Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/124861
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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
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
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