{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:20:07Z","timestamp":1787883607244,"version":"build-2784847793"},"reference-count":20,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Watch-and-wait is standard of care in asymptomatic early-stage chronic lymphocytic leukemia (CLL). The CLL12 trial investigated ibrutinib vs placebo for patients with early-stage CLL with intermediate to very high risk of progression, improving event-free survival (EFS) but not overall survival (OS). Building on these findings, our analysis examined whether a benefit could be identified within distinct genetic subgroups. After a median follow-up of 69.3 months, there were 166 EFS and 32 OS events in 515 trial patients. In the placebo arm, del(17p), del(11q), +12, unmutated immunoglobulin heavy variable chain (U-IGHV), and mutations in NOTCH1, ATM, NRAS\/KRAS\/BRAF, and NFKBIE correlated with shorter EFS. With ibrutinib, only del(17p) and TP53 and NFKBIE mutations significantly compromised EFS. Ibrutinib offered substantial EFS benefit in subgroups with U-IGHV, del(11q), +12, NOTCH1, ATM, and NFKBIE mutations. No EFS improvement was seen for patients with asymptomatic early-stage CLL with del(17p) or TP53 mutations. Ibrutinib provided no OS benefits in any genetic subgroup. Multivariable analysis revealed ibrutinib treatment as independent favorable factor for EFS, whereas U-IGHV, del(17p), POT1, RAS\/RAF, and NFKBIE mutations were adverse prognostic factors. Results confirm watch-and-wait as standard of care for patients with early-stage CLL, especially in high-risk CLL characterized by del(17p) and\/or mutated TP53. This trial was registered at the European Union Drug Regulating Authorities Clinical Trials Database (2013-003211-22).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025032806","type":"journal-article","created":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T07:55:23Z","timestamp":1781942123000},"page":"1108-1114","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Ibrutinib for early-stage CLL: genetic risk factors and treatment outcome in the GCLLSG CLL12 trial"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-5827-5506","authenticated-orcid":false,"given":"Armin","family":"Riecke","sequence":"first","affiliation":[{"name":"1Division of Chronic Lymphocytic Leukaemia, Department of Internal Medicine III, Ulm University, Ulm, Germany"},{"name":"2German Military Hospital Ulm, Federal Armed Forces, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8848-6655","authenticated-orcid":false,"given":"Sandra","family":"Robrecht","sequence":"additional","affiliation":[{"name":"3Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-4398","authenticated-orcid":false,"given":"Deyan Y.","family":"Yosifov","sequence":"additional","affiliation":[{"name":"1Division of Chronic Lymphocytic Leukaemia, Department of Internal Medicine III, Ulm University, Ulm, Germany"},{"name":"4German Cancer Research Center, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Schneider","sequence":"additional","affiliation":[{"name":"1Division of Chronic Lymphocytic Leukaemia, Department of Internal Medicine III, Ulm University, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Giza","sequence":"additional","affiliation":[{"name":"3Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-4650","authenticated-orcid":false,"given":"Lothar","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"5Study Centrum Unter Ems, Practice for Oncology and Hematology, Leer, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Vehling-Kaiser","sequence":"additional","affiliation":[{"name":"6Outpatient Clinic, Landshut, 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Eichhorst","sequence":"additional","affiliation":[{"name":"3Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7425-4455","authenticated-orcid":false,"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[{"name":"3Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 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