Ibrutinib in early stage CLL: Genetic risk factors and treatment outcome in the GCLLSG CLL12 trial
Abstract
Watch & wait is the standard of care in asymptomatic early-stage chronic lymphocytic leukemia (CLL). The CLL12 trial investigated ibrutinib versus placebo in early-stage patients with intermediate to very high risk of progression, showing improved event-free survival (EFS) but no overall survival (OS) benefit10. Building on these findings, our analysis examined whether a significant 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, 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 asymptomatic early-stage patients with del(17p) or TP53 mutations. Ibrutinib provided no OS benefits in any genetic subgroup. Multivariable analysis revealed ibrutinib treatment as an independent favorable factor for EFS, while U-IGHV, del(17p), POT1, RAS/RAF, and NFKBIE mutations were adverse prognostic factors. The results confirm watch-and-wait as standard of care for early-stage CLL patients, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. EudraCT Number: 2013-003211-22
Article Details
Authors (19)
Armin Riecke
German Military Hospital Ulm, Germany
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Deyan Yordanov Yosifov
German Cancer Research Center (DKFZ) Heidelberg, Germany
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Adam Giza
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
Lothar Müller
Studienzentrum UnterEms, Leer, Germany
Ursula Vehling-Kaiser
Day Clinic Hematology Oncology Palliative Care
Michael J. Eckart
Hämatologie und Onkologie, Nürnberg, Germany
Werner Freier
Medicinum, Hildesheim, Alabama, Germany
Björn Schöttker
32Hämatologisch-Onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany
Tobias Gaska
Bruederkrankenhaus Paderborn, Paderborn, Germany
Marcel Reiser
PIOH, Cologne, Germany
Anna-Maria Fink
University Hospital of Cologne, Cologne, Germany
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Barbara F. Eichhorst
University of Cologne, Cologne, Germany
Michael J Hallek
University of Cologne, Cologne, Germany
Petra Langerbeins
University Hospital, Cologne, Germany
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany