BTK inhibitor ibrutinib in CLL and mantle cell lymphoma

Bruton’s tyrosine kinase (BTK) is a critical component of B-cell–receptor signaling that mediates interactions with the tumor microenvironment and promotes survival and proliferation of chronic lymphocytic leukemia (CLL) cells. Ibrutinib is a first-in-class oral covalent inhibitor of BTK designed for the treatment of B-cell cancers. In a phase 1b/2 study reported by Byrd and colleagues, ibrutinib treatment was found to produce high rates of durable responses in patients with relapsed or refractory CLL or small lymphocytic lymphoma. In the multicenter study of 82 patients with relapsed or refractory CLL and 3 patients with small lymphocytic lymphoma, 51 patients received continuous ibrutinib once daily at 420 mg and 34 patients received 840 mg. Patients had a median age of 66 years and 76% were men. Patients had received a median of 4 prior therapies and the median time from last treatment was 3 months (range, 1-98 months). The most common prior treatments were rituximab (98%), nucleoside analogues (95%), and alkylators (89%). Most patients (65%) had high-risk disease (Rai stage III or IV) and unmutated immunoglobulin variableregion heavy-chain genes (81%). Bulky nodes of 5 mm and 10 mm in diameter were present in 52% and 15% of patients, respectively. High-risk cytogenetic abnormalities consisted of 17p13.1 deletion in 33% of patients and 11q22.3 deletion in 36%. Response was observed in 36 of 51 patients (71%) in the 420-mg group (including 2 complete responses) and 24 of 34 (71%) in the 840-mg group (all partial responses). In addition, 10 patients (20%) in the 420-mg group and 5 (15%) in the 840-mg group had a partial response with persistent lymphocytosis. Response was independent of baseline clinical and genomic risk factors, including advanced-stage disease, number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival (PFS) rate was 75% and the overall survival (OS) rate was 83%. Among patients with 17p13.1 deletion, estimated 26-month PFS was 57% and OS was 70%. Disease progression occurred in 11 patients (13%) during follow-up, with 7 having progression by biologic transformation. The median time from diagnosis to transformation was 98 months (range,