Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
X
X
publication

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


DiNardo, C.D. et al.
Blood (2020)
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, 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.



Authors

DiNardo, C.D., Tiong, I.S., Quaglieri, A., MacRaild, S., Loghavi, S., Brown, F.C., Thijssen, R., Pomilio, G., Ivey, A., Salmon, J.M., Glytsou, C., Fleming, S.A., Zhang, Q., Ma, H., Patel, K.P., Kornblau, S.M., Xu, Z., Chua, C.C., Chen, X., Blombery, P., Flensburg, C., Cummings, N., Aifantis, I., Kantarjian, H., Huang, D.C.S., Roberts, A.W., Majewski, I.J., Konopleva, M., Wei, A.H.



VIEW

publication
Clonal evolution and heterogeneity in advanced systemic mastocytosis revealed by single-cell DNA sequencing
Lim, K.
Blood Advances
publication
Joint profiling of DNA and proteins in single cells to dissect genotype-phenotype associations in leukemia
Demaree, B.
Nature Communications
publication
Single-cell DNA sequencing reveals complex mechanisms of resistance to quizartinib
Peretz, C.A.C
Blood Advances (2021)
publication
Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome
Alyssa L. Kennedy
Nature Communications (2021)