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      Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 37 , 38 , 38 , 1 , 1 , 38 , 39 ,
      Leukemia
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          Abstract

          This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

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          Most cited references25

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          Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.

          BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.
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            Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

            Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.
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              Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox.

              Recombinant immunotoxins are fusion proteins that contain the cytotoxic portion of a protein toxin fused to the Fv portion of an antibody. The Fv binds to an antigen on a target cell and brings the toxin into the cell interior, where it arrests protein synthesis and initiates the apoptotic cascade. Moxetumomab pasudotox, previously called HA22 or CAT-8015, is a recombinant immunotoxin composed of the Fv fragment of an anti-CD22 monoclonal antibody fused to a 38-kDa fragment of Pseudomonas exotoxin A, called PE38. Moxetumomab pasudotox is an improved, more active form of a predecessor recombinant immunotoxin, BL22 (also called CAT-3888), which produced complete remission in relapsed/refractory hairy cell leukemia (HCL), but it had a <20% response rate in chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL), diseases in which the leukemic cells contain much lower numbers of CD22 target sites. Compared with BL22, moxetumomab pasudotox is up to 50-fold more active on lymphoma cell lines and leukemic cells from patients with CLL and HCL. A phase I trial was recently completed in HCL patients, who achieved response rates similar to those obtained with BL22 but without dose-limiting toxicity. In addition to further testing in HCL, moxetumomab pasudotox is being evaluated in phase I trials in patients with CLL, B-cell lymphomas, and childhood ALL. Moreover, protein engineering is being used to increase its activity, decrease nonspecific side effects, and remove B-cell epitopes. ©2011 AACR.
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                Author and article information

                Contributors
                +281-796-1752 , frankgiles@aol.com
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                20 July 2018
                20 July 2018
                2018
                : 32
                : 8
                : 1768-1777
                Affiliations
                [1 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Cancer Institute, , National Institutes of Health, ; Bethesda, MD USA
                [2 ]ISNI 0000 0001 0304 893X, GRID grid.5072.0, The Royal Marsden NHS Foundation Trust, ; London, UK
                [3 ]ISNI 0000 0004 1757 1758, GRID grid.6292.f, Institute of Hematology, , Seràgnoli University of Bologna, ; Bologna, Italy
                [4 ]ISNI 0000 0000 9635 9413, GRID grid.410458.c, Hospital Clinic, ; Barcelona, Spain
                [5 ]ISNI 0000 0001 0288 2594, GRID grid.411430.3, Centre Hospitalier Lyon Sud, ; Pierre-bénite, France
                [6 ]GRID grid.413767.0, Medical University of Lodz, , Copernicus Memorial Hospital, ; Lodz, Poland
                [7 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Johns Hopkins Kimmel Cancer Center, ; Baltimore, MD USA
                [8 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Charité Universitätsmedizin, ; Berlin, Germany
                [9 ]ISNI 0000 0001 0328 4908, GRID grid.5253.1, Universitätsklinikum Heidelberg, ; Heidelberg, Baden-Württemberg Germany
                [10 ]ISNI 0000 0000 8743 1110, GRID grid.418577.8, Clinical Center of Serbia, ; Belgrade, Serbia
                [11 ]GRID grid.17089.37, University of Alberta, ; Edmonton, Alberta Canada
                [12 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Ghent University Hospital, ; Ghent, Belgium
                [13 ]ISNI 0000 0000 9632 6718, GRID grid.19006.3e, David Geffen School of Medicine, , UCLA, ; Los Angeles, CA USA
                [14 ]ISNI 0000 0004 1936 8606, GRID grid.26790.3a, Sylvester Comprehensive Cancer Center, , University of Miami, ; Miami, FL USA
                [15 ]ISNI 0000 0004 0617 8280, GRID grid.416409.e, St. James’s Hospital, ; Dublin, Ireland
                [16 ]ISNI 0000 0004 1757 4641, GRID grid.9024.f, Azienda Ospedaliera Universitaria, , University of Siena, ; Siena, Italy
                [17 ]ISNI 0000 0004 0593 7118, GRID grid.42399.35, Service d’hématologie, , CHU Bordeaux, ; F-33000 Bordeaux, France
                [18 ]Ziekenhuis Netwerk Antwerpe, Antwerp, Belgium
                [19 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, , University of Milan, ; Milan, Italy
                [20 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Northwestern Medicine Feinberg School of Medicine, ; Chicago, IL USA
                [21 ]ISNI 0000 0001 2194 0956, GRID grid.10267.32, Masaryk University, ; Brno, Czech Republic
                [22 ]ISNI 0000 0000 9753 1393, GRID grid.412008.f, Helse Bergen HF Haukeland University Hospital, ; Bergen, Norway
                [23 ]Clinic of Hematology, Ospedale Policlinico San Martino, Genova, Italy
                [24 ]ISNI 0000 0001 0531 3426, GRID grid.11451.30, Department of Hematology and Transplantation, , Medical University of Gdańsk, ; Gdańsk, Poland
                [25 ]Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France
                [26 ]SOL, Clinique Sainte-Anne, Strasbourg, France
                [27 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, MD Anderson Cancer Center, ; Houston, TX USA
                [28 ]ISNI 0000 0001 2177 7052, GRID grid.418080.5, Centre Hospitalier de Versailles, ; INSERM U1173 Le Chesnay, France
                [29 ]ISNI 0000 0001 2323 0229, GRID grid.12832.3a, Université Versailles Saint-Quentin-en-Yvelines, ; Paris Saclay, France
                [30 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, Justus-Liebig University, ; Giessen, Germany
                [31 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, City of Hope National Medical Center, ; Duarte, CA USA
                [32 ]GRID grid.414529.f, Bnai Zion Medical Center, ; Haifa, Israel
                [33 ]L’hôpital Côte de Nacre, Caen Cedex 9, Caen, France
                [34 ]ISNI 0000 0001 2188 8502, GRID grid.266832.b, University of New Mexico, ; Albuquerque, NM USA
                [35 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, University of Turin, ; Turin, Italy
                [36 ]ISNI 0000 0000 8499 1112, GRID grid.413734.6, Weill Cornell Medicine, , The New York Presbyterian Hospital, ; New York, NY USA
                [37 ]GRID grid.418152.b, MedImmune, ; South San Francisco, CA USA
                [38 ]GRID grid.418152.b, MedImmune, ; Gaithersburg, MD USA
                [39 ]Developmental Therapeutics Consortium, Chicago, IL USA
                Author information
                http://orcid.org/0000-0001-8484-2990
                http://orcid.org/0000-0002-8590-0328
                http://orcid.org/0000-0001-9358-9704
                Article
                210
                10.1038/s41375-018-0210-1
                6087717
                30030507
                7a1c8c9d-7d24-440d-89a1-0d29c01f6bca
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 June 2018
                : 8 June 2018
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                © Springer Nature Limited 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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