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

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

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) progresses 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 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca21 mobilization (iCa21), in vitro (r = 0.70; P<.0001). High sIgM levels/ signaling strongly correlated with short TTNT (P<.05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = 20.68; P = .01) or iCa21 (r = 20.71; P = .009). In patients, sIgM-mediated iCa21 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, whereas it was minimal when sIgM expression was low (P<.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 that is able to migrate to tissue and receive proliferative stimuli, which may require targeting by combined approaches.

2473-9529
5494-5504
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
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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, 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 patients with CLL. Blood Advances, 6 (18), 5494-5504. (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) progresses 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 patients with CLL (median follow-up of 66 months) and correlated it with pretreatment sIgM levels and signaling characteristics. Pretreatment sIgM levels correlated with signaling capacity, as measured by intracellular Ca21 mobilization (iCa21), in vitro (r = 0.70; P<.0001). High sIgM levels/ signaling strongly correlated with short TTNT (P<.05), and 36% of patients with CLLhigh vs 8% of patients with CLLlow progressed to require a new treatment. In vitro, capacity of ibrutinib to inhibit sIgM-mediated signaling inversely correlated with pretherapy sIgM levels (r = 20.68; P = .01) or iCa21 (r = 20.71; P = .009). In patients, sIgM-mediated iCa21 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, whereas it was minimal when sIgM expression was low (P<.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 that is 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: 27 September 2022
Additional Information: Funding Information: This work was funded by Blood Cancer UK (grant 18009), the Eyles Cancer Immunology Fellowship, Cancer Research UK (ECRIN-M3 accelerator award C42023/A29370, Southampton Experimental Cancer Medicine Centre grant C24563/A15581, Cancer Research UK Southampton Centre grant C34999/ A18087, program C2750/A23669, and BTERP project C36811/ A29101), and the Czech Science Foundation (20-02566S). Publisher Copyright: © 2022 by The American Society of Hematology.

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

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Date deposited: 22 Jun 2022 16:31
Last modified: 17 Mar 2024 03:47

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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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