1. Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes.
- Author
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Palma M, Krstic A, Peña Perez L, Berglöf A, Meinke S, Wang Q, Blomberg KEM, Kamali-Moghaddam M, Shen Q, Jaremko G, Lundin J, De Paepe A, Höglund P, Kimby E, Österborg A, Månsson R, and Smith CIE
- Subjects
- Adenine analogs & derivatives, Aged, Antineoplastic Agents therapeutic use, B-Lymphocytes drug effects, B-Lymphocytes immunology, Female, Gene Expression Profiling methods, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymph Nodes pathology, Lymphocyte Activation drug effects, Male, Middle Aged, Piperidines, Pyrazoles therapeutic use, Pyrimidines therapeutic use, RNA, Neoplasm genetics, Transcription, Genetic drug effects, Antineoplastic Agents pharmacology, Down-Regulation drug effects, Inflammation Mediators metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Pyrazoles pharmacology, Pyrimidines pharmacology
- 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., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)- Published
- 2018
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