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The irreversible Bruton tyrosine kinase (BTK) inhibitor ibrutinib has changed the therapeutic landscape of patients affected by chronic lymphocytic leukemia (CLL), leading to high clinical response rates and durable remissions both in treatment-naïve or in the relapsed/refractory setting, also in patients with unmutated immunoglobulin genes or harboring TP53 deletion or mutations [1-3]. Ibrutinib irreversibly binds BTK at the cysteine 481 (C481) residue. BTK is a Tec family kinase implicated in the intracellular propagation of B-cell receptor (BCR) signaling, which mediates proliferative and survival signals in CLL cells. By blocking BTK, leukemic cells are rapidly extruded from the tissue microenvironment, obtaining the progressive reduction of the CLL clone by inducing apoptotic cell-death. Although ibrutinib therapy may induce prolonged remissions in the majority of patients, progressive disease may occur in some …