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

Nat Commun. 2017 Dec 19;8(1):2185. doi: 10.1038/s41467-017-02329-y.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Clonal Evolution / drug effects*
  • Clonal Evolution / genetics
  • Disease Progression
  • Down-Regulation
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • 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
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation
  • Phospholipase C gamma / genetics
  • Prognosis
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Rituximab / pharmacology
  • Rituximab / therapeutic use
  • Signal Transduction
  • Treatment Outcome
  • Whole Exome Sequencing

Substances

  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Rituximab
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Phospholipase C gamma