The evolutionary landscape of chronic lymphocytic leukemia treated with ibrutinib targeted therapy. Academic Article uri icon

Overview

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.

authors

  • Landau, Dan Avi
  • 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

publication date

  • December 19, 2017

Research

keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Clonal Evolution
  • Gene Expression Regulation, Neoplastic
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Protein-Tyrosine Kinases
  • Pyrazoles
  • Pyrimidines

Identity

PubMed Central ID

  • PMC5736707

Scopus Document Identifier

  • 85038627612

Digital Object Identifier (DOI)

  • 10.1093/nar/gkq636

PubMed ID

  • 29259203

Additional Document Info

volume

  • 8

issue

  • 1