PMID- 34758069 OWN - NLM STAT- MEDLINE DCOM- 20220307 LR - 20220307 IS - 1528-0020 (Electronic) IS - 0006-4971 (Linking) VI - 139 IP - 2 DP - 2022 Jan 13 TI - The CLL12 trial: ibrutinib vs placebo in treatment-naive, early-stage chronic lymphocytic leukemia. PG - 177-187 LID - 10.1182/blood.2021010845 [doi] AB - Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naive Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of "watch and wait." This trial was registered at www.clinicaltrials.gov as #NCT02863718. CI - (c) 2022 by The American Society of Hematology. FAU - Langerbeins, Petra AU - Langerbeins P AUID- ORCID: 0000-0002-6654-0304 AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Zhang, Can AU - Zhang C AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Robrecht, Sandra AU - Robrecht S AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Cramer, Paula AU - Cramer P AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Furstenau, Moritz AU - Furstenau M AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Al-Sawaf, Othman AU - Al-Sawaf O AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - von Tresckow, Julia AU - von Tresckow J AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. AD - Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. FAU - Fink, Anna-Maria AU - Fink AM AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Kreuzer, Karl-Anton AU - Kreuzer KA AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Vehling-Kaiser, Ursula AU - Vehling-Kaiser U AD - Outpatient Clinic, Landshut, Germany. FAU - Tausch, Eugen AU - Tausch E AD - Department of Internal Medicine III, Ulm University, Ulm, Germany. FAU - Muller, Lothar AU - Muller L AUID- ORCID: 0000-0001-9252-4650 AD - Study Centrum Unter Ems, Practice for Oncology and Hematology, Leer, Germany. FAU - Eckart, Michael Josef AU - Eckart MJ AD - Practice for Oncology and Hematology, Erlangen, Germany. FAU - Schlag, Rudolf AU - Schlag R AD - Practice for Oncology and Hematology, Wurzburg, Germany. FAU - Freier, Werner AU - Freier W AUID- ORCID: 0000-0002-0046-6471 AD - Medicinum, Hildesheim, Germany. FAU - Gaska, Tobias AU - Gaska T AD - Department of Hematology, Bruder Krankenhaus, Paderborn, Germany. FAU - Balser, Christina AU - Balser C AD - Practice for Internal Medicine, Marburg, Germany. FAU - Reiser, Marcel AU - Reiser M AD - Practice for Oncology and Hematology, Cologne, Germany. FAU - Stauch, Martina AU - Stauch M AD - Practice for Internal Medicine, Kronach, Germany; and. FAU - Wendtner, Clemens-Martin AU - Wendtner CM AD - Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany. FAU - Fischer, Kirsten AU - Fischer K AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Stilgenbauer, Stephan AU - Stilgenbauer S AD - Department of Internal Medicine III, Ulm University, Ulm, Germany. FAU - Eichhorst, Barbara AU - Eichhorst B AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. FAU - Hallek, Michael AU - Hallek M AD - Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne and Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. LA - eng SI - ClinicalTrials.gov/NCT02863718 PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 1X70OSD4VX (ibrutinib) RN - JAC85A2161 (Adenine) SB - IM CIN - Blood. 2022 Jan 13;139(2):151-152. PMID: 35024815 MH - Adenine/adverse effects/*analogs & derivatives/therapeutic use MH - Adult MH - Aged MH - Aged, 80 and over MH - Disease Progression MH - Double-Blind Method MH - Female MH - Humans MH - Kaplan-Meier Estimate MH - Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis/*drug therapy/pathology MH - Male MH - Middle Aged MH - Piperidines/adverse effects/*therapeutic use MH - Placebo Effect MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use EDAT- 2021/11/11 06:00 MHDA- 2022/03/08 06:00 CRDT- 2021/11/10 18:04 PHST- 2021/01/15 00:00 [received] PHST- 2021/10/22 00:00 [accepted] PHST- 2021/11/11 06:00 [pubmed] PHST- 2022/03/08 06:00 [medline] PHST- 2021/11/10 18:04 [entrez] AID - S0006-4971(21)01872-3 [pii] AID - 10.1182/blood.2021010845 [doi] PST - ppublish SO - Blood. 2022 Jan 13;139(2):177-187. doi: 10.1182/blood.2021010845.