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Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disorder that remains incurable with standard therapies. In a phase I study, ibrutinib — an inhibitor of Bruton tyrosine kinase (BTK) and a key component of the B-cell receptor (BCR) signaling pathway — demonstrated antitumor activity in patients with relapsed or refractory B-cell malignancies (J Clin Oncol 2013 Jan; 31:88). Now, investigators have conducted an industry-sponsored, multicenter, open-label, phase Ib–II trial of ibrutinib (420 mg or 840 mg daily) in 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma.
The overall response rate was 71%. Two patients achieved complete remission. Response was similar with both doses. Responses were observed in patients with the poor-risk cytogenetic subtypes del(17p) and del(11q). Adenopathy and splenomegaly regressed quickly in most patients, with a concomitant rise in lymphocytosis, as cells mobilized from tissues into the circulation. The most common toxicities, typically grade 1 or 2, included diarrhea, fatigue, and upper respiratory infections. Pneumonia occurred in 12% of patients.
Byrd JC et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013 Jul 4; 369:32. (http://dx.doi.org/10.1056/NEJMoa1215637)
Foà R and Guarini A. A mechanism-driven treatment for chronic lymphocytic leukemia. N Engl J Med 2013 Jul 4; 369:85. (http://dx.doi.org/10.1056/NEJMe1303054)
Comment
B-cell receptor signaling is constitutively activated in most B-cell lymphoproliferative disorders, and numerous agents are under study to target the pathway. Traditional therapy with cytotoxic agents, corticosteroids, and monoclonal antibodies promises to be supplemented with or supplanted by BCR inhibitors such as ibrutinib. These agents, alone or in combination regimens, are now being tested in front-line as well as relapsed and refractory settings.