Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma
Michail S Lionakis, Kieron Dunleavy, Mark Roschewski, Brigitte C Widemann, John A Butman, Roland Schmitz, Yandan Yang, Diane E Cole, Christopher Melani, Christine S Higham, Jigar V Desai, Michele Ceribelli, Lu Chen, Craig J Thomas, Richard F Little, Juan Gea-Banacloche, Sucharita Bhaumik, Maryalice Stetler-Stevenson, Stefania Pittaluga, Elaine S Jaffe, John Heiss, Nicole Lucas, Seth M Steinberg, Louis M Staudt, Wyndham H Wilson, Michail S Lionakis, Kieron Dunleavy, Mark Roschewski, Brigitte C Widemann, John A Butman, Roland Schmitz, Yandan Yang, Diane E Cole, Christopher Melani, Christine S Higham, Jigar V Desai, Michele Ceribelli, Lu Chen, Craig J Thomas, Richard F Little, Juan Gea-Banacloche, Sucharita Bhaumik, Maryalice Stetler-Stevenson, Stefania Pittaluga, Elaine S Jaffe, John Heiss, Nicole Lucas, Seth M Steinberg, Louis M Staudt, Wyndham H Wilson
Abstract
Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.
Keywords: ABC DLBCL; Aspergillus fumigatus; B cell receptor signaling; BTK; ibrutinib; macrophage; primary CNS lymphoma.
Published by Elsevier Inc.
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Source: PubMed