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Chronic Lymphocytic Leukemia
Bendamustine followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia: primary endpoint analysis of a multicenter, open-label, phase II trial (CLL2-BIO)
Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):543-554
Paula Cramer,1 Julia von Tresckow,1 Sandra Robrecht,1 Jasmin Bahlo,1 Moritz Fürstenau,1 Petra Langerbeins,1 Natali Pflug,1 Othman Al-Sawaf,1 Werner J. Heinz,2 Ursula Vehling-Kaiser,3 Jan Dürig,4 Eugen Tausch,5 Manfred Hensel,6 Stephanie Sasse,1 Anna-Maria Fink,1 Kirsten Fischer,1 Karl-Anton Kreuzer,1 Sebastian Böttcher,7, 8 Matthias Ritgen,8 Michael Kneba,8 Clemens-Martin Wendtner,1,9 Stephan Stilgenbauer,5 Barbara Eichhorst1 and Michael Hallek1
1Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Cologne; 2Medical Center, Medical Clinic II, University of Würzburg, Würzburg; 3Tagesklinik Landshut, Landshut; 4Department of Hematology, West German Cancer Center, University Hospital Essen, Essen; 5Department III of Internal Medicine, University Hospital Ulm, Ulm; 6Mannheimer Onkologie Praxis, Mannheim; 7Department III of Internal Medicine, Rostock University Medical Center, Rostock; 8Department of Internal Medicine II, Campus Kiel, University of Schleswig-Holstein, Kiel and 9Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany
ABSTRACT
The introduction of targeted agents has revolutionized the treatment of chronic lymphocytic leukemia but only few patients achieve a complete remission and minimal residual disease negativity with ibrutinib monotherapy. This multicenter, investigator-initiated, phase II study is evaluating 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 popula- tion, 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-naïve and 26 patients (40%) had relapsed/refractory chronic lymphocytic leukemia, 21 patients (32%) had a del(17p) and/or TP53 mutation and 45 patients (69%) had unmutated IGHV status. At the end of the induction, 60 of 65 patients (92%) responded and nine (14%) achieved minimal residual disease negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred. The most common grade 3 or 4 adverse events, according to the Common Toxicity Criteria, were neutropenia, anemia, infusion-related reactions, and diarrhea. This sequential treatment of bendamustine debulking, followed by ofatumum- ab 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.
Introduction
The introduction of targeted agents has led to profound changes in the treatment of chronic lymphocytic leukemia (CLL)1 and the Bruton tyrosine kinase inhibitor ibrutinib has become a preferred treatment option not only in relapsed/refractory and high-risk patients, but also for first-line therapy.2-6 However, only very few patients treated with single-agent ibrutinib achieve a complete remission (CR) and
Correspondence:
PAULA CRAMER
paula.cramer@uk-koeln.de
Received: April 9, 2019. Accepted: February 25, 2020. Pre-published: February 27, 2020.
https://doi.org/10.3324/haematol.2019.223693
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