{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:21:23Z","timestamp":1793733683535,"version":"4.6.1"},"reference-count":30,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"4","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:sec>\n            <jats:title>PURPOSE<\/jats:title>\n            <jats:p>The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS<\/jats:title>\n            <jats:p>The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-na\u00efve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS<\/jats:title>\n            <jats:p>\n              Ibrutinib significantly delayed progression to symptomatic disease (\n              <jats:italic>P<\/jats:italic>\n              &lt; .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases (\n              <jats:italic>P<\/jats:italic>\n              = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSION<\/jats:title>\n            <jats:p>Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1200\/jco.24.00975","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T20:59:12Z","timestamp":1732741152000},"page":"392-402","update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":20,"title":["Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial"],"prefix":"10.1200","volume":"43","clinical-trial-number":[{"clinical-trial-number":"nct02863718","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6654-0304","authenticated-orcid":true,"given":"Petra","family":"Langerbeins","sequence":"first","affiliation":[{"name":"Department 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"}]},{"given":"Sandra","family":"Robrecht","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0003-0607-3561","authenticated-orcid":true,"given":"Pascal","family":"Nieper","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0003-4046-9922","authenticated-orcid":true,"given":"Paula","family":"Cramer","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0002-6593-0140","authenticated-orcid":true,"given":"Moritz","family":"F\u00fcrstenau","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0001-9895-0570","authenticated-orcid":true,"given":"Othman","family":"Al-Sawaf","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0002-2700-3717","authenticated-orcid":true,"given":"Florian","family":"Simon","sequence":"additional","affiliation":[{"name":"Department 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\/0000-0002-7669-7890","authenticated-orcid":true,"given":"Anna-Maria","family":"Fink","sequence":"additional","affiliation":[{"name":"Department 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"}]},{"given":"Karl-Anton","family":"Kreuzer","sequence":"additional","affiliation":[{"name":"Department 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"}]},{"given":"Ursula","family":"Vehling-Kaiser","sequence":"additional","affiliation":[{"name":"\u00dcBAG MVZ Dr Vehling-Kaiser GmbH, Landshut, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-1226","authenticated-orcid":true,"given":"Eugen","family":"Tausch","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III, Ulm University, 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, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9252-4650","authenticated-orcid":true,"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":"Michael Josef","family":"Eckart","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf","family":"Schlag","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Freier","sequence":"additional","affiliation":[{"name":"Medicinum, Hildesheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Gaska","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Br\u00fcderkrankenhaus, Paderborn, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Balser","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Erlenring 9, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Reiser","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Stauch","sequence":"additional","affiliation":[{"name":"Practice for Internal Medicine, Kronach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark-Oliver","family":"Zahn","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, K\u00f6sliner Stra\u00dfe 14, Goslar, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"D\u00f6rfel","sequence":"additional","affiliation":[{"name":"Onkozentrum Dresden Freiberg, Leipziger Stra\u00dfe 118, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Staib","sequence":"additional","affiliation":[{"name":"St Antonius Hospital Eschweiler, Dechant-Deckers-Stra\u00dfe 8, Eschweiler, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Behlendorf","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Niemeyerstra\u00dfe Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Hensel","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Q5, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4536-9955","authenticated-orcid":true,"given":"Holger","family":"Hebart","sequence":"additional","affiliation":[{"name":"Stauferklinikum Schw\u00e4bisch Gm\u00fcnd, Department for Internal Medicine, Hematology and Oncology, Wetzgauer Stra\u00dfe 85, Mutlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Klaproth","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Hebbelstra\u00dfe 2, Neunkirchen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Block","sequence":"additional","affiliation":[{"name":"Department II of Internal Medicine, University of Hamburg, Martinistra\u00dfe 52, Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00fcdiger","family":"Liersch","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Steinfurter Stra\u00dfe 60b, M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Hauch","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Neuwerkstra\u00dfe 51, Erfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Heinrich","sequence":"additional","affiliation":[{"name":"Practice for Oncology and Hematology, Halderstr. 29, Augsburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens-Martin","family":"Wendtner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Ludwig-Maximilians University (LMU), Munich, 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, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[{"name":"Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Eichhorst","sequence":"additional","affiliation":[{"name":"Department 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":true,"given":"Michael","family":"Hallek","sequence":"additional","affiliation":[{"name":"Department 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"}]}],"member":"233","reference":[{"key":"e_1_3_9_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-214346"},{"key":"e_1_3_9_3_2","first-page":"2109","article-title":"Clinical staging of chronic lymphocytic leukemia","volume":"128","author":"Rai KR","year":"2016","unstructured":"Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 128:2109, 2016","journal-title":"Blood"},{"key":"e_1_3_9_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19810701)48:1<198::AID-CNCR2820480131>3.0.CO;2-V"},{"key":"e_1_3_9_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199805213382104"},{"key":"e_1_3_9_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2900060103"},{"key":"e_1_3_9_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2017.246"},{"key":"e_1_3_9_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0747-7"},{"key":"e_1_3_9_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30029-8"},{"key":"e_1_3_9_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-02-556399"},{"key":"e_1_3_9_11_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-09-806398"},{"key":"e_1_3_9_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021010845"},{"key":"e_1_3_9_13_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014960"},{"key":"e_1_3_9_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc2005943"},{"key":"e_1_3_9_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.29438"},{"key":"e_1_3_9_16_2","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.182006"},{"key":"e_1_3_9_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2007.06801.x"},{"key":"e_1_3_9_18_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.17.5398"},{"key":"e_1_3_9_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2020.06.1024"},{"key":"e_1_3_9_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02113-6"},{"key":"e_1_3_9_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01927-8"},{"key":"e_1_3_9_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021006434"},{"key":"e_1_3_9_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1812836"},{"key":"e_1_3_9_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00144-4"},{"key":"e_1_3_9_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0250-6"},{"key":"e_1_3_9_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-021-00290-z"},{"key":"e_1_3_9_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2021.106520"},{"key":"e_1_3_9_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0602-x"},{"key":"e_1_3_9_29_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01414"},{"key":"e_1_3_9_30_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-123824"},{"key":"e_1_3_9_31_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200012283432602"}],"container-title":["Journal of Clinical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/JCO.24.00975","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T22:59:31Z","timestamp":1738191571000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/JCO.24.00975"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":30,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1200\/JCO.24.00975"],"URL":"https:\/\/doi.org\/10.1200\/jco.24.00975","relation":{},"ISSN":["0732-183X","1527-7755"],"issn-type":[{"value":"0732-183X","type":"print"},{"value":"1527-7755","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]},"assertion":[{"value":"2024-05-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-26","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}