Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML.

Autor:	DiNardo CD; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Tiong IS; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Quaglieri A; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., MacRaild S; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia., Loghavi S; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX., Brown FC; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Thijssen R; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., Pomilio G; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Ivey A; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia., Salmon JM; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Glytsou C; Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY., Fleming SA; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Zhang Q; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Ma H; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Patel KP; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Kornblau SM; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Xu Z; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., Chua CC; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia., Chen X; Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY., Blombery P; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; and.; Department of Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia., Flensburg C; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., Cummings N; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia., Aifantis I; Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY., Kantarjian H; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Huang DCS; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., Roberts AW; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and.; Department of Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia., Majewski IJ; Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.; Department of Medical Biology and., Konopleva M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX., Wei AH; Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia.; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Mar 12; Vol. 135 (11), pp. 791-803.
DOI:	10.1182/blood.2019003988
Abstrakt:	The BCL-2 inhibitor venetoclax combined with hypomethylating agents or low-dose cytarabine represents an important new therapy for older or unfit patients with acute myeloid leukemia (AML). We analyzed 81 patients receiving these venetoclax-based combinations to identify molecular correlates of durable remission, response followed by relapse (adaptive resistance), or refractory disease (primary resistance). High response rates and durable remissions were typically associated with NPM1 or IDH2 mutations, with prolonged molecular remissions prevalent for NPM1 mutations. Primary and adaptive resistance to venetoclax-based combinations was most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS or biallelically perturbing TP53. Single-cell studies highlighted the polyclonal nature of intratumoral resistance mechanisms in some cases. Among cases that were primary refractory, we identified heterogeneous and sometimes divergent interval changes in leukemic clones within a single cycle of therapy, highlighting the dynamic and rapid occurrence of therapeutic selection in AML. In functional studies, FLT3 internal tandem duplication gain or TP53 loss conferred cross-resistance to both venetoclax and cytotoxic-based therapies. Collectively, we highlight molecular determinants of outcome with clinical relevance to patients with AML receiving venetoclax-based combination therapies. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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