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Despite the advent of modern chemoand radioimmunotherapies, the disease course in most mature B-cell malignancies (with the exception of diffuse large B-cell lymphoma [DLBCL] and Burkitt lymphoma) is highlighted by frequent relapses, progressively shorter remissions, and eventual emergence of therapy resistance. An effective salvage therapy in this setting remains an area of unmet medical need. 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 malignant B-cells. The BTK protein itself is a Tec family tyrosine kinase that is activated by spleen tyrosine kinase following B-cell-receptor stimulation and which is then required for downstream events including calcium release, activation of the NF B and NFAT pathways, cell survival and proliferation. The fundamental role of BTK in B-cell function is underscored by the human disease X-linked agammaglobulinemia, which is caused by loss of function mutations in BTK. These mutations result in the virtual absence of all B cells and immunoglobulins, leading to recurrent bacterial infections. Ibrutinib (formally known as PCI-32765) is the first-in-class BTK inhibitor to enter clinical trials. In a multicenter phase 1 dose-escalating study, 56 patients with relapsed or refractory B-cell lymphomas received escalated doses of oral ibrutinib either on an intermittent or continuous daily dosing schedule. The most common adverse effects were grade 1-2 nonhematologic toxicities, which included rash, nausea, fatigue, diarrhea, muscle spasms/myalgia, and arthralgia. An overall response rate (ORR) of 60% was achieved across all histological types with the best efficacy seen in patients with mantle cell lymphoma (MCL; 78%) and chronic lymphocytic leukemia (CLL; 68%). While both intermittent and continuous dosing schedules demonstrated efficacy, the study favored continuous dosing for future trials. Two recent key trials providing further proof of the remarkable activity of BTK inhibitors in CLL and MCL are discussed in the Community Translations section of this issue on page XXX. In the study, the investigators reported high ORRs (about 70%) with single-agent ibrutinib in patients with relapsed or refractory CLL. Perhaps the most important finding of this study is the encouraging activity of this agent in patients with high-risk features historically associated with a dismal prognosis, such as chromosome 17p deletion and unmutated immunoglobulin variable-region heavy chain (IgVH) gene status. The ORR was 68% in the 17p deleted patients and 77% in those with unmutated IgVH gene. These responses appear durable. At 26 months, the estimated progression-free survival (PFS) was 75% and overall survival (OS) was 83%. Typically in CLL patients, an increase in peripheral blood lymphocytosis during therapy is considered a sign of disease progression. A unique feature of ibrutinib treatment in CLL patients is the rapid resolution of enlarged lymph nodes along with a transient surge in peripheral blood lymphocytosis, likely mediated by inhibition of cell adhesion. Treating physicians will need to be aware of this phenomenon with ibrutinib therapy so as not to confuse it with disease progression. The safety profile of ibrutinib appears favorable; however the possible risk of bleeding complications with this agent warrants further investigation. Seven patients in this study developed Richter’s transformation. It is not known whether ibrutinib promotes histologic transformation by altering tumor microenvironment. The key clinical question focuses on how these results will impact our practice in the coming years.

Dawn of a new era: targeting the B-cell receptor signaling pathway to conquer B-cell lymphomas