Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes

Br J Haematol. 2018 Oct;183(2):212-224. doi: 10.1111/bjh.15516. Epub 2018 Aug 20.

Abstract

In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19+ circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN.

Keywords: RNA sequencing; chemokines; chronic lymphocytic leukaemia; flow-cytometry; ibrutinib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • Down-Regulation / drug effects*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Inflammation Mediators / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / blood
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Lymph Nodes / pathology
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • Pyrazoles / pharmacology*
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • RNA, Neoplasm / genetics
  • Transcription, Genetic / drug effects

Substances

  • Antineoplastic Agents
  • Inflammation Mediators
  • Pyrazoles
  • Pyrimidines
  • RNA, Neoplasm
  • ibrutinib