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

• Published in: British journal of haematology Vol. 183; no. 2; pp. 212 - 224
• Main Authors: Palma, Marzia, Krstic, Aleksandra, Peña Perez, Lucia, Berglöf, Anna, Meinke, Stephan, Wang, Qing, Blomberg, K. Emelie M., Kamali‐Moghaddam, Masood, Shen, Qiujin, Jaremko, Georg, Lundin, Jeanette, De Paepe, Ayla, Höglund, Petter, Kimby, Eva, Österborg, Anders, Månsson, Robert, Smith, C. I. Edvard
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2018
• Subjects: Aged; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; CD19 antigen; Cell activation; Cell migration; Chemokines; chronic lymphocytic leukaemia; Chronic lymphocytic leukemia; Down-Regulation - drug effects; Enzyme inhibitors; Female; flow-cytometry; Gene Expression Profiling - methods; Gene Expression Regulation, Leukemic - drug effects; Hematology; Humans; ibrutinib; Inflammation; Inflammation Mediators - metabolism; Inflammatory response; Leukemia; 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; Lymph Nodes - pathology; Lymphatic system; Lymphocyte Activation - drug effects; Lymphocytes B; Male; Medicin och hälsovetenskap; Middle Aged; Patients; Peripheral blood; Protein-tyrosine kinase; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Ribonucleic acid; RNA; RNA sequencing; RNA, Neoplasm - genetics; Signal transduction; Transcription factors; Transcription, Genetic - drug effects; Tumors; RNA sequencing; ibrutinib; chronic lymphocytic leukaemia; chemokines; flow-cytometry
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.15516

Summary 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.