Bruton's Tyrosine Kinase Inhibitors in Primary Immune Thrombocytopenia

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder driven by antiplatelet autoantibodies and cell-mediated immune mechanisms that cause accelerated peripheral platelet destruction and impaired megakaryopoiesis. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase of the Tec family, functions as a central node in two key pathophysiological pathways in ITP: B-cell receptor signaling, which governs the maturation and expansion of autoantibody-producing B-cell clones, and Fcγ receptor signaling in splenic and hepatic macrophages, which mediates the phagocytosis of opsonized platelets.

BTK inhibitors (BTKi) deliver a rational dual-blockade therapeutic strategy by concurrently attenuating autoantibody generation and diminishing macrophage-mediated platelet clearance. First-generation BTKi developed for B-cell malignancies (including ibrutinib, acalabrutinib, and zanubrutinib) irreversibly inhibit the catalytic site and can disrupt BTK-dependent platelet function mediated by glycoprotein VI (GPVI) and GPIb-IX-V receptors. In contrast, rilzabrutinib is an oral, covalent, reversible inhibitor specifically designed to maintain primary hemostasis.

Clinical evaluation in the LUNA 2 (phase 1/2) and LUNA 3 (phase 3) trials led to the US Food and Drug Administration approval of rilzabrutinib (Wayrilz) in August 2025 as the first BTKi approved for ITP. Earlier-stage clinical development also continues for orelabrutinib and other BTK inhibitors in this disease setting.