PMID- 35640238 OWN - NLM STAT- MEDLINE DCOM- 20220928 LR - 20240210 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 6 IP - 18 DP - 2022 Sep 27 TI - High surface IgM levels associate with shorter response to ibrutinib and BTK bypass in patients with CLL. PG - 5494-5504 LID - 10.1182/bloodadvances.2021006659 [doi] AB - 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. CI - (c) 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Chiodin, Giorgia AU - Chiodin G AUID- ORCID: 0000-0002-1456-8997 AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Drennan, Samantha AU - Drennan S AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. AD - T-Cypher Bio, Oxford, United Kingdom. FAU - Martino, Enrica A AU - Martino EA AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. AD - Department of Haematology, Azienda Ospedaliera di Cosenza, Cosenza, Italy. FAU - Ondrisova, Laura AU - Ondrisova L AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. AD - Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic. AD - Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic. FAU - Henderson, Isla AU - Henderson I AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Del Rio, Luis AU - Del Rio L AUID- ORCID: 0000-0002-5926-9448 AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Tracy, Ian AU - Tracy I AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - D'Avola, Annalisa AU - D'Avola A AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. AD - The Francis Crick Institute, London, United Kingdom. FAU - Parker, Helen AU - Parker H AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Bonfiglio, Silvia AU - Bonfiglio S AD - Strategic Research Program on CLL and B-cell Neoplasia Unit, Experimental Oncology, Universita Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy. FAU - Scarfo, Lydia AU - Scarfo L AUID- ORCID: 0000-0002-0844-0989 AD - Strategic Research Program on CLL and B-cell Neoplasia Unit, Experimental Oncology, Universita Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy. FAU - Sutton, Lesley-Ann AU - Sutton LA AD - Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; and. FAU - Strefford, Jonathan C AU - Strefford JC AUID- ORCID: 0000-0002-0972-2881 AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Forster, Jade AU - Forster J AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Brake, Oliver AU - Brake O AD - Haematology Department, Cancer Care Directorate, University Hospital Southampton NHS Trust, Southampton, United Kingdom. FAU - Potter, Kathleen N AU - Potter KN AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Sale, Benjamin AU - Sale B AUID- ORCID: 0000-0003-3292-1886 AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Lanham, Stuart AU - Lanham S AUID- ORCID: 0000-0002-4516-264X AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Mraz, Marek AU - Mraz M AUID- ORCID: 0000-0001-6975-8838 AD - Molecular Medicine, CEITEC Masaryk University, Brno, Czech Republic. AD - Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic. FAU - Ghia, Paolo AU - Ghia P AUID- ORCID: 0000-0003-3750-7342 AD - Strategic Research Program on CLL and B-cell Neoplasia Unit, Experimental Oncology, Universita Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy. FAU - Stevenson, Freda K AU - Stevenson FK AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. FAU - Forconi, Francesco AU - Forconi F AUID- ORCID: 0000-0002-2211-1831 AD - School of Cancer Sciences, Cancer Research UK and NIHR Experimental Cancer Medicine Centres, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. AD - Haematology Department, Cancer Care Directorate, University Hospital Southampton NHS Trust, Southampton, United Kingdom. LA - eng GR - 29370/CRUK_/Cancer Research UK/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Immunoglobulin M) RN - 0 (Piperidines) RN - 1X70OSD4VX (ibrutinib) RN - JAC85A2161 (Adenine) RN - SY7Q814VUP (Calcium) SB - IM MH - Adenine/analogs & derivatives MH - Calcium MH - Humans MH - Immunoglobulin M MH - *Leukemia, Lymphocytic, Chronic, B-Cell/metabolism MH - Piperidines PMC - PMC9631698 EDAT- 2022/06/01 06:00 MHDA- 2022/09/28 06:00 PMCR- 2022/09/26 CRDT- 2022/05/31 17:13 PHST- 2021/11/23 00:00 [received] PHST- 2022/05/21 00:00 [accepted] PHST- 2022/06/01 06:00 [pubmed] PHST- 2022/09/28 06:00 [medline] PHST- 2022/05/31 17:13 [entrez] PHST- 2022/09/26 00:00 [pmc-release] AID - 485430 [pii] AID - 2022/ADV2021006659 [pii] AID - 10.1182/bloodadvances.2021006659 [doi] PST - ppublish SO - Blood Adv. 2022 Sep 27;6(18):5494-5504. doi: 10.1182/bloodadvances.2021006659.