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

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 mechan...

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Bibliographic Details
Published in:EJHaem 2022-08, Vol.3 (3), p.794-803
Main Authors: Symeonidou, Vasiliki, Metzner, Marlen, Usukhbayar, Batchimeg, Jackson, Aimee E., Fox, Sonia, Craddock, Charles F., Vyas, Paresh
Format: Article
Language:English
Subjects:
acute myeloid leukaemia
Acute myeloid leukemia
azacitidine
Bone marrow
Chemotherapy
clonal evolution
Cytotoxicity
Evolution
Haematologic Malignancy ‐ Myeloid
hypomethylating agents
immune microenvironment
Leukemia
Lymphocytes T
Microenvironments
Mutation
Patients
Remission
Remission (Medicine)
Tumors
Variance analysis
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Summary: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.
ISSN:2688-6146
2688-6146
DOI:10.1002/jha2.527