Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial
Abstract
PURPOSE The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies. METHODS The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve 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. RESULTS Ibrutinib significantly delayed progression to symptomatic disease ( P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .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. CONCLUSION 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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (36)
Petra Langerbeins
University Hospital, Cologne, Germany
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Pascal Nieper
Paula Cramer
18Department I of Internal Medicine, Faculty of Medicine and University Hospital of Cologne, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German Chronic Lymphocytic Leukemia Study Group, University of Cologne, Cologne, Germany
Moritz Fürstenau
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Othman Al-Sawaf
Florian Simon
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Anna-Maria Fink
University Hospital of Cologne, Cologne, Germany
Karl-Anton Kreuzer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Ursula Vehling-Kaiser
Day Clinic Hematology Oncology Palliative Care
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Lothar Müller
Studienzentrum UnterEms, Leer, Germany
Michael Josef Eckart
Practice for Oncology and Hematology, Erlangen, Germany
Rudolf Schlag
Practice for Oncology and Hematology, Würzburg, Germany
Werner Freier
Medicinum, Hildesheim, Alabama, Germany
Tobias Gaska
Bruederkrankenhaus Paderborn, Paderborn, Germany
Christina Balser
OnkoNet Marburg GmbH, Marburg, Germany
Marcel Reiser
PIOH, Cologne, Germany
Martina Stauch
Practice for Internal Medicine, Kronach, Germany
Mark-Oliver Zahn
30MVZ Onkologische Kooperation Harz, Goslar, Germany
Steffen Dörfel
Onkozentrum Dresden Freiberg, Leipziger Straße 118, Dresden, Germany
Peter Staib
4Department of Haematology and Oncology, St. Antonius Krankenhaus Eschweiler, Eschweiler, Germany
Timo Behlendorf
Practice for Oncology and Hematology, Niemeyerstraße Halle, Germany
Manfred Hensel
16Mannheimer Onkologie Praxis, Mannheim, Germany
Holger Hebart
2Kliniken Ostalb, Mutlangen, Germany
Holger Klaproth
Practice for Oncology and Hematology, Hebbelstraße 2, Neunkirchen, Germany
Andreas Block
4University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Rüdiger Liersch
5Gemeinschaftspraxis für Hämatologie und Onkologie, Clemenshospital Münster, Münster, Germany
Ulrich Hauch
Practice for Oncology and Hematology, Neuwerkstraße 51, Erfurt, Germany
Bernhard Heinrich
10Hämatologisch-Onkologische Praxis Heinrich/Bangerter, Augsburg, Germany
Clemens-Martin Wendtner
Ludwig-Maximilians University (LMU), Medical Clinic III, Munich, Germany
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Barbara Eichhorst
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Michael Hallek
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany