Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy

Vasiliki Symeonidou; Marlen Metzner; Batchimeg Usukhbayar; Aimee E. Jackson; Sonia Fox; Charles F. Craddock; Paresh Vyas

doi:10.1002/jha2.527

Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy

Vasiliki Symeonidou, Marlen Metzner, Batchimeg Usukhbayar, Aimee E. Jackson, Sonia Fox, Charles F. Craddock, Paresh Vyas^*

^*Corresponding author for this work

Cancer Clinical Trials Unit

Research output: Contribution to journal › Article › peer-review

Abstract

Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.

Original language	English
Pages (from-to)	794-803
Number of pages	10
Journal	EJHaem
Volume	3
Issue number	3
DOIs	https://doi.org/10.1002/jha2.527
Publication status	Published - 29 Aug 2022

Bibliographical note

Acknowledgments:
We would like to acknowledge Celgene who provided free of charge azacitidine. Additionally, we are grateful to the patients and their families for participating in the RAvVA trial. The original RAvVA trial was funded by Blood Cancer UK grant code 11031 as part of the Trials Acceleration Programme (TAP). CC was supported by the Birmingham Cancer Research UK Experimental Cancer Medicine Centre and by the Cancer Research UK Clinical Trials Unit core funding (C22436/A15958). PV is supported by MRC Molecular Haematology Unit (MC_UU_12009/11), NIHR the Hematology Theme of the Oxford Biomedical Research Centre, Blood Cancer Specialist Program Grant 13001 and Celgene. Funding for this study was received from Celgene.

Copyright:
© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

Keywords

acute myeloid leukaemia
azacitidine
clonal evolution
hypomethylating agents
immune microenvironment

Access to Document

10.1002/jha2.527Licence: Creative Commons: Attribution (CC BY)

SymeonidouV2022HeterogeneousFinal published version, 1.95 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

@article{fd4148d8bd7141878cb3986793d5bacf,

title = "Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy",

abstract = "Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of na{\"i}ve helper T cells in non-responders.",

keywords = "acute myeloid leukaemia, azacitidine, clonal evolution, hypomethylating agents, immune microenvironment",

author = "Vasiliki Symeonidou and Marlen Metzner and Batchimeg Usukhbayar and Jackson, {Aimee E.} and Sonia Fox and Craddock, {Charles F.} and Paresh Vyas",

note = "Acknowledgments: We would like to acknowledge Celgene who provided free of charge azacitidine. Additionally, we are grateful to the patients and their families for participating in the RAvVA trial. The original RAvVA trial was funded by Blood Cancer UK grant code 11031 as part of the Trials Acceleration Programme (TAP). CC was supported by the Birmingham Cancer Research UK Experimental Cancer Medicine Centre and by the Cancer Research UK Clinical Trials Unit core funding (C22436/A15958). PV is supported by MRC Molecular Haematology Unit (MC_UU_12009/11), NIHR the Hematology Theme of the Oxford Biomedical Research Centre, Blood Cancer Specialist Program Grant 13001 and Celgene. Funding for this study was received from Celgene. Copyright: {\textcopyright} 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.",

year = "2022",

month = aug,

day = "29",

doi = "10.1002/jha2.527",

language = "English",

volume = "3",

pages = "794--803",

journal = "EJHaem",

issn = "2688-6146",

publisher = "Wiley",

number = "3",

}

TY - JOUR

T1 - Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy

AU - Symeonidou, Vasiliki

AU - Metzner, Marlen

AU - Usukhbayar, Batchimeg

AU - Jackson, Aimee E.

AU - Fox, Sonia

AU - Craddock, Charles F.

AU - Vyas, Paresh

N1 - Acknowledgments: We would like to acknowledge Celgene who provided free of charge azacitidine. Additionally, we are grateful to the patients and their families for participating in the RAvVA trial. The original RAvVA trial was funded by Blood Cancer UK grant code 11031 as part of the Trials Acceleration Programme (TAP). CC was supported by the Birmingham Cancer Research UK Experimental Cancer Medicine Centre and by the Cancer Research UK Clinical Trials Unit core funding (C22436/A15958). PV is supported by MRC Molecular Haematology Unit (MC_UU_12009/11), NIHR the Hematology Theme of the Oxford Biomedical Research Centre, Blood Cancer Specialist Program Grant 13001 and Celgene. Funding for this study was received from Celgene. Copyright: © 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

PY - 2022/8/29

Y1 - 2022/8/29

N2 - Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.

AB - Acute myeloid leukaemia is prevalent in older patients that are often ineligible for intensive chemotherapy and treatment options remain limited with azacitidine being at the forefront. Azacitidine has been used in the clinic for decades, however, we still lack a complete understanding of the mechanisms by which the drug exerts its anti-tumour effect. To gain insight into the mechanism of action, we defined the mutational profile of sequential samples of patients treated with azacitidine. We did not identify any mutations that could predict response and observed lack of a uniform pattern of clonal evolution. Focusing on responders, at remission, we observed three types of response: (1) an almost complete elimination of mutations (33%), (2) no change (17%), and (3) change with no discernible pattern (50%). Heterogeneous patterns were also observed at relapse, with no clonal evolution between remission and relapse in some patients. Lack of clonal evolution suggests that non-genetic mechanisms might be involved. Towards understanding such mechanisms, we investigated the immune microenvironment in a number of patients and we observed lack of a uniform response following therapy. We identified a higher frequency of cytotoxic T cells in responders and higher frequency of naïve helper T cells in non-responders.

KW - acute myeloid leukaemia

KW - azacitidine

KW - clonal evolution

KW - hypomethylating agents

KW - immune microenvironment

U2 - 10.1002/jha2.527

DO - 10.1002/jha2.527

M3 - Article

C2 - 36051087

SN - 2688-6146

VL - 3

SP - 794

EP - 803

JO - EJHaem

JF - EJHaem

IS - 3

ER -

Heterogeneous genetic and non-genetic mechanisms contribute to response and resistance to azacitidine monotherapy

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this