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. JaffeJohn Heiss, Nicole Lucas, Seth M. Steinberg, Louis M. Staudt, Wyndham H. Wilson

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)833-843.e5
JournalCancer cell
Volume31
Issue number6
DOIs
StatePublished - Jun 12 2017

Keywords

  • ABC DLBCL
  • Aspergillus fumigatus
  • B cell receptor signaling
  • BTK
  • ibrutinib
  • macrophage
  • primary CNS lymphoma

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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