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


Despite the advent of modern chemo- and 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.1,2 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 NFB and NFAT pathways, cell survival and proliferation.1 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.3 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.4 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%).

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