Ibrutinib for early-stage CLL: genetic risk factors and treatment outcome in the GCLLSG CLL12 trial

Author(s): Armin Riecke1,2; Sandra Robrecht3; Deyan Y. Yosifov1,4; Christof Schneider1; Adam Giza3; Lothar Müller5; Ursula Vehling-Kaiser6; Michael Eckart7; Werner Freier8; Björn Schöttker9; Tobias Gaska10; Marcel Reiser11; Anna-Maria Fink3; Kirsten Fischer3; Barbara Eichhorst3; Michael Hallek3; Petra Langerbeins3; Stephan Stilgenbauer1; Eugen Tausch1;
Source: Blood (2026) 148 (9): 1108–1114.
Original Article
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Patients with high-risk asymptomatic early-stage CLL (del(17p) or mutated TP53) do not derive an EFS benefit from early ibrutinib treatment. Watch-and-wait remains standard for early-stage CLL regardless of genetic subgroup; genetic test findings must not prompt early treatment

ABSTRACT

Watch-and-wait is standard of care in asymptomatic early-stage chronic lymphocytic leukemia (CLL). The CLL12 trial investigated ibrutinib vs placebo for patients with early-stage CLL with intermediate to very high risk of progression, improving event-free survival (EFS) but not overall survival (OS). Building on these findings, our analysis examined whether a 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, unmutated immunoglobulin heavy variable chain (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 patients with asymptomatic early-stage CLL with del(17p) or TP53 mutations. Ibrutinib provided no OS benefits in any genetic subgroup. Multivariable analysis revealed ibrutinib treatment as independent favorable factor for EFS, whereas U-IGHV, del(17p), POT1, RAS/RAF, and NFKBIE mutations were adverse prognostic factors. Results confirm watch-and-wait as standard of care for patients with early-stage CLL, especially in high-risk CLL characterized by del(17p) and/or mutated TP53. This trial was registered at the European Union Drug Regulating Authorities Clinical Trials Database (2013-003211-22).

Author Affiliations

1Division of Chronic Lymphocytic Leukaemia, Department of Internal Medicine III, Ulm University, Ulm, Germany; 2German Military Hospital Ulm, Federal Armed Forces, Ulm, Germany; 3Department 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; 4German Cancer Research Center, Heidelberg, Germany; 5Study Centrum Unter Ems, Practice for Oncology and Hematology, Leer, Germany; 6Outpatient Clinic, Landshut, Germany; 7Practice for Oncology and Hematology, Erlangen, Germany; 8Medicinum, Hildesheim, Germany; 9Practice for Hematology and Oncology, Würzburg, Germany; 10Department of Hematology and Oncology, Brüderkrankenhaus, Paderborn, Germany; 11Practice for Oncology and Hematology, Cologne, Germany;

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