Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma.

Therapeutic Approaches

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.

Authors

Lionakis, Michail S; Dunleavy, Kieron; Roschewski, Mark; Widemann, Brigitte C; Butman, John A; Schmitz, Roland; Yang, Yandan; Cole, Diane E; Melani, Christopher; Higham, Christine S; Desai, Jigar V; Ceribelli, Michele; Chen, Lu; Thomas, Craig; Little, Richard F; Gea-Banacloche, Juan; Bhaumik, Sucharita; Stetler-Stevenson, Maryalice; Pittaluga, Stefania; Jaffe, Elaine S; Heiss, John; Lucas, Nicole; Steinberg, Seth M; Staudt, Louis M; Wilson, Wyndham H;

Keywords

  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, CD79/ genetics
  • Aspergillosis/ epidemiology
  • Aspergillosis/ immunology
  • Brain Neoplasms/ drug therapy
  • Brain Neoplasms/ metabolism
  • Drug Therapy, Combination
  • Enzyme Inhibitors/ adverse effects
  • Enzyme Inhibitors/ pharmacokinetics
  • Enzyme Inhibitors/ therapeutic use
  • Female
  • Gene Knockout Techniques
  • Humans
  • Lymphoma/ drug therapy
  • Lymphoma/ metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Myeloid Differentiation Factor 88/ genetics
  • Protein-Tyrosine Kinases/ antagonists & inhibitors
  • Protein-Tyrosine Kinases/ genetics
  • Protein-Tyrosine Kinases/ immunology
  • Pyrazoles/ adverse effects
  • Pyrazoles/ pharmacokinetics
  • Pyrazoles/ therapeutic use
  • Pyrimidines/ adverse effects
  • Pyrimidines/ pharmacokinetics
  • Pyrimidines/ therapeutic use
  • Receptors, Antigen, B-Cell/ metabolism
  • Signal Transduction/ drug effects

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