Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma

Christian Grommes, Alessandro Pastore, Nicolaos Palaskas, Sarah S. Tang, Carl Campos, Derrek Schartz, Paolo Codega, Donna Nichol, Owen Clark, Wan Ying Hsieh, Dan Rohle, Marc Rosenblum, Agnes Viale, Viviane S. Tabar, Cameron W. Brennan, Igor T. Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Antonio Omuro, Elena PentsovaAlissa A. Thomas, Elina Tsyvkin, Ariela Noy, M. Lia Palomba, Paul Hamlin, Craig S. Sauter, Craig Moskowitz, Julia Wolfe, Ahmet Dogan, Minhee Won, Jon Glass, Scott Peak, Enrico C. Lallana, Vaios Hatzoglou, Anne S. Reiner, Philip H. Gutin, Jason T. Huse, Katherine S. Panageas, Thomas G. Graeber, Nikolaus Schultz, Lisa M. DeAngelis, Ingo K. Mellinghoff

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells. Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B -mutant human PCNSLs.

Original languageEnglish (US)
Pages (from-to)1018-1029
Number of pages12
JournalCancer Discovery
Volume7
Issue number9
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

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Lymphoma
Central Nervous System
Sirolimus
Phosphatidylinositol 3-Kinases
B-Cell Antigen Receptors
Clinical Trials, Phase I
Mutation
Lymphoma, Large B-Cell, Diffuse
PCI 32765
Agammaglobulinaemia tyrosine kinase
Toll-Like Receptors
B-Cell Lymphoma
Protein Isoforms
Cell Death
Staining and Labeling
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Oncology

Cite this

Grommes, C., Pastore, A., Palaskas, N., Tang, S. S., Campos, C., Schartz, D., ... Mellinghoff, I. K. (2017). Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Cancer Discovery, 7(9), 1018-1029. https://doi.org/10.1158/2159-8290.CD-17-0613

Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. / Grommes, Christian; Pastore, Alessandro; Palaskas, Nicolaos; Tang, Sarah S.; Campos, Carl; Schartz, Derrek; Codega, Paolo; Nichol, Donna; Clark, Owen; Hsieh, Wan Ying; Rohle, Dan; Rosenblum, Marc; Viale, Agnes; Tabar, Viviane S.; Brennan, Cameron W.; Gavrilovic, Igor T.; Kaley, Thomas J.; Nolan, Craig P.; Omuro, Antonio; Pentsova, Elena; Thomas, Alissa A.; Tsyvkin, Elina; Noy, Ariela; Lia Palomba, M.; Hamlin, Paul; Sauter, Craig S.; Moskowitz, Craig; Wolfe, Julia; Dogan, Ahmet; Won, Minhee; Glass, Jon; Peak, Scott; Lallana, Enrico C.; Hatzoglou, Vaios; Reiner, Anne S.; Gutin, Philip H.; Huse, Jason T.; Panageas, Katherine S.; Graeber, Thomas G.; Schultz, Nikolaus; DeAngelis, Lisa M.; Mellinghoff, Ingo K.

In: Cancer Discovery, Vol. 7, No. 9, 01.09.2017, p. 1018-1029.

Research output: Contribution to journalArticle

Grommes, C, Pastore, A, Palaskas, N, Tang, SS, Campos, C, Schartz, D, Codega, P, Nichol, D, Clark, O, Hsieh, WY, Rohle, D, Rosenblum, M, Viale, A, Tabar, VS, Brennan, CW, Gavrilovic, IT, Kaley, TJ, Nolan, CP, Omuro, A, Pentsova, E, Thomas, AA, Tsyvkin, E, Noy, A, Lia Palomba, M, Hamlin, P, Sauter, CS, Moskowitz, C, Wolfe, J, Dogan, A, Won, M, Glass, J, Peak, S, Lallana, EC, Hatzoglou, V, Reiner, AS, Gutin, PH, Huse, JT, Panageas, KS, Graeber, TG, Schultz, N, DeAngelis, LM & Mellinghoff, IK 2017, 'Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma', Cancer Discovery, vol. 7, no. 9, pp. 1018-1029. https://doi.org/10.1158/2159-8290.CD-17-0613
Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D et al. Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Cancer Discovery. 2017 Sep 1;7(9):1018-1029. https://doi.org/10.1158/2159-8290.CD-17-0613
Grommes, Christian ; Pastore, Alessandro ; Palaskas, Nicolaos ; Tang, Sarah S. ; Campos, Carl ; Schartz, Derrek ; Codega, Paolo ; Nichol, Donna ; Clark, Owen ; Hsieh, Wan Ying ; Rohle, Dan ; Rosenblum, Marc ; Viale, Agnes ; Tabar, Viviane S. ; Brennan, Cameron W. ; Gavrilovic, Igor T. ; Kaley, Thomas J. ; Nolan, Craig P. ; Omuro, Antonio ; Pentsova, Elena ; Thomas, Alissa A. ; Tsyvkin, Elina ; Noy, Ariela ; Lia Palomba, M. ; Hamlin, Paul ; Sauter, Craig S. ; Moskowitz, Craig ; Wolfe, Julia ; Dogan, Ahmet ; Won, Minhee ; Glass, Jon ; Peak, Scott ; Lallana, Enrico C. ; Hatzoglou, Vaios ; Reiner, Anne S. ; Gutin, Philip H. ; Huse, Jason T. ; Panageas, Katherine S. ; Graeber, Thomas G. ; Schultz, Nikolaus ; DeAngelis, Lisa M. ; Mellinghoff, Ingo K. / Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. In: Cancer Discovery. 2017 ; Vol. 7, No. 9. pp. 1018-1029.
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abstract = "Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77{\%}) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells. Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B -mutant human PCNSLs.",
author = "Christian Grommes and Alessandro Pastore and Nicolaos Palaskas and Tang, {Sarah S.} and Carl Campos and Derrek Schartz and Paolo Codega and Donna Nichol and Owen Clark and Hsieh, {Wan Ying} and Dan Rohle and Marc Rosenblum and Agnes Viale and Tabar, {Viviane S.} and Brennan, {Cameron W.} and Gavrilovic, {Igor T.} and Kaley, {Thomas J.} and Nolan, {Craig P.} and Antonio Omuro and Elena Pentsova and Thomas, {Alissa A.} and Elina Tsyvkin and Ariela Noy and {Lia Palomba}, M. and Paul Hamlin and Sauter, {Craig S.} and Craig Moskowitz and Julia Wolfe and Ahmet Dogan and Minhee Won and Jon Glass and Scott Peak and Lallana, {Enrico C.} and Vaios Hatzoglou and Reiner, {Anne S.} and Gutin, {Philip H.} and Huse, {Jason T.} and Panageas, {Katherine S.} and Graeber, {Thomas G.} and Nikolaus Schultz and DeAngelis, {Lisa M.} and Mellinghoff, {Ingo K.}",
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AU - Grommes, Christian

AU - Pastore, Alessandro

AU - Palaskas, Nicolaos

AU - Tang, Sarah S.

AU - Campos, Carl

AU - Schartz, Derrek

AU - Codega, Paolo

AU - Nichol, Donna

AU - Clark, Owen

AU - Hsieh, Wan Ying

AU - Rohle, Dan

AU - Rosenblum, Marc

AU - Viale, Agnes

AU - Tabar, Viviane S.

AU - Brennan, Cameron W.

AU - Gavrilovic, Igor T.

AU - Kaley, Thomas J.

AU - Nolan, Craig P.

AU - Omuro, Antonio

AU - Pentsova, Elena

AU - Thomas, Alissa A.

AU - Tsyvkin, Elina

AU - Noy, Ariela

AU - Lia Palomba, M.

AU - Hamlin, Paul

AU - Sauter, Craig S.

AU - Moskowitz, Craig

AU - Wolfe, Julia

AU - Dogan, Ahmet

AU - Won, Minhee

AU - Glass, Jon

AU - Peak, Scott

AU - Lallana, Enrico C.

AU - Hatzoglou, Vaios

AU - Reiner, Anne S.

AU - Gutin, Philip H.

AU - Huse, Jason T.

AU - Panageas, Katherine S.

AU - Graeber, Thomas G.

AU - Schultz, Nikolaus

AU - DeAngelis, Lisa M.

AU - Mellinghoff, Ingo K.

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