Year: 2020
Type: article
Study design: Clinical Trial
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.
Source: Blood
Authors: Geoffrey L. Uy, Ibrahim Aldoss, Matthew C. Foster, Peter H. Sayre, Matthew J. Wieduwilt, Anjali S. Advani, John E. Godwin, Martha L. Arellano, Kendra L. Sweet, Ashkan Emadi, Farhad Ravandi, Harry P. Erba, Michael Byrne, Laura Michaelis, Max S. Topp, Norbert Vey, Fabio Ciceri, Matteo Giovanni Carrabba, Stefania Paolini, Gerwin A. Huls, Mojca Jongen-Lavrencic, Martin Wermke, Patrice Chevallier, Emmanuel Gyan, Christian Récher, Patrick J. Stiff, Kristen M. Pettit, Bob Löwenberg, Sarah E. Church, Erica Anderson, Jayakumar Vadakekolathu, Marianne Santaguida, Michael P. Rettig, John Muth, Teia Curtis, Erin Fehr, Kuo Guo, Jian Zhao, Ouiam Bakkacha, Kenneth Jacobs, Kathy Tran, Patrick Kaminker, Maya Kostova, Ezio Bonvini, Roland B. Walter, Jan K. Davidson-Moncada, Sergio Rutella, John F. DiPersio
Institutions: Washington University in St. Louis, City Of Hope National Medical Center, City of Hope, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, University of California, San Francisco, University of California San Diego, Moores Cancer Center, Cleveland Clinic, Providence Portland Medical Center, Emory University, Winship Cancer Institute, Moffitt Cancer Center, University of Maryland, Baltimore, University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, The University of Texas MD Anderson Cancer Center, Duke University, Duke Medical Center, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Froedtert Hospital, Medical College of Wisconsin, University of Würzburg, Universitätsklinikum Würzburg, Institut Paoli-Calmettes, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, University of Bologna, University Medical Center Groningen, Erasmus MC, University Hospital Carl Gustav Carus, Technische Universität Dresden, Centre Hospitalier Universitaire de Toulouse, Institut universitaire du cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Universitaire de Tours, Hôpital Bretonneau, Loyola University Medical Center, Michigan Medicine, C. S. Mott Children's Hospital, Nanostring Technologies (United States), Notable Labs (United States), Nottingham Trent University, MacroGenics (United States), Fred Hutch Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3085208365