Inhibition of Bruton’s tyrosine kinase (Btk) is emerging as a promising mechanism for targeting B-cell malignancies such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) where the B-cell antigen receptor (BCR) is thought to possess an oncogenic role. BCR is composed of surface immunoglobulins that recognize foreign antigens. Upon binding to antigens, the downstream effector pathway, of which Btk is a central mediator, proceeds as shown in Figure 1.1 Non-receptor tyrosine kinases, including Btk, Src, Jak, Abl, Syk, and Fak, serve multiple roles in amplifying the signals from a number of surface receptors. Btk phosphorylates and activates phospholipase-Cλ (PLC-λ) and protein kinase C (PKC).2 The resulting expression of transcription factors, such as NF-κB, is critical to the survival, proliferation, and differentiation of B lymphocytes.3 Mutations in the gene encoding for Btk causes X-linked agammaglobulinemia (XLA) resulting in recurrent infections such as pneumonia, otitis media, skin infections, and septic arthritis.3

Figure 1.

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A number of Btk inhibitors have been synthesized.5 Two compounds, PCI-32765 and AVL-292 have entered clinical trials and the results will be summarized here.

PCI-32765 is an orally administered irreversible inhibitor of Btk. In a series of pre-clinical studies in CLL cells, the compound inhibited BCR- and chemokine receptor-related intracellular signals, chemokine secretion, cell migration, and survival.6 A fluorescent affinity probe for Btk demonstrated that occupancy of the kinase by PCI-32765 correlated with evidence of decreased BCR signaling.7

Fifty-six patients with relapsed/refractory B-cell malignancies were enrolled in a Phase I dose escalation trial of PCI-32765 to define a maximum tolerated dose or a dose that is three dose levels above attainment of full Btk occupancy.8 Daily dosing in 28-day cycles followed by a 7-day holiday was evaluated in five dose cohorts, and a once-daily continuous dosing was evaluated in two dose cohorts. Possibly related grade 3 or higher (adverse events) AEs occurred in 16% of patients, with less than 7% experiencing grade 3 or higher neutropenia or thrombocytopenia. No dose-limiting toxicity was identified. Objective responses (complete response plus partial response) were observed in 30 of 50 (60%) evaluable patients, regardless of dose level or histology:

  • CLL/small lymphocytic lymphoma (SLL) 11/14 (79%)
  • Follicular lymphoma 6/13 (46%)
  • MCL 7/9 (78%)
  • Diffuse large B-cell lymphoma (DLBCL) 2/7 (29%)
  • Waldenström macroglobulinemia 3/4 (75%)
  • MALT or marginal zone lymphoma 1/3 (33%)

At the time of data analysis, with median follow-up of 6 months, 25 patients continued to take the study medication without disease progression.