Pevonedistat with azacitidine in older patients with TP53-mutated AML: a phase 2 study with laboratory correlates

• Type of Material: Article
• Authors: Antoine N Saliba, Mayo Clinic; Scott H Kaufmann, Mayo Clinic; Eytan M Stein, Memorial Sloan-Kettering Cancer Center; Ptapti A Patel, UT Southwestern Medical School; Maria R Baer, University of Maryland Marlene and Stewart Greenebaum Cancer Center; Wendy Stock, Section of Hematology Oncology, The University of Chicago; Michael Deininger, University of Utah School of Medicine; William Blum, Emory University; Gary J Schiller, David Geffen School of Medicine at UCLA; Rebecca L Olin, University of California, San Francisco; Mark R Litzow, Mayo Clinic; Tara L Lin, University of Kansas Medical Center; Brian J Ball, City of Hope National Med Center; Michael M Boyiadzis, University of Pittsburgh; Elie Traer, Oregon Health & Science University; Olatoyosi Odenike, University of Chicago; Martha Arellano, Emory University; Alison Walker, The Ohio State University; Vu H Duong, University of Maryland Marlene and Stewart Greenebaum Cancer Center; Tibor Kovacsovics, University of Utah School of Medicine; Robbert H Collins, UT Southwestern Medical School; Abigail B Shoben, The Ohio State University; Nyla A Heerema, The Ohio State University; Matthew C Foster, The University of North Carolina at Chapel Hill; Kevin L Peterson, Mayo Clinic; Paula A Schneider, Mayo Clinic; Molly Martycz, The Ohio State University; Theophilus J Gana, Biopharmatech Consulting, Inc; Leonard Rosenberg, Sociedad de Lucha Contra la Leucemia y el Linfoma; Sonja Marcus, Sociedad de Lucha Contra la Leucemia y el Linfoma; Ashley O Yocum, Sociedad de Lucha Contra la Leucemia y el Linfoma; Timothy Chen, The Ohio State University; Mona Stefanos, The Ohio State University; Alice S Mims, The Ohio State University; Uma Borate, The Ohio State University; Amy Burd, Sociedad de Lucha Contra la Leucemia y el Linfoma; Brian J Druker, Oregon Health & Science University; Ross L Levine, Memorial Sloan-Kettering Cancer Center; John C Byrd, University of Cincinnati; James M Foran, Mayo Clinic in Jacksonville, Florida
• Language: English
• Date: 2023-06-13
• Publisher: The American Society of Hematology
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by The American Society of Hematology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2022008625
• Title of Journal or Parent Work: Blood Advances
• Volume: 7
• Issue: 11
• Start Page: 2360
• End Page: 2363
• Keywords: Leukemia, Myeloid, Acute; Tumor Suppressor Protein p53; Humans; Cyclopentanes; Pyrimidines; Aged; Azacitidine

Abstract

Finding safe and effective treatment strategies for patients with TP53-mutated acute myeloid leukemia (AML) remains an important unmet need.1,2 Among all somatic mutations found in AML, TP53 mutations are associated with intrinsic resistance to cytotoxic therapy, shorter overall survival (OS), and inferior outcomes with allogeneic hematopoietic cell transplantation.3, 4, 5, 6 The NEDD8-activating enzyme inhibitor pevonedistat (PEVO) has been shown to induce apoptosis in AML via increased reactive oxygen species7 as well as accumulation of the oncoprotein MYC and transactivation of the gene encoding the BH3-only protein NOXA in AML cell lines and primary AML samples.8 Additional studies have demonstrated that PEVO enhances the cytotoxicity of hypomethylating agents in preclinical AML models.9 Consistent with these observations, a phase 1b study of PEVO with azacitidine (AZA) demonstrated a composite complete remission (CCR) rate of 30%, with an additional 11% partial remission rate. Responses occurred irrespective of poor-risk disease features and were observed in 6 of 8 patients with TP53-mutated AML.10 Here, we report the results of a phase 2 study of PEVO + AZA in older patients with previously untreated TP53-mutated AML that builds on the previous results. This was a substudy of the Beat AML “umbrella” Master trial (www.clinicaltrials.gov, #NCT03013998) evaluating targeted therapies using prospective genomic profiling of previously untreated older patients with AML.11