BACKGROUND: The treatment of relapsed chronic lymphocytic leukemia (CLL) has 
resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential 
component of B-cell-receptor signaling, mediates interactions with the tumor 
microenvironment and promotes the survival and proliferation of CLL cells.
METHODS: We conducted a phase 1b-2 multicenter study to assess the safety, 
efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a 
first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell 
cancers, in patients with relapsed or refractory CLL or small lymphocytic 
lymphoma. A total of 85 patients, the majority of whom were considered to have 
high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 
34 received 840 mg.
RESULTS: Toxic effects were predominantly grade 1 or 2 and included transient 
diarrhea, fatigue, and upper respiratory tract infection; thus, patients could 
receive extended treatment with minimal hematologic toxic effects. The overall 
response rate was the same in the group that received 420 mg and the group that 
received 840 mg (71%), and an additional 20% and 15% of patients in the 
respective groups had a partial response with lymphocytosis. The response was 
independent of clinical and genomic risk factors present before treatment, 
including advanced-stage disease, the number of previous therapies, and the 
17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 
75% and the rate of overall survival was 83%.
CONCLUSIONS: Ibrutinib was associated with a high frequency of durable 
remissions in patients with relapsed or refractory CLL and small lymphocytic 
lymphoma, including patients with high-risk genetic lesions. (Funded by 
Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).