Bendamustine, followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia (CLL2-BIO): primary endpoint analysis of a multicenter, open-label phase-II trial
Paula Cramer,
Julia v. Tresckow,
Sandra Robrecht,
Jasmin Bahlo,
Moritz Fürstenau,
Petra Langerbeins,
Natali Pflug,
Othman Al-Sawaf,
Werner J. Heinz,
Ursula Vehling-Kaiser,
Jan Dürig,
Eugen Tausch,
Manfred Hensel,
Stephanie Sasse,
Anna-Maria Fink,
Kirsten Fischer,
Karl-Anton Kreuzer,
Sebastian Böttcher,
Matthias Ritgen,
Michael Kneba,
Clemens-Martin Wendtner,
Stephan Stilgenbauer,
Barbara Eichhorst,
Michael Hallek
Affiliations
Paula Cramer
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Julia v. Tresckow
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Sandra Robrecht
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Jasmin Bahlo
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Moritz Fürstenau
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Petra Langerbeins
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Natali Pflug
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Othman Al-Sawaf
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Werner J. Heinz
University of Würzburg, Medical Center, Medical Clinic II, Würzburg, Germany;
Ursula Vehling-Kaiser
Tagesklinik Landshut, Landshut, Germany;
Jan Dürig
University Hospital Essen, Department for Hematology, West German Cancer Center, Essen, Germany;
Eugen Tausch
Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany;
Manfred Hensel
Mannheimer Onkologie Praxis, Mannheim, Germany;
Stephanie Sasse
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Anna-Maria Fink
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Kirsten Fischer
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Karl-Anton Kreuzer
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Sebastian Böttcher
Department III of Internal Medicine, Rostock University Medical Center, Rostock, Germany;
Matthias Ritgen
Department of Internal Medicine II, Campus Kiel, University of Schleswig-Holstein, Kiel, Germany;
Michael Kneba
Department of Internal Medicine II, Campus Kiel, University of Schleswig-Holstein, Kiel, Germany;
Clemens-Martin Wendtner
Department of Hematology, Oncology, Immunology, Klinikum Schwabing, Munich, Germany
Stephan Stilgenbauer
Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany;
Barbara Eichhorst
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
Michael Hallek
University of Cologne, Dept. of Internal Medic University Hospital of Cologne, Germany;
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumor load, followed by ofatumumab and ibrutinib induction and maintenance treatment. An all-comer population, irrespective of prior treatment, physical fitness and genetic factors was included. The primary endpoint was the investigator assessed overall response rate at the end of induction treatment. Of 66 patients enrolled, one patient with early treatment discontinuation was excluded from the efficacy analysis as predefined by the protocol. Thirty-nine patients (60%) were treatment-naive and 26 patients (40%) had relapsed/refractory CLL, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had an unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and 9 (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias, anaemia, infusion-related reactions, and diarrhoea. This sequential treatment of bendamustine debulking, followed by ofatumumab and ibrutinib was well tolerated without unexpected safety signals and showed a good efficacy with an overall response rate of 92%. Ongoing maintenance treatment aims at deeper responses with minimal residual disease negativity. However, ibrutinib should still be used as a single agent outside clinical trials. Clinicaltrials.gov number: NCT02689141.
