This study evaluated the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib, a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase (BTK), in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. A total of 85 patients, mostly considered high-risk, received ibrutinib orally once daily at either 420 mg or 840 mg. The majority of toxic effects were grade 1 or 2, including transient diarrhea, fatigue, and upper respiratory tract infections. The overall response rate was 71% in both dose groups, with an additional 20% and 15% of patients, respectively, achieving a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors, including advanced-stage disease, number of previous therapies, and 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75%, and the overall survival rate was 83%. Ibrutinib demonstrated durable remissions in patients with relapsed or refractory CLL, including those with high-risk genetic lesions, and showed a favorable therapeutic index.This study evaluated the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib, a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase (BTK), in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. A total of 85 patients, mostly considered high-risk, received ibrutinib orally once daily at either 420 mg or 840 mg. The majority of toxic effects were grade 1 or 2, including transient diarrhea, fatigue, and upper respiratory tract infections. The overall response rate was 71% in both dose groups, with an additional 20% and 15% of patients, respectively, achieving a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors, including advanced-stage disease, number of previous therapies, and 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75%, and the overall survival rate was 83%. Ibrutinib demonstrated durable remissions in patients with relapsed or refractory CLL, including those with high-risk genetic lesions, and showed a favorable therapeutic index.