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, 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

Abstract

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.

Figures

Figure 1.
Figure 1.
CONSORT diagram. Patients’ flow through the study. pts: patients; AE: adverse event; MRD: minimal residual disease.
Figure 2.
Figure 2.
Improvement of response, time to first minimal residual disease negativity and treatment discontinuation. (A) Change in response with continued treatment. (B) Time to first documentation of minimal residual disease negativity and treatment discontinuation. CR: complete remission; CRi: CR with incomplete recovery of bone marrow; PD: progressive disease; PR: partial response; SD: stable disease; *Clinical CR/CRi is a remission fulfilling all criteria of a CR/CRi according to International Workshop on Chronic Lymphocytic Leukemia criteria except a bone marrow examination and/or computed tomography/ magnetic resonance imaging scan: the lymphocyte count had to be normalized, patients had to be asymptomatic and have no evidence of lymphadenopathy and hepatosplenomegaly in clinical examination and ultrasound or other imaging.
Figure 3.
Figure 3.
Progression-free and overall survival. (A) Progression-free survival. (B) Overall survival. FL: patients treated first-line; RR: relapsed/refractory patients

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