Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial

Author(s): Petra Langerbeins, MD¹;Sandra Robrecht, PhD¹;Pascal Nieper, MD¹;Paula Cramer, MD¹;Moritz Fürstenau, MD¹;Othman Al-Sawaf, MD¹;Florian Simon, MD¹;Anna-Maria Fink, MD¹;Karl-Anton Kreuzer, MD¹;Ursula Vehling-Kaiser, MD²;Eugen Tausch, MD³;Christof Schneider, MD³;Lothar Müller, MD⁴;Michael Josef Eckart, MD⁵;Rudolf Schlag, MD⁶;Werner Freier, MD⁷;Tobias Gaska, MD⁸;Christina Balser, MD⁹;Marcel Reiser, MD¹⁰;Martina Stauch, MD¹¹;Mark-Oliver Zahn, MD¹²;Steffen Dörfel, MD¹³;Peter Staib, MD¹⁴;Timo Behlendorf, MD¹⁵;Manfred Hensel, MD¹⁶;Holger Hebart, MD¹⁷;Holger Klaproth, MD¹⁸;Andreas Block, MD, MBA¹⁹;Rüdiger Liersch, MD²⁰;Ulrich Hauch, MD²¹;Bernhard Heinrich, MD²²;Clemens-Martin Wendtner, MD²³;Kirsten Fischer, MD¹;Stephan Stilgenbauer, MD³;Barbara Eichhorst, MD¹;Michael Hallek, MD¹

Source: https://doi.org/10.1200/JCO.24.00975

Dr. Maen Hussein's Thoughts

Ibrutinib delays disease progression for asymptomatic patients but has no overall survival (OS) benefit; hence, still watch and wait in those patients.

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.

Author Affiliations

¹Department 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;²ÜBAG MVZ Dr Vehling-Kaiser GmbH, Landshut, Germany;³Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany;⁴Study Centrum Unter Ems, Practice for Oncology and Hematology, Leer, Germany;⁵Practice for Oncology and Hematology, Erlangen, Germany;⁶Practice for Oncology and Hematology, Würzburg, Germany;⁷Medicinum, Hildesheim, Germany;⁸Department of Hematology and Oncology, Brüderkrankenhaus, Paderborn, Germany;⁹Practice for Oncology and Hematology, Erlenring 9, Marburg, Germany;¹⁰Practice for Oncology and Hematology, Cologne, Germany;¹¹Practice for Internal Medicine, Kronach, Germany;¹²Practice for Oncology and Hematology, Kösliner Straße 14, Goslar, Germany;¹³Onkozentrum Dresden Freiberg, Leipziger Straße 118, Dresden, Germany;¹⁴St Antonius Hospital Eschweiler, Dechant-Deckers-Straße 8, Eschweiler, Germany;¹⁵Practice for Oncology and Hematology, Niemeyerstraße Halle, Germany;¹⁶Practice for Oncology and Hematology, Q5, Mannheim, Germany;¹⁷Stauferklinikum Schwäbisch Gmünd, Department for Internal Medicine, Hematology and Oncology, Wetzgauer Straße 85, Mutlangen, Germany;¹⁸Practice for Oncology and Hematology, Hebbelstraße 2, Neunkirchen, Germany;¹⁹Department II of Internal Medicine, University of Hamburg, Martinistraße 52, Hamburg, Germany;²⁰Practice for Oncology and Hematology, Steinfurter Straße 60b, Münster, Germany;²¹Practice for Oncology and Hematology, Neuwerkstraße 51, Erfurt, Germany;²²Practice for Oncology and Hematology, Halderstr. 29, Augsburg, Germany;²³Department of Internal Medicine III, Ludwig-Maximilians University (LMU), Munich, Germany

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