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

doi:10.1016/j.ccell.2017.04.012

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.

Authors

Michail S Lionakis¹, Kieron Dunleavy², Mark Roschewski², Brigitte C Widemann³, John A Butman⁴, Roland Schmitz², Yandan Yang², Diane E Cole³, Christopher Melani², Christine S Higham³, Jigar V Desai², Michele Ceribelli⁵, Lu Chen⁵, Craig J Thomas⁶, Richard F Little⁷, Juan Gea-Banacloche³, Sucharita Bhaumik³, Maryalice Stetler-Stevenson³, Stefania Pittaluga³, Elaine S Jaffe³, John Heiss³, Nicole Lucas², Seth M Steinberg³, Louis M Staudt⁸, Wyndham H Wilson⁹

Affiliations

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.

Published by Elsevier Inc.

MeSH terms

Adenine / analogs & derivatives
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
Piperidines
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
Piperidines
Pyrazoles
Pyrimidines
Receptors, Antigen, B-Cell
ibrutinib
Protein-Tyrosine Kinases
Agammaglobulinaemia Tyrosine Kinase
BTK protein, human
Btk protein, mouse
Adenine

Abstract

MeSH terms

Substances

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