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High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients

High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients
High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients
Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progress more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 CLL patients (median follow-up of 66 months) and correlated it with pre-treatment sIgM levels and signaling characteristics. Pre-treatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r=0.70; p<0.0001). High sIgM levels/signaling strongly correlated with short TTNT (p<0.05), and 36% CLLhigh versus 8% CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pre-therapy sIgM levels (r=-0.68, p=0.01) or iCa2+ (r=-0.71, p=0.009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy, but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, while it was minimal when sIgM expression was low (p<0.05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction, able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.
2473-9529
Chiodin, Giorgia
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Forconi, Francesco
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Henderson, Isla
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Del Rio Fernandez, Luis
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Tracy, Ian
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Parker, Helen
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Strefford, Jonathan
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Forster, Jade
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Potter, Nora
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Sale, Benjamin
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Lanham, Stuart
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Stevenson, Freda
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Martino, Enrica Antonia
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Ondrisova, Laura
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D'Avola, Annalisa
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Bonfiglio, Silvia
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Scarfo, Lydia
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Sutton, Lesley-Ann
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Brake, Oliver
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Mraz, Marek
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Ghia, Paolo
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Drennan, Samantha J.
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Chiodin, Giorgia
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Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Henderson, Isla
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Del Rio Fernandez, Luis
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Tracy, Ian
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Parker, Helen
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Strefford, Jonathan
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Forster, Jade
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Potter, Nora
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Sale, Benjamin
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Lanham, Stuart
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Stevenson, Freda
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Martino, Enrica Antonia
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Ondrisova, Laura
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D'Avola, Annalisa
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Bonfiglio, Silvia
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Scarfo, Lydia
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Sutton, Lesley-Ann
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Brake, Oliver
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Mraz, Marek
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Ghia, Paolo
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Drennan, Samantha J.
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Chiodin, Giorgia, Forconi, Francesco, Henderson, Isla, Del Rio Fernandez, Luis, Tracy, Ian, Parker, Helen, Strefford, Jonathan, Forster, Jade, Potter, Nora, Sale, Benjamin, Lanham, Stuart, Stevenson, Freda, Martino, Enrica Antonia, Ondrisova, Laura, D'Avola, Annalisa, Bonfiglio, Silvia, Scarfo, Lydia, Sutton, Lesley-Ann, Brake, Oliver, Mraz, Marek, Ghia, Paolo and Drennan, Samantha J. (2022) High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in CLL patients. Blood Advances. (doi:10.1182/bloodadvances.2021006659).

Record type: Article

Abstract

Chronic lymphocytic leukemia (CLL) cells have variably low surface IgM (sIgM) levels/signaling capacity, influenced by chronic antigen engagement at tissue sites. Within these low levels, CLL with relatively high sIgM (CLLhigh) progress more rapidly than CLL with low sIgM (CLLlow). During ibrutinib therapy, surviving CLL cells redistribute into the peripheral blood and can recover sIgM expression. Return of CLL cells to tissue may eventually recur, where cells with high sIgM could promote tumor growth. We analyzed time to new treatment (TTNT) following ibrutinib in 70 CLL patients (median follow-up of 66 months) and correlated it with pre-treatment sIgM levels and signaling characteristics. Pre-treatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca2+ mobilization (iCa2+), in vitro (r=0.70; p<0.0001). High sIgM levels/signaling strongly correlated with short TTNT (p<0.05), and 36% CLLhigh versus 8% CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pre-therapy sIgM levels (r=-0.68, p=0.01) or iCa2+ (r=-0.71, p=0.009). In patients, sIgM-mediated iCa2+ and ERK phosphorylation levels were reduced by ibrutinib therapy, but not abolished. The residual signaling capacity downstream of BTK was associated with high expression of sIgM, while it was minimal when sIgM expression was low (p<0.05). These results suggested that high sIgM levels facilitated CLL cell resistance to ibrutinib in patients. The CLL cells, surviving in the periphery with high sIgM expression, include a dangerous fraction, able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.

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Accepted/In Press date: 21 May 2022
Published date: 31 May 2022

Identifiers

Local EPrints ID: 457913
URI: http://eprints.soton.ac.uk/id/eprint/457913
ISSN: 2473-9529
PURE UUID: 81bf6da9-c220-4785-aeac-cfc07235bcc6
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831
ORCID for Ian Tracy: ORCID iD orcid.org/0000-0003-4624-672X
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Jonathan Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Benjamin Sale: ORCID iD orcid.org/0000-0003-3292-1886
ORCID for Stuart Lanham: ORCID iD orcid.org/0000-0002-4516-264X
ORCID for Freda Stevenson: ORCID iD orcid.org/0000-0002-0933-5021

Catalogue record

Date deposited: 22 Jun 2022 16:31
Last modified: 24 Nov 2022 02:44

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Contributors

Author: Giorgia Chiodin
Author: Isla Henderson
Author: Luis Del Rio Fernandez
Author: Ian Tracy ORCID iD
Author: Helen Parker ORCID iD
Author: Jade Forster
Author: Nora Potter
Author: Benjamin Sale ORCID iD
Author: Stuart Lanham ORCID iD
Author: Freda Stevenson ORCID iD
Author: Enrica Antonia Martino
Author: Laura Ondrisova
Author: Annalisa D'Avola
Author: Silvia Bonfiglio
Author: Lydia Scarfo
Author: Lesley-Ann Sutton
Author: Oliver Brake
Author: Marek Mraz
Author: Paolo Ghia
Author: Samantha J. Drennan

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