SUMMARY: BTK is predominantly expressed in B-cells and is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK is necessary for the proliferation and survival of B-cell tumors. Ibrutinib (PCI-32765) is an oral, irreversible inhibitor of BTK and thereby inhibits cell proliferation and promotes programmed cell death (Apoptosis). In this phase Ib/II trial, 116 patients with CLL were enrolled who were either treatment naïve or had relapsed/ refractory CLL or Small Lymphocytic Lymphoma. Patients with high risk cytogenetic features were included as well and patients were divided into 5 groups and received Ibrutinib at fixed doses of 420mg or 840mg daily, until disease progression. The primary objective of this study was to determine the safety of the two dosing regimens. Secondary objectives were to assess efficacy, pharmacokinetics and long-term safety. In the treatment naïve group, the Complete Response (CR) was seen in 10% of the patients, PR (Partial Response) in 61% and the estimated 22 month PFS (Progression Free Survival) and OS (Overall Survival) was 96%. In the relapsed/refractory group, the CR was 3% and PR was 64%, whereas in the high risk cytogenetics group, there were no CR’s and PR was 50%. Estimated 22 month PFS and OS for the relapsed/refractory as well as high risk groups were 76% and 85% respectively. This benefit was achieved with minimal toxicity which included diarrhea, fatigue, skin rash and arthralgias. The authors concluded that treatment with Ibrutinib resulted in significant disease control extending beyond 12 months with minimal adverse events in this difficult-to-treat CLL patients. Byrd JC, Furman RR, Coutre S, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 189
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