The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy

Dan A. Landau; Clare Sun; Daniel Rosebrock; Sarah E.M. Herman; Joshua Fein; Mariela Sivina; Chingiz Underbayev; Delong Liu; Julia Hoellenriegel; Sarangan Ravichandran; Mohammed Z.H. Farooqui; Wandi Zhang; Carrie Cibulskis; Asaf Zviran; Donna S. Neuberg; Dimitri Livitz; Ivana Bozic; Ignaty Leshchiner; Gad Getz; Jan A. Burger; Adrian Wiestner; Catherine J. Wu

doi:10.1038/s41467-017-02329-y

The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy

Dan A. Landau, Clare Sun, Daniel Rosebrock, Sarah E.M. Herman, Joshua Fein, Mariela Sivina, Chingiz Underbayev, Delong Liu, Julia Hoellenriegel, Sarangan Ravichandran, Mohammed Z.H. Farooqui, Wandi Zhang, Carrie Cibulskis, Asaf Zviran, Donna S. Neuberg, Dimitri Livitz, Ivana Bozic, Ignaty Leshchiner, Gad Getz, Jan A. BurgerAdrian Wiestner, Catherine J. Wu

Leukemia

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126 Scopus citations

Abstract

Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.

Original language	English (US)
Article number	2185
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02329-y
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Landau, D. A., Sun, C., Rosebrock, D., Herman, S. E. M., Fein, J., Sivina, M., Underbayev, C., Liu, D., Hoellenriegel, J., Ravichandran, S., Farooqui, M. Z. H., Zhang, W., Cibulskis, C., Zviran, A., Neuberg, D. S., Livitz, D., Bozic, I., Leshchiner, I., Getz, G., ... Wu, C. J. (2017). The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Nature communications, 8(1), Article 2185. https://doi.org/10.1038/s41467-017-02329-y

Landau, DA, Sun, C, Rosebrock, D, Herman, SEM, Fein, J, Sivina, M, Underbayev, C, Liu, D, Hoellenriegel, J, Ravichandran, S, Farooqui, MZH, Zhang, W, Cibulskis, C, Zviran, A, Neuberg, DS, Livitz, D, Bozic, I, Leshchiner, I, Getz, G, Burger, JA, Wiestner, A & Wu, CJ 2017, 'The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy', Nature communications, vol. 8, no. 1, 2185. https://doi.org/10.1038/s41467-017-02329-y

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abstract = "Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.",

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AU - Zviran, Asaf

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AU - Livitz, Dimitri

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AU - Burger, Jan A.

AU - Wiestner, Adrian

AU - Wu, Catherine J.

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AB - Treatment of chronic lymphocytic leukemia (CLL) has shifted from chemo-immunotherapy to targeted agents. To define the evolutionary dynamics induced by targeted therapy in CLL, we perform serial exome and transcriptome sequencing for 61 ibrutinib-treated CLLs. Here, we report clonal shifts (change >0.1 in clonal cancer cell fraction, Q < 0.1) in 31% of patients during the first year of therapy, associated with adverse outcome. We also observe transcriptional downregulation of pathways mediating energy metabolism, cell cycle, and B cell receptor signaling. Known and previously undescribed mutations in BTK and PLCG2, or uncommonly, other candidate alterations are present in seventeen subjects at the time of progression. Thus, the frequently observed clonal shifts during the early treatment period and its potential association with adverse outcome may reflect greater evolutionary capacity, heralding the emergence of drug-resistant clones.

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The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy

Abstract

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