BTK is essential for signaling by means of the BCR, but it also plays an important role for the signaling of chemokine receptors and adhesion molecules, which chronic lymphocytic leukemia (CLL) cells use for survival and proliferation, or tissue homing and tissue retention, respectively. CLL is characterized by the accumulation of monoclonal CD5+ B lymphocytes, with expansion of the CLL clone in blood, bone marrow, and secondary lymphoid organs (lymph nodes, spleen). These malignant B cells depend on BCR signaling for survival and proliferation.

Patients with CLL who require treatment are often older and may have age-associated comorbidities. Although front-line chemoimmunotherapy has been recommended for younger patients with low-risk CLL and mutated (ie, more favorable) immunoglobulin heavy chain variable region (IGHV ) gene status, such therapies with intensive chemotherapy-based backbones are not well tolerated in populations of older patients. Novel therapies such as ibrutinib and idelalisib that act through the BCR pathway have been introduced, providing such patients with additional therapy options. Ibrutinib is approved by the US Food and Drug Administration as both a front-line and a relapsed/refractory CLL therapy. Idelalisib is approved for relapsed/refractory patients in combination with rituximab, but is not recommended for first-line CLL treatment.

Successes with BTK inhibition are also demonstrable across several other malignancies of B-cell origin, including in Waldenström’s macroglobulinemia (WM) and in mantle cell lymphoma (MCL). WM is a clinicopathologic entity associated with lymphoplasmacytic lymphoma in the bone marrow, with an immunoglobulin M monoclonal gammopathy in the blood. MCL is also derived from mature B cells; in approximately 80% of cases, the cell of origin is a naive B cell, while the remaining cases are somatically hypermutated and believed to be derived from antigen-stimulated B cells.