Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/124861
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML |
Author: | DiNardo, C.D. Tiong, I.S. Quaglieri, A. MacRaild, S. Loghavi, S. Brown, F.C. Thijssen, R. Pomilio, G. Ivey, A. Salmon, J. Glytsou, C. Fleming, S.A. Zhang, Q. Ma, H. Patel, K.P. Kornblau, S.M. Xu, Z. Chua, C.C. Chen, X. Blombery, P. et al. |
Citation: | Blood, 2020; 135(11):791-803 |
Publisher: | American Society of Hematology |
Issue Date: | 2020 |
ISSN: | 0006-4971 1528-0020 |
Statement of Responsibility: | C. D. DiNardo, I. S. Tiong, A. Quaglieri, S. MacRaild, S. Loghavi ... Ing Soo Tiong ... et al. |
Abstract: | 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 (mut), with prolonged molecular remissions prevalent for NPM1mut. Primary and adaptive resistance to venetoclax-based combinations were most commonly characterized by acquisition or enrichment of clones activating signaling pathways such as FLT3 or RAS, or bi-allelically perturbing TP53. Single cell studies highlighted the polyclonal nature of intra-tumoral 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-ITD 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. |
Keywords: | Humans Sulfonamides Antineoplastic Combined Chemotherapy Protocols Prognosis Treatment Outcome Treatment Failure Retreatment Gene Expression Profiling Computational Biology Age Factors Drug Resistance, Neoplasm Mutation Alleles Aged Aged, 80 and over Middle Aged Male Leukemia, Myeloid, Acute Biomarkers, Tumor Bridged Bicyclo Compounds, Heterocyclic Nucleophosmin |
Rights: | © 2020 by The American Society of Hematology |
DOI: | 10.1182/blood.2019003988 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1162809 http://purl.org/au-research/grants/nhmrc/1113133 http://purl.org/au-research/grants/nhmrc/1113577 http://purl.org/au-research/grants/nhmrc/126843 http://purl.org/au-research/grants/nhmrc/1141460 |
Published version: | http://dx.doi.org/10.1182/blood.2019003988 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
Files in This Item:
There are no files associated with this item.
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.