Bruton's tyrosine kinase inhibitors in primary immune thrombocytopenia: pathophysiology and clinical evidence.
- 1Hematology Department, Hospital Universitario de Burgos, Burgos, Spain.
- 2Department of Research, Sanquin Blood Supply Foundation, Amsterdam, The Netherlands.
- 3Landsteiner Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands.
Abstract
Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, mediated by both antiplatelet autoantibodies and cell-mediated immune mechanisms, that leads to accelerated peripheral platelet destruction and impaired megakaryopoiesis. Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase of the Tec family that occupies a central node in 2 pathways of major pathophysiological relevance in ITP: B-cell receptor signaling, required for the maturation and expansion of autoantibody-producing B-cell clones; and Fcγ receptor signaling in splenic and hepatic macrophages, responsible for the phagocytosis of opsonized platelets. BTK inhibitors (BTKi) therefore represent a rational dual-blockade therapeutic strategy: they reduce autoantibody production while simultaneously decreasing macrophage-mediated platelet destruction. Unlike first-generation BTKi developed for B-cell malignancies (ibrutinib, acalabrutinib, zanubrutinib), which irreversibly inhibit the catalytic site and can impair BTK-dependent platelet function (glycoprotein [GP] VI and GPIb-IX-V receptors), the most clinically advanced agent in ITP, rilzabrutinib, is an oral, covalent, reversible inhibitor specifically designed to preserve primary hemostasis. This review summarizes the molecular basis of BTK and BTKi, and synthesizes the available clinical evidence, with emphasis on the LUNA 2 (phase 1/2) and LUNA 3 (phase 3) trials of rilzabrutinib, which led to its US Food and Drug Administration approval in August 2025 as the first BTKi approved for ITP (Wayrilz), as well as the earlier-stage development of orelabrutinib and other BTKi in this indication.
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BibTeX
@article{gonzalezlopez2026brutons,
title = {{Bruton's tyrosine kinase inhibitors in primary immune thrombocytopenia: pathophysiology and clinical evidence.}},
author = {Tomás José González-López and Rick Kapur},
journal = {Blood vessels, thrombosis \& hemostasis},
year = {2026},
month = sep,
doi = {10.1016/j.bvth.2026.100223},
url = {https://europepmc.org/article/MED/42999879},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Bruton's tyrosine kinase inhibitors in primary immune thrombocytopenia: pathophysiology and clinical evidence.
AU - Tomás José González-López
AU - Rick Kapur
PY - 2026
DA - 2026/09/24
JO - Blood vessels, thrombosis & hemostasis
DO - 10.1016/j.bvth.2026.100223
UR - https://europepmc.org/article/MED/42999879
AB - Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, mediated by both antiplatelet autoantibodies and cell-mediated immune mechanisms, that leads to accelerated peripheral platelet destruction and impaired megakaryopoiesis. Bruton's tyrosine kinase (BTK) is a nonreceptor tyrosine kinase of the Tec family that occupies a central node in 2 pathways of major pathophysiological relevance in ITP: B-cell receptor signaling, required for the maturation and expansion of autoantibody-producing B-cell clones; and Fcγ receptor signaling in splenic and hepatic macrophages, responsible for the phagocytosis of opsonized platelets. BTK inhibitors (BTKi) therefore represent a rational dual-blockade therapeutic strategy: they reduce autoantibody production while simultaneously decreasing macrophage-mediated platelet destruction. Unlike first-generation BTKi developed for B-cell malignancies (ibrutinib, acalabrutinib, zanubrutinib), which irreversibly inhibit the catalytic site and can impair BTK-dependent platelet function (glycoprotein [GP] VI and GPIb-IX-V receptors), the most clinically advanced agent in ITP, rilzabrutinib, is an oral, covalent, reversible inhibitor specifically designed to preserve primary hemostasis. This review summarizes the molecular basis of BTK and BTKi, and synthesizes the available clinical evidence, with emphasis on the LUNA 2 (phase 1/2) and LUNA 3 (phase 3) trials of rilzabrutinib, which led to its US Food and Drug Administration approval in August 2025 as the first BTKi approved for ITP (Wayrilz), as well as the earlier-stage development of orelabrutinib and other BTKi in this indication.
SN - 2950-3272
ER -