse events such as diarrhea, upper respiratory tract infection, and fatigue that resolved without requiring treatment suspension. Hematologic toxic effects were rare, indicating that ibrutinib does not target normal blood cells. The overall response rate was 71%, including 2 complete responses and 58 partial responses, and an additional 18% of patients had partial responses with persistent lymphocytosis or increased lymphocyte levels in the blood. Sustained improvement was also observed in the majority of patients with baseline thrombocytopenia (78%), anemia (82%), or neutropenia (77%). Importantly, the estimated progression-free survival rate at 26 months was 75%, and the overall survival rate was 83%. Patients with high-risk cytogenetic features such as deletion of 17p13.1 or 11q22.3 were most likely to ultimately develop progressive disease but had similarly high response rates and had a prolonged time to progression. These results suggest that ibrutinib monotherapy is safe and effective in relapsed or refractory CLL or small lymphocytic lymphoma and have led to the initiation of randomized phase III trials in which ibrutinib is compared with standard CLL treatments.

Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013 Jun 19 [Epub ahead of print].