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, 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.

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

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30205 Hematology
• Country of publisher: Netherlands
• Confidentiality degree: is not subject to a state or trade secret
• WWW: 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
• Tags: rivok
• Tags: International impact, Reviewed

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 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.