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

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

Center for Discovery and Innovation

National Institutes of Health

Research output: Contribution to journal › Article › peer-review

480 Scopus citations

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 language	English
Pages (from-to)	833-843.e5
Journal	Cancer Cell
Volume	31
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2017.04.012
State	Published - 12 Jun 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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10.1016/j.ccell.2017.04.012

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Lionakis, M. S., Dunleavy, K., Roschewski, M., Widemann, B. C., Butman, J. A., Schmitz, R., Yang, Y., Cole, D. E., Melani, C., Higham, C. S., Desai, J. V., Ceribelli, M., Chen, L., Thomas, C. J., Little, R. F., Gea-Banacloche, J., Bhaumik, S., Stetler-Stevenson, M., Pittaluga, S., ... Wilson, W. H. (2017). Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell, 31(6), 833-843.e5. https://doi.org/10.1016/j.ccell.2017.04.012

@article{8965fb5c07bc460daebff70f08e3e6c9,

title = "Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma",

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",

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

note = "Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = jun,

day = "12",

doi = "10.1016/j.ccell.2017.04.012",

language = "English",

volume = "31",

pages = "833--843.e5",

journal = "Cancer Cell",

issn = "1535-6108",

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number = "6",

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Lionakis, MS, Dunleavy, K, Roschewski, M, Widemann, BC, Butman, JA, Schmitz, R, Yang, Y, Cole, DE, Melani, C, Higham, CS, Desai, JV, Ceribelli, M, Chen, L, Thomas, CJ, Little, RF, Gea-Banacloche, J, Bhaumik, S, Stetler-Stevenson, M, Pittaluga, S, Jaffe, ES, Heiss, J, Lucas, N, Steinberg, SM, Staudt, LM & Wilson, WH 2017, 'Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma', Cancer Cell, vol. 31, no. 6, pp. 833-843.e5. https://doi.org/10.1016/j.ccell.2017.04.012

TY - JOUR

T1 - Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma

AU - Lionakis, Michail S.

AU - Dunleavy, Kieron

AU - Roschewski, Mark

AU - Widemann, Brigitte C.

AU - Butman, John A.

AU - Schmitz, Roland

AU - Yang, Yandan

AU - Cole, Diane E.

AU - Melani, Christopher

AU - Higham, Christine S.

AU - Desai, Jigar V.

AU - Ceribelli, Michele

AU - Chen, Lu

AU - Thomas, Craig J.

AU - Little, Richard F.

AU - Gea-Banacloche, Juan

AU - Bhaumik, Sucharita

AU - Stetler-Stevenson, Maryalice

AU - Pittaluga, Stefania

AU - Jaffe, Elaine S.

AU - Heiss, John

AU - Lucas, Nicole

AU - Steinberg, Seth M.

AU - Staudt, Louis M.

AU - Wilson, Wyndham H.

PY - 2017/6/12

Y1 - 2017/6/12

N2 - 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.

AB - 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.

KW - ABC DLBCL

KW - Aspergillus fumigatus

KW - B cell receptor signaling

KW - BTK

KW - ibrutinib

KW - macrophage

KW - primary CNS lymphoma

UR - https://www.scopus.com/pages/publications/85019938452

U2 - 10.1016/j.ccell.2017.04.012

DO - 10.1016/j.ccell.2017.04.012

M3 - Article

C2 - 28552327

AN - SCOPUS:85019938452

SN - 1535-6108

VL - 31

SP - 833-843.e5

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

Abstract

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Keywords

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