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

• Published in: Nature communications Vol. 8; no. 1; pp. 2185 - 12
• Main Authors: Landau, Dan A., Sun, Clare, Rosebrock, Daniel, Herman, Sarah E. M., Fein, Joshua, Sivina, Mariela, Underbayev, Chingiz, Liu, Delong, Hoellenriegel, Julia, Ravichandran, Sarangan, Farooqui, Mohammed Z. H., Zhang, Wandi, Cibulskis, Carrie, Zviran, Asaf, Neuberg, Donna S., Livitz, Dimitri, Bozic, Ivana, Leshchiner, Ignaty, Getz, Gad, Burger, Jan A., Wiestner, Adrian, Wu, Catherine J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/182; 631/67/69; Adenine - analogs & derivatives; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer; Cell cycle; Chronic lymphocytic leukemia; Clonal Evolution - drug effects; Clonal Evolution - genetics; Disease Progression; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Energy metabolism; Evolution; Exome Sequencing; Female; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Immunotherapy; Inhibitor drugs; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Longitudinal Studies; Lymphatic leukemia; Lymphocyte receptors; Lymphocytes B; Male; Metabolism; Middle Aged; Molecular Targeted Therapy - methods; multidisciplinary; Mutation; Phospholipase C gamma - genetics; Piperidines; Prognosis; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rituximab - pharmacology; Rituximab - therapeutic use; Science; Science (multidisciplinary); Signal Transduction; Signaling; Targeted cancer therapy; Therapy; Transcription; Treatment Outcome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02329-y

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. In a subset of patients with chronic lymphocytic leukemia (CLL) treated with targeted agents, such as ibrutinib, drug resistant subclones emerge. Here, the authors report on transcriptional changes in CLL patients treated with ibrutinib and identify early clonal shifts associated with evolution of resistant clones.