{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T12:27:27Z","timestamp":1793795247746,"version":"4.6.1"},"reference-count":42,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004331","name":"Johnson and Johnson","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004331","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003390","name":"Fritz Thyssen Stiftung","doi-asserted-by":"publisher","award":["10.23.1.012MN"],"award-info":[{"award-number":["10.23.1.012MN"]}],"id":[{"id":"10.13039\/501100003390","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1279"],"award-info":[{"award-number":["CRC1279"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    is a point mutation enabling autonomous B\u2010cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL). It has been associated with shorter time to first treatment and overall survival, but its effects have not been evaluated in phase 3 clinical trials or in patients treated with Bruton tyrosine kinase inhibitors. Here, we analyzed samples from the phase 3 CLL12 study that compared ibrutinib vs. placebo in untreated early\u2010stage CLL patients with intermediate to very high risk of disease progression, while patients with low risk of disease progression were allocated to watch\u2010and\u2010wait (w&amp;w). Four detection methods (targeted next\u2010generation sequencing, Sanger sequencing, multiplex IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    \u2010specific PCR, and flow cytometry) were compared, yielding highly consistent results. Overall, 34\/515 (6.6%) patients had productive\n                    <jats:italic>IGLV3\u201021<\/jats:italic>\n                    rearrangements: 5\/152 (3.3%) in w&amp;w, 15\/181 (8.3%) in placebo, and 14\/182 (7.7%) in the ibrutinib group. Of these, 25 were IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    \u2010positive (3\/5, 12\/15, and 10\/14). IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    was associated with shorter event\u2010free survival (EFS) across all arms: w&amp;w (hazard ratio [HR] 17.03, 95% confidence interval [CI 95%]: 4.99\u201358.13,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001), placebo (HR 2.31, CI 95%: 1.16\u20134.6, P\u2009=\u20090.017), and ibrutinib (HR 2.99, CI 95%: 1.17\u20137.65, P\u2009=\u20090.023). Multivariable analysis identified IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    as an independent prognostic factor for shorter EFS (HR 3.18, CI 95%: 1.73\u20135.83, P\u2009&lt;\u20090.001). Notably, IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    was associated with reduced clinical effectiveness of ibrutinib. Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010flux and cell viability assays using patient\u2010derived BCRs expressed in murine B\u2010cells confirmed reduced ibrutinib efficacy in IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    cases, especially regarding inhibition of antigen\u2010stimulated signaling. In summary, IGLV3\u201021\n                    <jats:sup>R110<\/jats:sup>\n                    is an independent prognostic factor for shorter EFS in early\u2010stage CLL and reduces ibrutinib effectiveness clinically and in vitro.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70385","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T09:43:20Z","timestamp":1781516600000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IGLV3\u201021\n                    <sup>R110<\/sup>\n                    and ibrutinib treatment: Results from the double\u2010blind, randomized, placebo\u2010controlled GCLLSG CLL12 trial in early\u2010stage CLL"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-4398","authenticated-orcid":false,"given":"Deyan Y.","family":"Yosifov","sequence":"first","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"},{"name":"German Cancer Research Center (DKFZ) Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Robrecht","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Giza","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Palash C.","family":"Maity","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research Ulm University Medical Center Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Riecke","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"},{"name":"Internal Medicine, Division of Hematology German Military Hospital Ulm Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Schneider","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"},{"name":"Comprehensive Cancer Center Ulm (CCCU) Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Billy M. C.","family":"Jebaraj","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashmi P.","family":"Dheenadayalan","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Jumaa","sequence":"additional","affiliation":[{"name":"Institute of Immunology Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Young","sequence":"additional","affiliation":[{"name":"Institute of Immunology Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research Ulm University Medical Center Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lothar","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Study Centrum Unter Ems Practice for Oncology and Hematology Leer Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Vehling\u2010Kaiser","sequence":"additional","affiliation":[{"name":"Outpatient Clinic Landshut Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Eckart","sequence":"additional","affiliation":[{"name":"Onkologische Schwerpunktpraxis Erlangen Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Freier","sequence":"additional","affiliation":[{"name":"Medicinum Hildesheim Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Sch\u00f6ttker","sequence":"additional","affiliation":[{"name":"H\u00e4matologisch\u2010onkologische Schwerpunktpraxis W\u00fcrzburg W\u00fcrzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Gaska","sequence":"additional","affiliation":[{"name":"Br\u00fcderkrankenhaus St. Josef Paderborn Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Reiser","sequence":"additional","affiliation":[{"name":"Praxis Internistischer Onkologie und H\u00e4matologie Frechen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna\u2010Maria","family":"Fink","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Fischer","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9990-6918","authenticated-orcid":false,"given":"Barbara","family":"Eichhorst","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Langerbeins","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf Faculty of Medicine and University Hospital Cologne Cologne Germany"},{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Tausch","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"},{"name":"Comprehensive Cancer Center Ulm (CCCU) Ulm University Hospital Ulm Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III Ulm University Hospital Ulm Germany"},{"name":"Comprehensive Cancer 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