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      Bendamustine followed by ofatumumab and ibrutinib in chronic lymphocytic leukemia: primary endpoint analysis of a multicenter, open-label, phase II trial (CLL2-BIO)

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          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 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-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 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.

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          Most cited references36

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          Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia

          The previous edition of the consensus guidelines of the International Workshop on Chronic Lymphocytic Leukemia (iwCLL), published in 2008, has found broad acceptance by physicians and investigators caring for patients with CLL. Recent advances including the discovery of the genomic landscape of the disease, the development of genetic tests with prognostic relevance, and the detection of minimal residual disease (MRD), coupled with the increased availability of novel targeted agents with impressive efficacy, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. These recommendations include a revised version of the iwCLL response criteria, an update on the use of MRD status for clinical evaluation, and recommendations regarding the assessment and prophylaxis of viral diseases during management of CLL.
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            Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.

            Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and is effective in chronic lymphocytic leukemia (CLL). Resistance to irreversible kinase inhibitors and resistance associated with BTK inhibition have not been characterized. Although only a small proportion of patients have had a relapse during ibrutinib therapy, an understanding of resistance mechanisms is important. We evaluated patients with relapsed disease to identify mutations that may mediate ibrutinib resistance. We performed whole-exome sequencing at baseline and the time of relapse on samples from six patients with acquired resistance to ibrutinib therapy. We then performed functional analysis of identified mutations. In addition, we performed Ion Torrent sequencing for identified resistance mutations on samples from nine patients with prolonged lymphocytosis. We identified a cysteine-to-serine mutation in BTK at the binding site of ibrutinib in five patients and identified three distinct mutations in PLCγ2 in two patients. Functional analysis showed that the C481S mutation of BTK results in a protein that is only reversibly inhibited by ibrutinib. The R665W and L845F mutations in PLCγ2 are both potentially gain-of-function mutations that lead to autonomous B-cell-receptor activity. These mutations were not found in any of the patients with prolonged lymphocytosis who were taking ibrutinib. Resistance to the irreversible BTK inhibitor ibrutinib often involves mutation of a cysteine residue where ibrutinib binding occurs. This finding, combined with two additional mutations in PLCγ2 that are immediately downstream of BTK, underscores the importance of the B-cell-receptor pathway in the mechanism of action of ibrutinib in CLL. (Funded by the National Cancer Institute and others.).
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              Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

              New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                HAEMA
                Haematologica
                Fondazione Ferrata Storti
                0390-6078
                1592-8721
                27 February 2020
                01 February 2021
                : 106
                : 2
                : 543-554
                Affiliations
                [1 ]Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Faculty of Medicine and University Hospital of Cologne, University of Cologne , Cologne
                [2 ]Medical Center, Medical Clinic II, University of Wurzburg , Wurzburg
                [3 ]Tagesklinik Landshut , Landshut
                [4 ]Department of Hematology, West German Cancer Center, University Hospital Essen , Essen
                [5 ]Department III of Internal Medicine, University Hospital Ulm , Ulm
                [6 ]Mannheimer Onkologie Praxis , Mannheim
                [7 ]Department III of Internal Medicine, Rostock University Medical Center , Rostock
                [8 ]Department of Internal Medicine II, Campus Kiel, University of Schleswig-Holstein , Kiel
                [9 ]Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine , Klinikum Schwabing, Munich, Germany
                Author notes

                Disclosures

                PC reports research funding from AbbVie, Acerta, F. Hoffmann-LaRoche, Gilead, GlaxoSmithKline, Janssen-Cilag and Novartis, honoraria for scientific talks from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag and for advisory boards from AbbVie, Acerta, AstraZeneca, Janssen-Cilag and Novartis, as well as travel grants from AbbVie, F. Hoffmann LaRoche, Gilead, Janssen-Cilag and Mundipharma. JvT reports research funding from F. Hoffmann-LaRoche and Janssen-Cilag, honoraria for advisory boards from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, as well as travel grants from Celgene, F. Hoffmann-LaRoche and Janssen-Cilag. JB reports honoraria and travel grants from F. Hoffmann-LaRoche. PL reports research funding from AbbVie, F. Hoffmann-LaRoche and Janssen-Cilag, honoraria from 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 from MSD (Merck Sharp & Dohme) and Pfizer, honoraria for scientific talks from Alexion, Basilea, Gilead, MSD (Merck Sharp & Dohme) and Pfizer, advisory boards from Gilead Science, MSD, Pfizer, travel grants from Alexion, Astellas, Basilea, Gilead Science, MSD and Pfizer (all outside the submitted work). UVK reports honoraria for advisory boards from AbbVie, Amgen, F. Hoffmann-LaRoche, Gilead, Lilly and MSD. JD reports honoraria for scientific talks from F. Hoffmann-LaRoche, Janssen-Cilag, Celgene; advisory boards from AbbVie, Amgen, Bristol-Myers Squibb, Janssen-Cilag, Novartis, Gilead; travel grants from Celgene, F. Hoffmann LaRoche, Gilead, Janssen-Cilag, and Mundipharma. ET reports travel grants from Abbvie, Celgene and Gilead. MHe reports honoraria for advisory boards from AbbVie and F. Hoffmann-LaRoche, and travel grants from AbbVie and F. Hoffmann-LaRoche. AMF reports research grants from Celgene and travel grants from 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 from AbbVie, F. Hoffmann-LaRoche and Mundipharma. SB reports grants and personal fees from AbbVie, F-Hoffmann-LaRoche and Janssen, grants from Celgene and Genentech, and 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 from AbbVie and F. Hoffmann-LaRoche. CMW reports research support, honoraria for consultancy or advisory boards and travel support from 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 from 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 from AbbVie and F. Hoffmann- LaRoche. MHa reports research support and honoraria from Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics and Abbvie. NP, SR and MF report no conflicts of interest.

                Contributions

                PC, JvT, JB, SB, BE and MH were responsible for the conception and design of the study; PC, JvT, SR, JB, MF, PL, NP, OAS, AMF and KF were responsible for the trial management; PC, JvT, MF, PL, NP, OA-S, WH, UV-K, JD, ET, MHe, SS, SB, MR, MK, CMW, SS, BE and MH were responsible for the recruitment and treatment of patients; PC, JvT, SR, JB, MF, PL and NP had access to the raw data; PC, MF, PL and NP performed a central review of all clinical data; ET, KAK, SB, MR, MK and SS performed the laboratory analyses; SR and JB performed the statistical analysis. All authors interpreted the data; PC wrote the first draft of the manuscript and all authors approved the final manuscript.

                Article
                10.3324/haematol.2019.223693
                7849583
                32107341
                7be1d31d-afce-40be-88d8-029fa83b845d
                Copyright© 2021 Ferrata Storti Foundation

                This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

                History
                : 09 April 2019
                : 25 February 2020
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 37, Pages: 12
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