Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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Abstract

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

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Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.

Hartmut Döhner, Elihu Estey, David Grimwade … (2017)

The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease.

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Chimeric antigen receptor T cells for sustained remissions in leukemia.

Shannon Maude, Noelle Frey, Pamela Shaw … (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap

Tauno Metsalu, Jaak Vilo (2015)

The Principal Component Analysis (PCA) is a widely used method of reducing the dimensionality of high-dimensional data, often followed by visualizing two of the components on the scatterplot. Although widely used, the method is lacking an easy-to-use web interface that scientists with little programming skills could use to make plots of their own data. The same applies to creating heatmaps: it is possible to add conditional formatting for Excel cells to show colored heatmaps, but for more advanced features such as clustering and experimental annotations, more sophisticated analysis tools have to be used. We present a web tool called ClustVis that aims to have an intuitive user interface. Users can upload data from a simple delimited text file that can be created in a spreadsheet program. It is possible to modify data processing methods and the final appearance of the PCA and heatmap plots by using drop-down menus, text boxes, sliders etc. Appropriate defaults are given to reduce the time needed by the user to specify input parameters. As an output, users can download PCA plot and heatmap in one of the preferred file formats. This web server is freely available at http://biit.cs.ut.ee/clustvis/.

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Author and article information

Contributors

Geoffrey L. Uy: (View ORCID Profile)

Anjali S. Advani: (View ORCID Profile)

Ashkan Emadi: (View ORCID Profile)

Harry P. Erba: (View ORCID Profile)

Matteo Giovanni Carrabba: (View ORCID Profile)

Emmanuel Gyan: (View ORCID Profile)

Christian Récher: (View ORCID Profile)

Bob Löwenberg: (View ORCID Profile)

Roland B. Walter: (View ORCID Profile)

Sergio Rutella: (View ORCID Profile)

Journal

Title: Blood

Publisher: American Society of Hematology

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date Created: February 11 2021

Publication date (Print): February 11 2021

Volume: 137

Issue: 6

Pages: 751-762

Affiliations

[1 ]Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO;

[2 ]Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA;

[3 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC;

[4 ]Division of Hematology and Blood and Marrow Transplantation, University of California San Francisco, San Francisco, CA;

[5 ]Moores Cancer Center, University of California, San Diego, La Jolla, CA;

[6 ]Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;

[7 ]Providence Cancer Institute, Portland, OR;

[8 ]Winship Cancer Institute, Emory University, Atlanta, GA;

[9 ]Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL;

[10 ]Marlene & Stewart Greenebaum Cancer, School of Medicine, University of Maryland, Baltimore, MD;

[11 ]Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;

[12 ]Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Centre, Durham, NC;

[13 ]Division of Hematology and Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN;

[14 ]Division of Hematology/Oncology, Froedtert Hospital, Medical College of Wisconsin, Milwaukee, WI;

[15 ]Medizinische Klinik Und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany;

[16 ]Hematologie Clinique, Institut Paoli-Calmettes, Marseille, France;

[17 ]Hematology and Bone Marrow Transplantation Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele, Milan, Italy;

[18 ]Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology L. and A. Seràgnoli, University of Bologna, Bologna, Italy;

[19 ]Hematology, University Medical Center Groningen, Groningen, The Netherlands;

[20 ]Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands;

[21 ]Universitätsklinikum Carl Gustav Carus an der Technische Universität, Dresden, Germany;

[22 ]Institut Universitaire du Cancer Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, Toulouse, France;

[23 ]Centre Hospitalier Universitaire de Nantes, Nantes, France;

[24 ]Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU) de Tours, Tours, France;

[25 ]Loyola University Medical Center, Maywood, IL;

[26 ]Michigan Medicine Bone Marrow Transplant and Leukemia, C. S. Mott Children’s Hospital, Ann Arbor, MI;

[27 ]NanoString Technologies Inc, Seattle, WA;

[28 ]Notable Labs, Foster City, CA;

[29 ]John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom;

[30 ]MacroGenics Inc, Rockville, MD;

[31 ]Fred Hutchinson Cancer Research Center, Seattle, WA; and

[32 ]Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom

Article

DOI: 10.1182/blood.2020007732

PubMed ID: 32929488

SO-VID: 38f3460e-72e7-4ffd-9662-1b1071b11957

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Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia

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Cancer Immunotherapy

Most cited references 40

Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.

Chimeric antigen receptor T cells for sustained remissions in leukemia.

ClustVis: a web tool for visualizing clustering of multivariate data using Principal Component Analysis and heatmap

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Cited by 104

Most referenced authors 942