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

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

Author information

1
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
3
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
4
Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
5
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Gaithersburg, MD 20850, USA.
6
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Gaithersburg, MD 20850, USA.
7
Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
8
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: lstaudt@mail.nih.gov.
9
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: wilsonw@mail.nih.gov.

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

PMID:
28552327
PMCID:
PMC5571650
DOI:
10.1016/j.ccell.2017.04.012
[Indexed for MEDLINE]
Free PMC Article

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