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

Cancer Cell. 2017 Jun 12;31(6):833-843.e5. doi: 10.1016/j.ccell.2017.04.012. Epub 2017 May 25.

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.

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Aged, 80 and over
  • Animals
  • Aspergillosis / epidemiology
  • Aspergillosis / immunology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • CD79 Antigens / genetics
  • 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

Substances

  • CD79 Antigens
  • Enzyme Inhibitors
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • PCI 32765
  • Pyrazoles
  • Pyrimidines
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Btk protein, mouse