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

Blood - Tập 135 Số 11 - Trang 791-803 - 2020
Courtney D. DiNardo1, Ing Soo Tiong2,3, Anna Quaglieri4,5, Sarah MacRaild3, Sanam Loghavi6, Fiona C. Brown2, Rachel Thijssen4,5, Giovanna Pomilio2, Adam Ivey3, Jessica M. Salmon2, Christina Glytsou7, Shaun Fleming2,3, Q. Zhang1, Huaxian Ma1, Keyur P. Patel1, Steven M. Kornblau1, Zhen Xu4,5, Chong Chyn Chua2,3, Xufeng Chen7, Piers Blombery8,9,10, Christoffer Flensburg4,5, Nik Cummings3, Iannis Aifantis7, Hagop M. Kantarjian1, David C.S. Huang4,5, Andrew W. Roberts8,4,5, Ian J. Majewski4,5, Marina Konopleva1, Andrew H. Wei2,3
1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
3Department of Haematology, The Alfred Hospital, Melbourne, VIC, Australia
4Department of Medical Biology and
5Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
6Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY;
8Department of Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia
9Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Vic, Australia
10Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; and

Tóm tắt

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.

Từ khóa


Tài liệu tham khảo

Juliusson, 2017, Prevalence and characteristics of survivors from acute myeloid leukemia in Sweden, Leukemia, 31, 728, 10.1038/leu.2016.312

Burnett, 2007, A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment, Cancer, 109, 1114, 10.1002/cncr.22496

Dombret, 2015, International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts, Blood, 126, 291, 10.1182/blood-2015-01-621664

DiNardo, 2019, Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia, Blood, 133, 7, 10.1182/blood-2018-08-868752

Wei, 2019, Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study, J Clin Oncol, 37, 1277, 10.1200/JCO.18.01600

McMahon, 2019, Clonal selection with RAS pathway activation mediates secondary clinical resistance to selective FLT3 inhibition in acute myeloid leukemia, Cancer Discov, 9, 1050, 10.1158/2159-8290.CD-18-1453

Quek, 2018, Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib, Nat Med, 24, 1167, 10.1038/s41591-018-0115-6

Chyla, 2018, Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia, Am J Hematol, 93, E202, 10.1002/ajh.25146

Grimwade, 2010, Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials, Blood, 116, 354, 10.1182/blood-2009-11-254441

Döhner, 2017, Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel, Blood, 129, 424, 10.1182/blood-2016-08-733196

Li, 2011, Loss of the wild-type allele contributes to myeloid expansion and disease aggressiveness in FLT3/ITD knockin mice, Blood, 118, 4935, 10.1182/blood-2011-01-328096

Kharazi, 2011, Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation, Blood, 118, 3613, 10.1182/blood-2010-06-289207

Loizou, 2019, A gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor FOXH1, Cancer Discov, 9, 962, 10.1158/2159-8290.CD-18-1391

Nabinger, 2019, Mutant p53 enhances leukemia-initiating cell self-renewal to promote leukemia development, Leukemia, 33, 1535, 10.1038/s41375-019-0377-0

DiNardo, 2018, Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study, Lancet Oncol, 19, 216, 10.1016/S1470-2045(18)30010-X

Smith, 2017, Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis, Blood, 130, 48, 10.1182/blood-2016-04-711820

Heidel, 2006, Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain, Blood, 107, 293, 10.1182/blood-2005-06-2469

Nechiporuk, 2019, The TP53 apoptotic network is a primary mediator of resistance to BCL2 inhibition in AML cells, Cancer Discov, 9, 910, 10.1158/2159-8290.CD-19-0125

Chen, 2019, Targeting mitochondrial structure sensitizes acute myeloid leukemia to venetoclax treatment, Cancer Discov, 9, 890, 10.1158/2159-8290.CD-19-0117

Prata, 2018, NPM1 mutation is not associated with prolonged complete remission in acute myeloid leukemia patients treated with hypomethylating agents, Haematologica, 103, e455, 10.3324/haematol.2018.189886

Daver, 2013, Effect of NPM1 and FLT3 mutations on the outcomes of elderly patients with acute myeloid leukemia receiving standard chemotherapy, Clin Lymphoma Myeloma Leuk, 13, 435, 10.1016/j.clml.2013.02.021

Kontro, 2017, HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia, Leukemia, 31, 301, 10.1038/leu.2016.222

Thông tin
Thông tin xuất bản

Blood

Tập 135 Số 11

791-803

Thông tin tác giả