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

J 2022

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

CHIODIN, Giorgia, Samantha DRENNAN, Enrica A MARTINO, Laura ONDRIŠOVÁ, Isla HENDERSON et. al.

Basic information

Original name

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

Authors

CHIODIN, Giorgia, Samantha DRENNAN, Enrica A MARTINO, Laura ONDRIŠOVÁ (703 Slovakia, belonging to the institution), Isla HENDERSON, del Rio LUIS, Ian TRACY, Annalisa D'AVOLA, Helen PARKER, Silvia BONFIGLIO, Lydia SCARF, Lesley-Ann SUTTON, Jonathan C STREFFORD, Jade FORSTER, Oliver BRAKE, Kathleen N POTTER, Benjamin SALE, Stuart LANHAM, Marek MRÁZ (203 Czech Republic, guarantor, belonging to the institution), Paolo GHIA, Freda K STEVENSON and Francesco FORCONI

Edition

BLOOD ADVANCES, WASHINGTON, AMER SOC HEMATOLOGY, 2022, 2473-9529

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30205 Hematology

Country of publisher

Netherlands

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.500

RIV identification code

RIV/00216224:14740/22:00127431

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1182/bloodadvances.2021006659

UT WoS

000874686400027

Keywords in English

CHRONIC LYMPHOCYTIC-LEUKEMIAB-CELL RECEPTORCD38 EXPRESSIONRESISTANCEACTIVATIONPCI-32765IMMUNOGLOBULININHIBITIONMUTATIONSPATHWAYS

Abstract

V originále

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 Ca2+ mobilization (iCa2+), 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 = -0.68; P = .01) or iCa2+ (r = -0.71; P = .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, 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.

Citovat

CHIODIN, Giorgia, Samantha DRENNAN, Enrica A MARTINO, Laura ONDRIŠOVÁ, Isla HENDERSON, del Rio LUIS, Ian TRACY, Annalisa D'AVOLA, Helen PARKER, Silvia BONFIGLIO, Lydia SCARF, Lesley-Ann SUTTON, Jonathan C STREFFORD, Jade FORSTER, Oliver BRAKE, Kathleen N POTTER, Benjamin SALE, Stuart LANHAM, Marek MRÁZ, Paolo GHIA, Freda K STEVENSON and Francesco FORCONI. High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. BLOOD ADVANCES. WASHINGTON: AMER SOC HEMATOLOGY, 2022, vol. 6, No 18, p. 5494-5504. ISSN 2473-9529. Available from: https://dx.doi.org/10.1182/bloodadvances.2021006659.

@article{2239433,
   author = {Chiodin, Giorgia and Drennan, Samantha and Martino, Enrica A and Ondrišová, Laura and Henderson, Isla and Luis, del Rio and Tracy, Ian and D'Avola, Annalisa and Parker, Helen and Bonfiglio, Silvia and Scarf, Lydia and Sutton, LesleyandAnn and Strefford, Jonathan C and Forster, Jade and Brake, Oliver and Potter, Kathleen N and Sale, Benjamin and Lanham, Stuart and Mráz, Marek and Ghia, Paolo and Stevenson, Freda K and Forconi, Francesco},
   article_location = {WASHINGTON},
   article_number = {18},
   doi = {http://dx.doi.org/10.1182/bloodadvances.2021006659},
   keywords = {CHRONIC LYMPHOCYTIC-LEUKEMIAB-CELL RECEPTORCD38 EXPRESSIONRESISTANCEACTIVATIONPCI-32765IMMUNOGLOBULININHIBITIONMUTATIONSPATHWAYS},
   language = {eng},
   issn = {2473-9529},
   journal = {BLOOD ADVANCES},
   title = {High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL},
   url = {https://ashpublications.org/bloodadvances/article/6/18/5494/485430/High-surface-IgM-levels-associate-with-shorter},
   volume = {6},
   year = {2022}
}

TY  - JOUR
ID  - 2239433
AU  - Chiodin, Giorgia - Drennan, Samantha - Martino, Enrica A - Ondrišová, Laura - Henderson, Isla - Luis, del Rio - Tracy, Ian - D'Avola, Annalisa - Parker, Helen - Bonfiglio, Silvia - Scarf, Lydia - Sutton, Lesley-Ann - Strefford, Jonathan C - Forster, Jade - Brake, Oliver - Potter, Kathleen N - Sale, Benjamin - Lanham, Stuart - Mráz, Marek - Ghia, Paolo - Stevenson, Freda K - Forconi, Francesco
PY  - 2022
TI  - High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL
JF  - BLOOD ADVANCES
VL  - 6
IS  - 18
SP  - 5494-5504
EP  - 5494-5504
PB  - AMER SOC HEMATOLOGY
SN  - 24739529
KW  - CHRONIC LYMPHOCYTIC-LEUKEMIAB-CELL RECEPTORCD38 EXPRESSIONRESISTANCEACTIVATIONPCI-32765IMMUNOGLOBULININHIBITIONMUTATIONSPATHWAYS
UR  - https://ashpublications.org/bloodadvances/article/6/18/5494/485430/High-surface-IgM-levels-associate-with-shorter
N2  - 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 Ca2+ mobilization (iCa2+), 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 = -0.68; P = .01) or iCa2+ (r = -0.71; P = .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, 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.
ER  -

CHIODIN, Giorgia, Samantha DRENNAN, Enrica A MARTINO, Laura ONDRIŠOVÁ, Isla HENDERSON, del Rio LUIS, Ian TRACY, Annalisa D'AVOLA, Helen PARKER, Silvia BONFIGLIO, Lydia SCARF, Lesley-Ann SUTTON, Jonathan C STREFFORD, Jade FORSTER, Oliver BRAKE, Kathleen N POTTER, Benjamin SALE, Stuart LANHAM, Marek MRÁZ, Paolo GHIA, Freda K STEVENSON and Francesco FORCONI. High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. \textit{BLOOD ADVANCES}. WASHINGTON: AMER SOC HEMATOLOGY, 2022, vol.~6, No~18, p.~5494-5504. ISSN~2473-9529. Available from: https://dx.doi.org/10.1182/bloodadvances.2021006659.

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