Bendamustine, Followed by Ofatumumab and Ibrutinib in Chronic Lymphocytic Leukaemia (CLL2-BIO): Primary Endpoint Analysis of a Multicentre, Open-Label Phase-II Trial

Background: The introduction of targeted agents has revolutionized the treatment of CLL but only few patients achieve complete remissions and minimal residual disease negativity with ibrutinib monotherapy. Methods: This multicentre, investigator-initiated phase-II study evaluates a sequential treatment with two cycles of bendamustine debulking for patients with a higher tumour 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. Findings: 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 (MRD) negativity (<10-4) in peripheral blood. No unexpected or cumulative toxicities occurred, most common CTC °III/IV adverse events were neutropenias and anaemia during the debulking with bendamustine and neutropenias, infusion-related reactions and diarrhoea during the induction with ofatumumab and ibrutinib. Interpretation: 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 MRD negativity. Clinical Trial Registration: (clinicaltrials.gov number: NCT02689141) Funding Statement: Novartis, GlaxoSmithKline and Janssen. Declaration of Interests: PC reports research funding from AbbVie, Acerta, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis, honoraria for scientific talks by AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag and for advisory boards by AbbVie, Acerta, AstraZeneca, Janssen-Cilag and Novartis, as well as travel grants by AbbVie, F. Hoffmann LaRoche, Gilead, Janssen-Cilag and Mundipharma. JvT reports research funding from F. Hoffmann-LaRoche and Janssen-Cilag, honoraria for advisory boards by AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, as well as travel grants by Celgene, F. Hoffmann-LaRoche and Janssen-Cilag. JB reports honoraria and travel grants by F. Hoffmann-LaRoche. PL reports research funding from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, honoraria Janssen-Cilag and travel grants from F. Hoffmann-LaRoche, Janssen-Cilag and Mundipharma. OA-S reports personal fees from F. Hoffmann-LaRoche, AbbVie and Gilead. WH reports research funding by MSD (Merck Shap & Dohme) and Pfizer, honoraria for scientific talks by Alexion, Basilea, Gilead, MSD (Merck Shap & Dohme) and Pfizer, advisory boards by Gilead Science, MSD, Pfizer, travel grants by Alexion, Astellas, Basilea, Gilead Science, MSD and Pfizer (all outside the submitted work). UVK reports honoraria for advisory boards by AbbVie, Amgen, F. Hoffmann-LaRoche, Gilead, Lilly and MSD. JD reports honoraria for scientific talks by F. Hoffmann-LaRoche, Janssen-Cilag, Celgene; advisory boards by AbbVie, Amgen, Bristol-Myers Squibb, Janssen-Cilag, Novartis, Gilead; travel grants by Celgene, F. Hoffmann LaRoche, Gilead, Janssen-Cilag, and Mundipharma. ET reports travel grants from Abbvie, Celgene and Gilead. MHe reports honoraria for advisory boards by AbbVie and F. Hoffmann-LaRoche, and travel grants AbbVie and by F. Hoffmann-LaRoche. AMF reports research grants by Celgene and travel grants by AbbVie, F. Hoffmann-LaRoche and Mundipharma. KF reports travel grants from F. Hoffmann-LaRoche. KAK reports research support and honoraria for consultancy or advisory boards by AbbVie, F. Hoffmann-LaRoche and Mundipharma. SB reports grants and personal fees from AbbVie, F-Hoffmann-LaRoche and Janssen, grants from Celgene and Genentech, personal fees from Becton Dickinson and Novartis MR reports research funding from AbbVie, Amgen, F. Hoffmann-LaRoche and Gilead. MK reports honoraria for consultancy or advisory boards by AbbVie and F. Hoffmann-LaRoche. CMW reports research support, honoraria for consultancy or advisory boards and travel support by AbbVie, F. Hoffmann-LaRoche, Genentech, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma and Pharmacyclics. SS reports research support, honoraria for consultancy or advisory boards and travel support by AbbVie, Amgen, Celgene, F. Hoffmann-LaRoche, Genentech, Gilead, GlaxoSmithKline, Janssen-Cilag, Mundipharma, Novartis and Pharmacyclics. BE reports research support and honoraria for consultancy or advisory boards by AbbVie and F. Hoffmann-LaRoche. MHa Research support and honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, Abbvie. NP, SR and MF report no conflict of interest. Ethics Approval Statement: All patients provided written informed consent. The study was approved by the health authorities and the institutional review board of each participating site, was registered at clinicaltrials.gov (NCT02689141) and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.