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Chronic lymphocytic leukemia

Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment

Leukemia volume 33, pages 1030–1051 (2019)Cite this article

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The BTK inhibitor ibrutinib is an established therapeutic option for chronic lymphocytic leukemia (CLL) and other mature B cell lymphomas. However, despite its overall impressive efficacy, responses to ibrutinib monotherapy are generally not complete, underscoring the existence of resistance mechanisms [1]. Acquired resistance to ibrutinib has been attributed to recurrent mutations within the BTK and PLCG2 genes [2]. However, mutations do not account for all cases of suboptimal responses to ibrutinib, hence raising the intriguing possibility of ‘functional’ resistance due to, e.g., decreased dependence on proximal B cell receptor (BcR) signaling as it might be occurring in the context of BcR anergy; and ‘bypass’ activation from other non-BcR immune pathways, in particular the Toll-like receptor (TLR) pathway. The latter hypothesis is grounded on the fact that BTK is involved in TLR signaling pathways [3], e.g., mediating synergistic signaling between BcR and TLR9 in B cells, without, however, being essential for TLR9-mediated cytokine induction [4]. Differential TLR expression and functionality profiles have been reported in CLL cases with distinct clinico-biological features [5]. With this in mind, here we investigated the effects of in vivo ibrutinib administration on both BcR and TLR immune signaling capacity in longitudinal samples from CLL patients.

Included in the study were 43 CLL patients diagnosed according to the revised iwCLL/NIH guidelines who received ibrutinib as monotherapy. Clinico-biological data for the studied cohort are given in Supplemental Table 1.

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Acknowledgements

This work was supported in part by the framework of action “IKY Fellowships of excellence for postgraduate studies in Greece - SIEMENS program”; GCH-CLL project funded by ERA-NET TRANSCAN-2 Joint Transnational Call for Proposals 2014 (JTC 2014) and project #179 NOVEL funded by ERA-NET TRANSCAN-2 JTC 2016, by the European Commission/DG Research and Innovation; ODYSSEUS Programme, implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund); AIRC Investigator grants #20246 and #16777, and Special Program AIRC 5 per mille #21198, Associazione Italiana per la Ricerca sul Cancro AIRC, Milano, Italy; Progetti di Rilevante Interesse Nazionale (PRIN) 2015ZMRFEA, MIUR, Roma, Italy. Maria Gounari and Theodoros Moysiadis are recipients of Marie Sklodowska-Curie individual fellowships (Grant Agreement Numbers: 796491 and 702714, respectively), funded by the European Union’s Horizon 2020 research and innovation programme. Kostas Stamatopoulos and Paolo Ghia received urestricted research funding to this project by Janssen Pharmaceuticals.

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Author notes

  1. These authors contributed equally: Maria Gounari, Stavroula Ntoufa

  2. Contributed equally as senior authors: Marta Muzio, Kostas Stamatopoulos, Paolo Ghia

Authors and Affiliations

  1. Institute of Applied Biosciences, CERTH, Thessaloniki, Greece

    Maria Gounari, Stavroula Ntoufa, Marina Gerousi, Theodoros Moysiadis, Konstantia Kotta, Nikos Papakonstantinou, Andreas Agathangelidis, Athanasia Nenou, Aliki Xochelli & Kostas Stamatopoulos

  2. Division of Experimental Oncology, IRCCS Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy

    Maria Gounari, Maria Giovanna Vilia, Lydia Scarfò, Eleonora Fonte, Pamela Ranghetti, Marta Muzio & Paolo Ghia

  3. Divisione di Ematologia dell’Università di Torino, Azienda Ospedaliero Universitaria S. Giovanni Battista di Torino, Torino, Italy

    Marta Coscia

  4. Department of Oncology/Haematology, Niguarda Cancer Center, Niguarda Ca Granda Hospital, Milan, Italy

    Alessandra Tedeschi

  5. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

    Niki Stavroyianni

  6. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    Kostas Stamatopoulos

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  1. Maria Gounari
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Contributions

MG and SN designed the research, performed the study, and wrote the manuscript; MG, MGV, KK, NP, AA, EF, PR, and AN assisted in experiments; TM performed statistical analysis; LS, AX, MC, AT, and NS provided patient samples and clinical information; MM, KS, and PG designed and supervised the research and wrote the manuscript.

Corresponding author

Correspondence to Kostas Stamatopoulos.

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Conflict of interest

KS received honoraria from AbbVie, Gilead Science, Janssen and reseach funding from AbbVie, Gilead, Janssen. PG received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Sunesis and reseach funding from AbbVie, Gilead, Janssen, Novartis. The remaining authors declare that they have no conflict of interest.

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Gounari, M., Ntoufa, S., Gerousi, M. et al. Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment. Leukemia 33, 1030–1051 (2019). https://doi.org/10.1038/s41375-018-0335-2

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